In a pregnant woman with a history of recurrent herpes simplex virus infection, what is the best way to prevent an outbreak of lesions near term?

Continue to the answer...

Obstetric patients with a history of recurrent herpes simplex infection should be treated with acyclovir 400 mg orally 3 times daily from 36 weeks until delivery. This regimen significantly reduces the likelihood of a recurrent outbreak near the time of delivery, which if it occurred, would necessitate a cesarean delivery. In patients at increased risk for preterm delivery, the prophylactic regimen should be started earlier.

Valacyclovir, 500 mg orally twice daily, is an acceptable alternative but is significantly more expensive.

In a pregnant woman with a history of recurrent herpes simplex virus infection, what is the best way to prevent an outbreak of lesions near term?

Continue to the answer...

Obstetric patients with a history of recurrent herpes simplex infection should be treated with acyclovir 400 mg orally 3 times daily from 36 weeks until delivery. This regimen significantly reduces the likelihood of a recurrent outbreak near the time of delivery, which if it occurred, would necessitate a cesarean delivery. In patients at increased risk for preterm delivery, the prophylactic regimen should be started earlier.

Valacyclovir, 500 mg orally twice daily, is an acceptable alternative but is significantly more expensive.

In a pregnant woman with a history of recurrent herpes simplex virus infection, what is the best way to prevent an outbreak of lesions near term?

Continue to the answer...

Obstetric patients with a history of recurrent herpes simplex infection should be treated with acyclovir 400 mg orally 3 times daily from 36 weeks until delivery. This regimen significantly reduces the likelihood of a recurrent outbreak near the time of delivery, which if it occurred, would necessitate a cesarean delivery. In patients at increased risk for preterm delivery, the prophylactic regimen should be started earlier.

Valacyclovir, 500 mg orally twice daily, is an acceptable alternative but is significantly more expensive.

Evidence summary

Alone or in combination with hCG, clomiphene citrate is effective

A 2018 multicenter prospective RCT (n = 283) compared the serum testosterone response in men (mean age, 41.8 ± 10.4 years) with hypogonadism before and after treatment with either CC, human chorionic gonadotropin (hCG), or a combination of both therapies.¹ All patients wanted to maintain fertility, had normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, had no history of testosterone therapy, had low (< 300 ng/dL) serum testosterone levels on at least 2 samples, and had at least 3 positive symptoms from the quantitative Androgen Deficiency in the Aging Male questionnaire (qADAM; a 10-item, graded-response tool measuring symptom severity from 1 to 5).

Patients were randomized into either the CC group (50 mg oral; n = 95), the hCG group (5000 IU injections twice weekly; n = 94), or the CC + hCG group (n = 94). Testosterone levels were measured at baseline and at 1 and 3 months after therapy initiation; qADAM questionnaire scores were also recorded but ultimately not used due to concerns with baseline heterogeneity among groups.

Average baseline serum testosterone levels for the CC, hCG, and CC + hCG groups were 243 ng/dL, 222 ng/dL, and 226 ng/dL, respectively. By 3 months, these levels had increased to 548 ng/dL (95% CI, 505-591) in the CC group, 467 ng/dL (95% CI, 440-494) in the hCG group, and 531 ng/dL (95% CI, 492-570) in the CC + hCG group. While there was not a significant difference between the CC and CC + hCG groups at 3 months (P = .579), both groups were superior to the hCG-only group (P = .002 for each).

CC and testosterone gel are comparable; testosterone injection is better

In a 2014 retrospective study, researchers reviewed the charts of 1150 men taking any form of testosterone supplementation therapy (TST). They compared treatment efficacy and qADAM satisfaction scores in 93 age-matched men with symptomatic hypogonadism who were treated with either CC (n = 31), testosterone injections (n = 31), or testosterone topical gel (n = 31).² Eugonadal men not taking TST (n = 31) served as controls.

Inclusion criteria were based on treatment regimens of CC and TST. Participants in the treatment groups had a baseline total testosterone level < 300 ng/dL and had reported ≤ 3 positive symptoms on the qADAM questionnaire. Treatment regimens included CC (25 mg orally once daily), testosterone injections (testosterone cypionate 100 to 200 mg intramuscularly once weekly), and testosterone gel (Testim 1% or AndroGel 1.62%, 2 to 4 pumps/d).

The study results demonstrated an increase in median testosterone from baseline levels in all treatment groups when compared to placebo: CC (from 247 to 504 ng/dL), testosterone injections (from 224 to 1104 ng/dL), and testosterone gels (from 230 to 412 ng/dL) (P < .05). Men receiving testosterone injections had the highest increase in serum testosterone levels (956 ng/dL).

While the final mean serum total testosterone was highest in the testosterone injection group (1014 ng/dL; P < .01), the mean levels for those using CC and those using testosterone gels were comparable (525 ng/dL vs 412 ng/dL). Serum estradiol levels were also higher in men receiving testosterone injections, compared to men using CC, those using testosterone gels, and those not receiving TST (6.0 vs 2.0, 2.0, and 2.0 ng/dL, respectively; each P < .01).

Continue to: The qADAM scores...

The qADAM scores for hypogonadal symptoms showed no significant difference in men treated with CC, testosterone injections, and testosterone gels and those not receiving TST (35, 39, 36, and 34, respectively). Men receiving testosterone injections reported greater libido (range, 1-5) than men using CC, those using testosterone gels, and those not on TST (4 vs 3, 3, and 3; P = .047, .04, and < .01, respectively), but it is uncertain if this is clinically meaningful.

Enclomiphene citrate demonstrates improvement in hormone levels

A 2014 Phase II RCT investigated the effects of oral EC—a trans-isomer of CC—compared to topical testosterone 1% gel (T gel) in 124 men with secondary hypogonadism.³ Entry criteria included a baseline morning total testosterone level of < 250 ng/dL on 2 occasions. Participants were divided into 4 groups: 12.5-mg dose of EC, 25-mg dose of EC, T gel, and placebo.

The EC groups and the T gel group had comparable increases in testosterone levels after 3 months of treatment, without statistical significance. The 3-month change in serum testosterone level from baseline was 217 to 471 ng/dL (95% CI, 399-543) in the 12.5-mg dose group; 209 to 405 ng/dL (95% CI, 349-462) in the 25-mg dose group; and 210 to 462 ng/dL (95% CI, 359-565) in the T gel group. The placebo group had a decrease in serum testosterone levels, from 213 to 198 ng/dL (95% CI, 171-226).

Men with low or low-normal serum luteinizing hormone levels may be good candidates for the use of SERMs for management of testosterone deficiency.

Also, the EC groups demonstrated increases in LH and FSH levels from baseline to 3 months, while the T gel group showed a suppression (to low-normal range) in both levels: LH, 1.4 mIU/mL (decrease of 4.4 mIU/mL) and FSH, 2.4 mIU/mL (decrease of 2.4 mIU/mL). Among a subset of men (n = 67) who had at least 2 assessments at the end of 3 months, the researchers also analyzed changes in sperm concentration, using the lower limit of normal (15 million/mL). The number of men with a low sperm concentration increased significantly in the topical T gel group (16% to 53%) compared to the 12.5-mg EC group (decrease from 16% to 12%; P = .0008) and the 25-mg EC group (decrease from 5% to 0%; P = .0007), as well as compared to the placebo group (increase from 8% to 15%; P = .007).

With EC, testosterone remains elevated after treatment cessation

A 2016 2-center parallel, double-blind, ­placebo-controlled RCT evaluated the effect of 2 doses of EC (12.5 mg and 25 mg; n = 85) vs testosterone gel (1.62%; n = 85) vs placebo (n = 86) on serum testosterone, LH, FSH, and sperm counts in 256 overweight and obese men ages 18 to 60 years who had 2 morning testosterone measurements < 300 ng/dL and a low or inappropriately normal LH level for 16 weeks.⁴ All baseline characteristics, including age, BMI, sperm concentration, and serum total testosterone were statistically consistent within groups at both centers. For men receiving EC who did not achieve a testosterone level > 450 ng/dL, there was an up-titration from 12.5 mg to 25 mg at Week 4.

Continue to: All active treatment groups...

All active treatment groups showed increases in testosterone level during treatment (P < .001); however, FSH and LH levels increased in the EC group and decreased in the testosterone gel group (P < .001). Serum testosterone levels improved to 428.8 ng/dL (95% CI, 395-462) and 368.8 ng/dL (95% CI, 307-431), respectively, in the combined EC and testosterone gel groups at 16 weeks. Of note, total testosterone levels after cessation of treatment (off-drug point) rapidly decreased below baseline in the testosterone gel group compared to the pooled EC group, which remained elevated above baseline for at least 7 days.

Composite end-point analysis was performed, with success considered if men achieved both testosterone in normal range (300-1040 ng/dL) and sperm concentrations ≥ 10 × 10⁶. The pooled data studies showed EC was more successful than testosterone gel in achieving both endpoints (63.5% vs 24.7%; P < .001). No difference in the incidence of treatment-related adverse effects between groups was noted.

There were no major adverse effects, even after 3+ years of treatment

A 2019 retrospective cohort study of 400 men treated for symptomatic hypogonadism with CC sought to determine if improvements in testosterone, hypogonadal symptoms, and adverse effects were similar for those treated for ≤ 3 years (n = 280) and those treated for > 3 years (n = 120).⁵ Outcomes included serum testosterone and estradiol levels, symptom improvement (by qADAM questionnaire), and adverse effects.

All participants had a baseline testosterone level < 300 ng/dL, and all participants received CC therapy. Men received 25 mg/d with titration to 50 mg/d when testosterone did not improve to ≥ 300 ng/dL after 4 weeks.

When comparing outcomes across the 2 groups, there were no significant differences. Serum testosterone levels improved to 579 ng/dL (95% CI, 554-605) and 542 ng/dL (95% CI, 504-580) in the ≤ 3 years and > 3 years groups, respectively. Meanwhile, 79% of men in the ≤ 3 years group reported symptom improvement (improvement in libido, erection, or 3 other of the 10 domains of the qADAM questionnaire), while 77% of those in the > 3 years group reported improvement (P = .60).

Continue to: Finally, the percentage of men reporting...

Finally, the percentage of men reporting adverse effects did not significantly differ between groups: 9% in the ≤ 3 years group and 8% in the > 3 years group (P = .85). The most common adverse effects reported in order of frequency were mood changes, blurred vision, breast tenderness, hypertension, hematocrit changes, and flushing. No major adverse events (eg, myocardial infarction, cerebrovascular accident, venous thromboembolism, suicidal behavior) were reported in any patients.

Both the American Urological Association and the Canadian Urological Association support the use of SERMs, especially in hypogonadal men who are interested in fertility preservation.

Of note, although measured estrogen levels at the end of treatment were similar for both groups (54.8 pg/mL in the ≤ 3 years group vs 54.6 pg/mL in the > 3 years group), 37% of patients treated for > 3 years did receive anastrozole treatment for hyperestrogenism compared to 15% in the ≤ 3 years group (P = .05). The authors caution, though, that due to only 20% of the cohort patients having data on pre- and post-treatment estradiol levels, the study was likely underpowered to detect true differences among subgroups.

Recommendations from others

Current American Urological Association and Canadian Urological Association Guidelines note that while greater study on nontraditional testosterone therapies is needed, both organizations support use of SERMs, especially in hypogonadal men who are interested in fertility preservation, as increases in endogenous serum testosterone production do not impact fertility potential, unlike exogenous hormonal replacement.^6,7 Additionally, men with low or low-normal serum LH levels may also be good candidates for the use of SERMs for management of testosterone deficiency.

Editor’s takeaway

Laboratory data (disease oriented) consistently shows that SERMs effectively increase testosterone levels to those comparable with testosterone gels. SERMs resulted in higher semen counts and maintained LH and FSH levels, but there were instances of hyperestrogenism. Data on longer-term benefits and adverse effects of both SERMs and testosterone supplementation are still needed.

Evidence summary

Alone or in combination with hCG, clomiphene citrate is effective

A 2018 multicenter prospective RCT (n = 283) compared the serum testosterone response in men (mean age, 41.8 ± 10.4 years) with hypogonadism before and after treatment with either CC, human chorionic gonadotropin (hCG), or a combination of both therapies.¹ All patients wanted to maintain fertility, had normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, had no history of testosterone therapy, had low (< 300 ng/dL) serum testosterone levels on at least 2 samples, and had at least 3 positive symptoms from the quantitative Androgen Deficiency in the Aging Male questionnaire (qADAM; a 10-item, graded-response tool measuring symptom severity from 1 to 5).

Patients were randomized into either the CC group (50 mg oral; n = 95), the hCG group (5000 IU injections twice weekly; n = 94), or the CC + hCG group (n = 94). Testosterone levels were measured at baseline and at 1 and 3 months after therapy initiation; qADAM questionnaire scores were also recorded but ultimately not used due to concerns with baseline heterogeneity among groups.

Average baseline serum testosterone levels for the CC, hCG, and CC + hCG groups were 243 ng/dL, 222 ng/dL, and 226 ng/dL, respectively. By 3 months, these levels had increased to 548 ng/dL (95% CI, 505-591) in the CC group, 467 ng/dL (95% CI, 440-494) in the hCG group, and 531 ng/dL (95% CI, 492-570) in the CC + hCG group. While there was not a significant difference between the CC and CC + hCG groups at 3 months (P = .579), both groups were superior to the hCG-only group (P = .002 for each).

CC and testosterone gel are comparable; testosterone injection is better

In a 2014 retrospective study, researchers reviewed the charts of 1150 men taking any form of testosterone supplementation therapy (TST). They compared treatment efficacy and qADAM satisfaction scores in 93 age-matched men with symptomatic hypogonadism who were treated with either CC (n = 31), testosterone injections (n = 31), or testosterone topical gel (n = 31).² Eugonadal men not taking TST (n = 31) served as controls.

Inclusion criteria were based on treatment regimens of CC and TST. Participants in the treatment groups had a baseline total testosterone level < 300 ng/dL and had reported ≤ 3 positive symptoms on the qADAM questionnaire. Treatment regimens included CC (25 mg orally once daily), testosterone injections (testosterone cypionate 100 to 200 mg intramuscularly once weekly), and testosterone gel (Testim 1% or AndroGel 1.62%, 2 to 4 pumps/d).

The study results demonstrated an increase in median testosterone from baseline levels in all treatment groups when compared to placebo: CC (from 247 to 504 ng/dL), testosterone injections (from 224 to 1104 ng/dL), and testosterone gels (from 230 to 412 ng/dL) (P < .05). Men receiving testosterone injections had the highest increase in serum testosterone levels (956 ng/dL).

While the final mean serum total testosterone was highest in the testosterone injection group (1014 ng/dL; P < .01), the mean levels for those using CC and those using testosterone gels were comparable (525 ng/dL vs 412 ng/dL). Serum estradiol levels were also higher in men receiving testosterone injections, compared to men using CC, those using testosterone gels, and those not receiving TST (6.0 vs 2.0, 2.0, and 2.0 ng/dL, respectively; each P < .01).

Continue to: The qADAM scores...

The qADAM scores for hypogonadal symptoms showed no significant difference in men treated with CC, testosterone injections, and testosterone gels and those not receiving TST (35, 39, 36, and 34, respectively). Men receiving testosterone injections reported greater libido (range, 1-5) than men using CC, those using testosterone gels, and those not on TST (4 vs 3, 3, and 3; P = .047, .04, and < .01, respectively), but it is uncertain if this is clinically meaningful.

Enclomiphene citrate demonstrates improvement in hormone levels

A 2014 Phase II RCT investigated the effects of oral EC—a trans-isomer of CC—compared to topical testosterone 1% gel (T gel) in 124 men with secondary hypogonadism.³ Entry criteria included a baseline morning total testosterone level of < 250 ng/dL on 2 occasions. Participants were divided into 4 groups: 12.5-mg dose of EC, 25-mg dose of EC, T gel, and placebo.

The EC groups and the T gel group had comparable increases in testosterone levels after 3 months of treatment, without statistical significance. The 3-month change in serum testosterone level from baseline was 217 to 471 ng/dL (95% CI, 399-543) in the 12.5-mg dose group; 209 to 405 ng/dL (95% CI, 349-462) in the 25-mg dose group; and 210 to 462 ng/dL (95% CI, 359-565) in the T gel group. The placebo group had a decrease in serum testosterone levels, from 213 to 198 ng/dL (95% CI, 171-226).

Men with low or low-normal serum luteinizing hormone levels may be good candidates for the use of SERMs for management of testosterone deficiency.

Also, the EC groups demonstrated increases in LH and FSH levels from baseline to 3 months, while the T gel group showed a suppression (to low-normal range) in both levels: LH, 1.4 mIU/mL (decrease of 4.4 mIU/mL) and FSH, 2.4 mIU/mL (decrease of 2.4 mIU/mL). Among a subset of men (n = 67) who had at least 2 assessments at the end of 3 months, the researchers also analyzed changes in sperm concentration, using the lower limit of normal (15 million/mL). The number of men with a low sperm concentration increased significantly in the topical T gel group (16% to 53%) compared to the 12.5-mg EC group (decrease from 16% to 12%; P = .0008) and the 25-mg EC group (decrease from 5% to 0%; P = .0007), as well as compared to the placebo group (increase from 8% to 15%; P = .007).

With EC, testosterone remains elevated after treatment cessation

A 2016 2-center parallel, double-blind, ­placebo-controlled RCT evaluated the effect of 2 doses of EC (12.5 mg and 25 mg; n = 85) vs testosterone gel (1.62%; n = 85) vs placebo (n = 86) on serum testosterone, LH, FSH, and sperm counts in 256 overweight and obese men ages 18 to 60 years who had 2 morning testosterone measurements < 300 ng/dL and a low or inappropriately normal LH level for 16 weeks.⁴ All baseline characteristics, including age, BMI, sperm concentration, and serum total testosterone were statistically consistent within groups at both centers. For men receiving EC who did not achieve a testosterone level > 450 ng/dL, there was an up-titration from 12.5 mg to 25 mg at Week 4.

Continue to: All active treatment groups...

All active treatment groups showed increases in testosterone level during treatment (P < .001); however, FSH and LH levels increased in the EC group and decreased in the testosterone gel group (P < .001). Serum testosterone levels improved to 428.8 ng/dL (95% CI, 395-462) and 368.8 ng/dL (95% CI, 307-431), respectively, in the combined EC and testosterone gel groups at 16 weeks. Of note, total testosterone levels after cessation of treatment (off-drug point) rapidly decreased below baseline in the testosterone gel group compared to the pooled EC group, which remained elevated above baseline for at least 7 days.

Composite end-point analysis was performed, with success considered if men achieved both testosterone in normal range (300-1040 ng/dL) and sperm concentrations ≥ 10 × 10⁶. The pooled data studies showed EC was more successful than testosterone gel in achieving both endpoints (63.5% vs 24.7%; P < .001). No difference in the incidence of treatment-related adverse effects between groups was noted.

There were no major adverse effects, even after 3+ years of treatment

A 2019 retrospective cohort study of 400 men treated for symptomatic hypogonadism with CC sought to determine if improvements in testosterone, hypogonadal symptoms, and adverse effects were similar for those treated for ≤ 3 years (n = 280) and those treated for > 3 years (n = 120).⁵ Outcomes included serum testosterone and estradiol levels, symptom improvement (by qADAM questionnaire), and adverse effects.

All participants had a baseline testosterone level < 300 ng/dL, and all participants received CC therapy. Men received 25 mg/d with titration to 50 mg/d when testosterone did not improve to ≥ 300 ng/dL after 4 weeks.

When comparing outcomes across the 2 groups, there were no significant differences. Serum testosterone levels improved to 579 ng/dL (95% CI, 554-605) and 542 ng/dL (95% CI, 504-580) in the ≤ 3 years and > 3 years groups, respectively. Meanwhile, 79% of men in the ≤ 3 years group reported symptom improvement (improvement in libido, erection, or 3 other of the 10 domains of the qADAM questionnaire), while 77% of those in the > 3 years group reported improvement (P = .60).

Continue to: Finally, the percentage of men reporting...

Finally, the percentage of men reporting adverse effects did not significantly differ between groups: 9% in the ≤ 3 years group and 8% in the > 3 years group (P = .85). The most common adverse effects reported in order of frequency were mood changes, blurred vision, breast tenderness, hypertension, hematocrit changes, and flushing. No major adverse events (eg, myocardial infarction, cerebrovascular accident, venous thromboembolism, suicidal behavior) were reported in any patients.

Both the American Urological Association and the Canadian Urological Association support the use of SERMs, especially in hypogonadal men who are interested in fertility preservation.

Of note, although measured estrogen levels at the end of treatment were similar for both groups (54.8 pg/mL in the ≤ 3 years group vs 54.6 pg/mL in the > 3 years group), 37% of patients treated for > 3 years did receive anastrozole treatment for hyperestrogenism compared to 15% in the ≤ 3 years group (P = .05). The authors caution, though, that due to only 20% of the cohort patients having data on pre- and post-treatment estradiol levels, the study was likely underpowered to detect true differences among subgroups.

Recommendations from others

Current American Urological Association and Canadian Urological Association Guidelines note that while greater study on nontraditional testosterone therapies is needed, both organizations support use of SERMs, especially in hypogonadal men who are interested in fertility preservation, as increases in endogenous serum testosterone production do not impact fertility potential, unlike exogenous hormonal replacement.^6,7 Additionally, men with low or low-normal serum LH levels may also be good candidates for the use of SERMs for management of testosterone deficiency.

Editor’s takeaway

Laboratory data (disease oriented) consistently shows that SERMs effectively increase testosterone levels to those comparable with testosterone gels. SERMs resulted in higher semen counts and maintained LH and FSH levels, but there were instances of hyperestrogenism. Data on longer-term benefits and adverse effects of both SERMs and testosterone supplementation are still needed.

Evidence summary

Alone or in combination with hCG, clomiphene citrate is effective

A 2018 multicenter prospective RCT (n = 283) compared the serum testosterone response in men (mean age, 41.8 ± 10.4 years) with hypogonadism before and after treatment with either CC, human chorionic gonadotropin (hCG), or a combination of both therapies.¹ All patients wanted to maintain fertility, had normal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, had no history of testosterone therapy, had low (< 300 ng/dL) serum testosterone levels on at least 2 samples, and had at least 3 positive symptoms from the quantitative Androgen Deficiency in the Aging Male questionnaire (qADAM; a 10-item, graded-response tool measuring symptom severity from 1 to 5).

Patients were randomized into either the CC group (50 mg oral; n = 95), the hCG group (5000 IU injections twice weekly; n = 94), or the CC + hCG group (n = 94). Testosterone levels were measured at baseline and at 1 and 3 months after therapy initiation; qADAM questionnaire scores were also recorded but ultimately not used due to concerns with baseline heterogeneity among groups.

Average baseline serum testosterone levels for the CC, hCG, and CC + hCG groups were 243 ng/dL, 222 ng/dL, and 226 ng/dL, respectively. By 3 months, these levels had increased to 548 ng/dL (95% CI, 505-591) in the CC group, 467 ng/dL (95% CI, 440-494) in the hCG group, and 531 ng/dL (95% CI, 492-570) in the CC + hCG group. While there was not a significant difference between the CC and CC + hCG groups at 3 months (P = .579), both groups were superior to the hCG-only group (P = .002 for each).

CC and testosterone gel are comparable; testosterone injection is better

In a 2014 retrospective study, researchers reviewed the charts of 1150 men taking any form of testosterone supplementation therapy (TST). They compared treatment efficacy and qADAM satisfaction scores in 93 age-matched men with symptomatic hypogonadism who were treated with either CC (n = 31), testosterone injections (n = 31), or testosterone topical gel (n = 31).² Eugonadal men not taking TST (n = 31) served as controls.

Inclusion criteria were based on treatment regimens of CC and TST. Participants in the treatment groups had a baseline total testosterone level < 300 ng/dL and had reported ≤ 3 positive symptoms on the qADAM questionnaire. Treatment regimens included CC (25 mg orally once daily), testosterone injections (testosterone cypionate 100 to 200 mg intramuscularly once weekly), and testosterone gel (Testim 1% or AndroGel 1.62%, 2 to 4 pumps/d).

The study results demonstrated an increase in median testosterone from baseline levels in all treatment groups when compared to placebo: CC (from 247 to 504 ng/dL), testosterone injections (from 224 to 1104 ng/dL), and testosterone gels (from 230 to 412 ng/dL) (P < .05). Men receiving testosterone injections had the highest increase in serum testosterone levels (956 ng/dL).

While the final mean serum total testosterone was highest in the testosterone injection group (1014 ng/dL; P < .01), the mean levels for those using CC and those using testosterone gels were comparable (525 ng/dL vs 412 ng/dL). Serum estradiol levels were also higher in men receiving testosterone injections, compared to men using CC, those using testosterone gels, and those not receiving TST (6.0 vs 2.0, 2.0, and 2.0 ng/dL, respectively; each P < .01).

Continue to: The qADAM scores...

The qADAM scores for hypogonadal symptoms showed no significant difference in men treated with CC, testosterone injections, and testosterone gels and those not receiving TST (35, 39, 36, and 34, respectively). Men receiving testosterone injections reported greater libido (range, 1-5) than men using CC, those using testosterone gels, and those not on TST (4 vs 3, 3, and 3; P = .047, .04, and < .01, respectively), but it is uncertain if this is clinically meaningful.

Enclomiphene citrate demonstrates improvement in hormone levels

A 2014 Phase II RCT investigated the effects of oral EC—a trans-isomer of CC—compared to topical testosterone 1% gel (T gel) in 124 men with secondary hypogonadism.³ Entry criteria included a baseline morning total testosterone level of < 250 ng/dL on 2 occasions. Participants were divided into 4 groups: 12.5-mg dose of EC, 25-mg dose of EC, T gel, and placebo.

The EC groups and the T gel group had comparable increases in testosterone levels after 3 months of treatment, without statistical significance. The 3-month change in serum testosterone level from baseline was 217 to 471 ng/dL (95% CI, 399-543) in the 12.5-mg dose group; 209 to 405 ng/dL (95% CI, 349-462) in the 25-mg dose group; and 210 to 462 ng/dL (95% CI, 359-565) in the T gel group. The placebo group had a decrease in serum testosterone levels, from 213 to 198 ng/dL (95% CI, 171-226).

Men with low or low-normal serum luteinizing hormone levels may be good candidates for the use of SERMs for management of testosterone deficiency.

Also, the EC groups demonstrated increases in LH and FSH levels from baseline to 3 months, while the T gel group showed a suppression (to low-normal range) in both levels: LH, 1.4 mIU/mL (decrease of 4.4 mIU/mL) and FSH, 2.4 mIU/mL (decrease of 2.4 mIU/mL). Among a subset of men (n = 67) who had at least 2 assessments at the end of 3 months, the researchers also analyzed changes in sperm concentration, using the lower limit of normal (15 million/mL). The number of men with a low sperm concentration increased significantly in the topical T gel group (16% to 53%) compared to the 12.5-mg EC group (decrease from 16% to 12%; P = .0008) and the 25-mg EC group (decrease from 5% to 0%; P = .0007), as well as compared to the placebo group (increase from 8% to 15%; P = .007).

With EC, testosterone remains elevated after treatment cessation

A 2016 2-center parallel, double-blind, ­placebo-controlled RCT evaluated the effect of 2 doses of EC (12.5 mg and 25 mg; n = 85) vs testosterone gel (1.62%; n = 85) vs placebo (n = 86) on serum testosterone, LH, FSH, and sperm counts in 256 overweight and obese men ages 18 to 60 years who had 2 morning testosterone measurements < 300 ng/dL and a low or inappropriately normal LH level for 16 weeks.⁴ All baseline characteristics, including age, BMI, sperm concentration, and serum total testosterone were statistically consistent within groups at both centers. For men receiving EC who did not achieve a testosterone level > 450 ng/dL, there was an up-titration from 12.5 mg to 25 mg at Week 4.

Continue to: All active treatment groups...

All active treatment groups showed increases in testosterone level during treatment (P < .001); however, FSH and LH levels increased in the EC group and decreased in the testosterone gel group (P < .001). Serum testosterone levels improved to 428.8 ng/dL (95% CI, 395-462) and 368.8 ng/dL (95% CI, 307-431), respectively, in the combined EC and testosterone gel groups at 16 weeks. Of note, total testosterone levels after cessation of treatment (off-drug point) rapidly decreased below baseline in the testosterone gel group compared to the pooled EC group, which remained elevated above baseline for at least 7 days.

Composite end-point analysis was performed, with success considered if men achieved both testosterone in normal range (300-1040 ng/dL) and sperm concentrations ≥ 10 × 10⁶. The pooled data studies showed EC was more successful than testosterone gel in achieving both endpoints (63.5% vs 24.7%; P < .001). No difference in the incidence of treatment-related adverse effects between groups was noted.

There were no major adverse effects, even after 3+ years of treatment

A 2019 retrospective cohort study of 400 men treated for symptomatic hypogonadism with CC sought to determine if improvements in testosterone, hypogonadal symptoms, and adverse effects were similar for those treated for ≤ 3 years (n = 280) and those treated for > 3 years (n = 120).⁵ Outcomes included serum testosterone and estradiol levels, symptom improvement (by qADAM questionnaire), and adverse effects.

All participants had a baseline testosterone level < 300 ng/dL, and all participants received CC therapy. Men received 25 mg/d with titration to 50 mg/d when testosterone did not improve to ≥ 300 ng/dL after 4 weeks.

When comparing outcomes across the 2 groups, there were no significant differences. Serum testosterone levels improved to 579 ng/dL (95% CI, 554-605) and 542 ng/dL (95% CI, 504-580) in the ≤ 3 years and > 3 years groups, respectively. Meanwhile, 79% of men in the ≤ 3 years group reported symptom improvement (improvement in libido, erection, or 3 other of the 10 domains of the qADAM questionnaire), while 77% of those in the > 3 years group reported improvement (P = .60).

Continue to: Finally, the percentage of men reporting...

Finally, the percentage of men reporting adverse effects did not significantly differ between groups: 9% in the ≤ 3 years group and 8% in the > 3 years group (P = .85). The most common adverse effects reported in order of frequency were mood changes, blurred vision, breast tenderness, hypertension, hematocrit changes, and flushing. No major adverse events (eg, myocardial infarction, cerebrovascular accident, venous thromboembolism, suicidal behavior) were reported in any patients.

Both the American Urological Association and the Canadian Urological Association support the use of SERMs, especially in hypogonadal men who are interested in fertility preservation.

Of note, although measured estrogen levels at the end of treatment were similar for both groups (54.8 pg/mL in the ≤ 3 years group vs 54.6 pg/mL in the > 3 years group), 37% of patients treated for > 3 years did receive anastrozole treatment for hyperestrogenism compared to 15% in the ≤ 3 years group (P = .05). The authors caution, though, that due to only 20% of the cohort patients having data on pre- and post-treatment estradiol levels, the study was likely underpowered to detect true differences among subgroups.

Recommendations from others

Current American Urological Association and Canadian Urological Association Guidelines note that while greater study on nontraditional testosterone therapies is needed, both organizations support use of SERMs, especially in hypogonadal men who are interested in fertility preservation, as increases in endogenous serum testosterone production do not impact fertility potential, unlike exogenous hormonal replacement.^6,7 Additionally, men with low or low-normal serum LH levels may also be good candidates for the use of SERMs for management of testosterone deficiency.

Editor’s takeaway

Laboratory data (disease oriented) consistently shows that SERMs effectively increase testosterone levels to those comparable with testosterone gels. SERMs resulted in higher semen counts and maintained LH and FSH levels, but there were instances of hyperestrogenism. Data on longer-term benefits and adverse effects of both SERMs and testosterone supplementation are still needed.

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).¹ There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.¹ The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.²

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.³

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).³ In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).³

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.^3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.⁵

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).³ As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.³

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).⁶ However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).⁶ The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.⁶

Continue to: Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”⁷ A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”⁸

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).⁹ On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”¹⁰ A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.¹⁰ However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”¹¹ as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”¹² Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.¹³

Studies comparing the 2 routes of administration (vaginal and IM) are underway.¹³

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).¹ There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.¹ The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.²

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.³

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).³ In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).³

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.^3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.⁵

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).³ As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.³

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).⁶ However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).⁶ The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.⁶

Continue to: Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”⁷ A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”⁸

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).⁹ On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”¹⁰ A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.¹⁰ However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”¹¹ as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”¹² Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.¹³

Studies comparing the 2 routes of administration (vaginal and IM) are underway.¹³

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).¹ There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.¹ The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.²

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.³

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).³ In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).³

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.^3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.⁵

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).³ As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.³

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).⁶ However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).⁶ The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.⁶

Continue to: Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”⁷ A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”⁸

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).⁹ On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”¹⁰ A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.¹⁰ However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”¹¹ as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”¹² Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.¹³

Studies comparing the 2 routes of administration (vaginal and IM) are underway.¹³

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

THE CASE

A 58-year-old African American man with a past medical history of prostate cancer, hypertension, hyperlipidemia, osteoarthritis, and gastroesophageal reflux disease presented to our office to establish care with a new provider. He complained of bilateral shoulder pain, that was worse on the right side, for the past year. He denied any previous falls, trauma, or injury. He reported that lifting his grandkids was becoming increasingly difficult due to the pain but denied any weakness or neurologic symptoms. He had been using over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), which provided minimal relief.

On physical examination, the overlying skin was normal and there was no tenderness to palpation. His shoulder range of motion was limited with complete flexion, but otherwise intact. Muscle strength was 5 out of 5 bilaterally, and neurovascular and sensory examinations were normal. On the right side, the Empty Can Test was positive, but the Neer and Apley tests were negative. All testing was negative on the left side.

The patient was referred for 10 sessions of physical therapy, which he completed. His pain persisted, and an x-ray of his right shoulder was performed. The x-ray indicated a high-riding humeral head, and magnetic resonance imaging (MRI) of the right shoulder was recommended due to possible rotator cuff tendinopathy.

The MRI demonstrated a full-thickness tear of the distal supraspinatus tendon along with “metastatic lesions” (FIGURE). As a result, a bone scan was obtained and revealed activity in the proximal right humerus; however, it was nonconclusive for osteoblastic metastasis. A positron emission tomography (PET) scan was ordered, which revealed findings suggestive of bony metastasis in the proximal left tibia, distal shaft of the right tibia, and the right and left humeral heads. The patient was then scheduled for a bone biopsy; a chest, abdomen, and pelvis computed tomography (CT) scan with IV and oral contrast was also ordered.

THE DIAGNOSIS

A bone biopsy of the left tibia indicated prominent non-necrotizing granulomatous inflammation and stains were negative for microorganisms. The CT scan demonstrated peribronchial vascular reticulonodular opacities in the upper lung zones compatible with sarcoidosis; no metastatic lesions were identified. Laboratory studies were obtained and demonstrated an elevated angiotensin-converting enzyme (ACE) level consistent with sarcoidosis. The cumulative test results pointed to a diagnosis of osseous sarcoidosis.

DISCUSSION

Osseous sarcoidosis is a rare manifestation of larger systemic disease. It is estimated that bony lesions occur in only 3% to 13% of patients with sarcoidosis.¹ Bone involvement is most common in African Americans and occurs primarily in the hands and feet.^1-3

Up to 50% of patients with bone lesions are symptomatic and may require treatment. Treatment is reserved for these symptomatic patients, with the goal of pain reduction.

Osseous lesions are comprised of noncaseating granulomatous inflammation.^4,5 They are often asymptomatic but can be painful and associated with overlying skin disease and soft-tissue swelling.^1,4 Although it’s not typical, patients may present with symptoms such as pain, stiffness, or fractures. On CT imaging and MRI (as in this case), osseous lesions can be confused with metastatic bone disease, and biopsy may be required for diagnosis.⁴

Continue to: There are multiple patterns of bone involvement

There are multiple patterns of bone involvement in osseous sarcoidosis, ranging from large cystic lesions that can lead to stress fractures to “tunnels” or “lace-like” reticulated patterns found in the bones of the hands and feet. ^2,3,5,6 Long bone involvement is typically limited to the proximal and distal thirds of the bone.⁶ Sarcoidosis is also known to involve the axial skeleton, and less commonly, the cranial vault.⁶ Although multiple variations may manifest over time, skin changes usually precede bone lesions^3,6; however, that was not the case with this patient.

Treatment entails pain management

Up to 50% of patients with bone lesions are symptomatic and may require treatment.^3,5 Treatment is reserved for these symptomatic patients, with the goal of pain reduction.^2,3,7

Low- to moderate-dose corticosteroids have been shown to relieve soft-tissue swelling and decrease pain.^2,3,7 A prolonged course of steroids is not recommended, due to the risk of osteoporosis and fractures, and does not normalize bone structure.^3,7

Other options. NSAIDs, such as colchicine and indomethacin, have also been found to be effective in pain management.⁷ Treatments such as methotrexate and hydroxychloroquine may be considered for those cases that are refractory to steroids.²

Given the extent of our patient’s disease, he was referred to multiple specialists to rule out further organ involvement. He was found to have neurosarcoidosis on brain imaging and was subsequently treated with prednisone 10 mg/d. The patient is being routinely monitored for active disease at various intervals or as symptoms arise.

THE TAKEAWAY

Consideration for systemic diseases (eg, sarcoidosis) should be given to patients presenting with musculoskeletal complaints without a significant history of trauma or injury. In those with risk factors associated with a higher incidence of sarcoidosis, such as age and race, a work-up should include imaging and biopsy. Treatment (eg, corticosteroids, NSAIDs) is provided to those patients who are symptomatic, with the goal of symptom relief.³

THE CASE

A 58-year-old African American man with a past medical history of prostate cancer, hypertension, hyperlipidemia, osteoarthritis, and gastroesophageal reflux disease presented to our office to establish care with a new provider. He complained of bilateral shoulder pain, that was worse on the right side, for the past year. He denied any previous falls, trauma, or injury. He reported that lifting his grandkids was becoming increasingly difficult due to the pain but denied any weakness or neurologic symptoms. He had been using over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), which provided minimal relief.

On physical examination, the overlying skin was normal and there was no tenderness to palpation. His shoulder range of motion was limited with complete flexion, but otherwise intact. Muscle strength was 5 out of 5 bilaterally, and neurovascular and sensory examinations were normal. On the right side, the Empty Can Test was positive, but the Neer and Apley tests were negative. All testing was negative on the left side.

The patient was referred for 10 sessions of physical therapy, which he completed. His pain persisted, and an x-ray of his right shoulder was performed. The x-ray indicated a high-riding humeral head, and magnetic resonance imaging (MRI) of the right shoulder was recommended due to possible rotator cuff tendinopathy.

The MRI demonstrated a full-thickness tear of the distal supraspinatus tendon along with “metastatic lesions” (FIGURE). As a result, a bone scan was obtained and revealed activity in the proximal right humerus; however, it was nonconclusive for osteoblastic metastasis. A positron emission tomography (PET) scan was ordered, which revealed findings suggestive of bony metastasis in the proximal left tibia, distal shaft of the right tibia, and the right and left humeral heads. The patient was then scheduled for a bone biopsy; a chest, abdomen, and pelvis computed tomography (CT) scan with IV and oral contrast was also ordered.

THE DIAGNOSIS

A bone biopsy of the left tibia indicated prominent non-necrotizing granulomatous inflammation and stains were negative for microorganisms. The CT scan demonstrated peribronchial vascular reticulonodular opacities in the upper lung zones compatible with sarcoidosis; no metastatic lesions were identified. Laboratory studies were obtained and demonstrated an elevated angiotensin-converting enzyme (ACE) level consistent with sarcoidosis. The cumulative test results pointed to a diagnosis of osseous sarcoidosis.

DISCUSSION

Osseous sarcoidosis is a rare manifestation of larger systemic disease. It is estimated that bony lesions occur in only 3% to 13% of patients with sarcoidosis.¹ Bone involvement is most common in African Americans and occurs primarily in the hands and feet.^1-3

Up to 50% of patients with bone lesions are symptomatic and may require treatment. Treatment is reserved for these symptomatic patients, with the goal of pain reduction.

Osseous lesions are comprised of noncaseating granulomatous inflammation.^4,5 They are often asymptomatic but can be painful and associated with overlying skin disease and soft-tissue swelling.^1,4 Although it’s not typical, patients may present with symptoms such as pain, stiffness, or fractures. On CT imaging and MRI (as in this case), osseous lesions can be confused with metastatic bone disease, and biopsy may be required for diagnosis.⁴

Continue to: There are multiple patterns of bone involvement

There are multiple patterns of bone involvement in osseous sarcoidosis, ranging from large cystic lesions that can lead to stress fractures to “tunnels” or “lace-like” reticulated patterns found in the bones of the hands and feet. ^2,3,5,6 Long bone involvement is typically limited to the proximal and distal thirds of the bone.⁶ Sarcoidosis is also known to involve the axial skeleton, and less commonly, the cranial vault.⁶ Although multiple variations may manifest over time, skin changes usually precede bone lesions^3,6; however, that was not the case with this patient.

Treatment entails pain management

Up to 50% of patients with bone lesions are symptomatic and may require treatment.^3,5 Treatment is reserved for these symptomatic patients, with the goal of pain reduction.^2,3,7

Low- to moderate-dose corticosteroids have been shown to relieve soft-tissue swelling and decrease pain.^2,3,7 A prolonged course of steroids is not recommended, due to the risk of osteoporosis and fractures, and does not normalize bone structure.^3,7

Other options. NSAIDs, such as colchicine and indomethacin, have also been found to be effective in pain management.⁷ Treatments such as methotrexate and hydroxychloroquine may be considered for those cases that are refractory to steroids.²

Given the extent of our patient’s disease, he was referred to multiple specialists to rule out further organ involvement. He was found to have neurosarcoidosis on brain imaging and was subsequently treated with prednisone 10 mg/d. The patient is being routinely monitored for active disease at various intervals or as symptoms arise.

THE TAKEAWAY

Consideration for systemic diseases (eg, sarcoidosis) should be given to patients presenting with musculoskeletal complaints without a significant history of trauma or injury. In those with risk factors associated with a higher incidence of sarcoidosis, such as age and race, a work-up should include imaging and biopsy. Treatment (eg, corticosteroids, NSAIDs) is provided to those patients who are symptomatic, with the goal of symptom relief.³

THE CASE

A 58-year-old African American man with a past medical history of prostate cancer, hypertension, hyperlipidemia, osteoarthritis, and gastroesophageal reflux disease presented to our office to establish care with a new provider. He complained of bilateral shoulder pain, that was worse on the right side, for the past year. He denied any previous falls, trauma, or injury. He reported that lifting his grandkids was becoming increasingly difficult due to the pain but denied any weakness or neurologic symptoms. He had been using over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), which provided minimal relief.

On physical examination, the overlying skin was normal and there was no tenderness to palpation. His shoulder range of motion was limited with complete flexion, but otherwise intact. Muscle strength was 5 out of 5 bilaterally, and neurovascular and sensory examinations were normal. On the right side, the Empty Can Test was positive, but the Neer and Apley tests were negative. All testing was negative on the left side.

The patient was referred for 10 sessions of physical therapy, which he completed. His pain persisted, and an x-ray of his right shoulder was performed. The x-ray indicated a high-riding humeral head, and magnetic resonance imaging (MRI) of the right shoulder was recommended due to possible rotator cuff tendinopathy.

The MRI demonstrated a full-thickness tear of the distal supraspinatus tendon along with “metastatic lesions” (FIGURE). As a result, a bone scan was obtained and revealed activity in the proximal right humerus; however, it was nonconclusive for osteoblastic metastasis. A positron emission tomography (PET) scan was ordered, which revealed findings suggestive of bony metastasis in the proximal left tibia, distal shaft of the right tibia, and the right and left humeral heads. The patient was then scheduled for a bone biopsy; a chest, abdomen, and pelvis computed tomography (CT) scan with IV and oral contrast was also ordered.

THE DIAGNOSIS

A bone biopsy of the left tibia indicated prominent non-necrotizing granulomatous inflammation and stains were negative for microorganisms. The CT scan demonstrated peribronchial vascular reticulonodular opacities in the upper lung zones compatible with sarcoidosis; no metastatic lesions were identified. Laboratory studies were obtained and demonstrated an elevated angiotensin-converting enzyme (ACE) level consistent with sarcoidosis. The cumulative test results pointed to a diagnosis of osseous sarcoidosis.

DISCUSSION

Osseous sarcoidosis is a rare manifestation of larger systemic disease. It is estimated that bony lesions occur in only 3% to 13% of patients with sarcoidosis.¹ Bone involvement is most common in African Americans and occurs primarily in the hands and feet.^1-3

Up to 50% of patients with bone lesions are symptomatic and may require treatment. Treatment is reserved for these symptomatic patients, with the goal of pain reduction.

Osseous lesions are comprised of noncaseating granulomatous inflammation.^4,5 They are often asymptomatic but can be painful and associated with overlying skin disease and soft-tissue swelling.^1,4 Although it’s not typical, patients may present with symptoms such as pain, stiffness, or fractures. On CT imaging and MRI (as in this case), osseous lesions can be confused with metastatic bone disease, and biopsy may be required for diagnosis.⁴

Continue to: There are multiple patterns of bone involvement

There are multiple patterns of bone involvement in osseous sarcoidosis, ranging from large cystic lesions that can lead to stress fractures to “tunnels” or “lace-like” reticulated patterns found in the bones of the hands and feet. ^2,3,5,6 Long bone involvement is typically limited to the proximal and distal thirds of the bone.⁶ Sarcoidosis is also known to involve the axial skeleton, and less commonly, the cranial vault.⁶ Although multiple variations may manifest over time, skin changes usually precede bone lesions^3,6; however, that was not the case with this patient.

Treatment entails pain management

Up to 50% of patients with bone lesions are symptomatic and may require treatment.^3,5 Treatment is reserved for these symptomatic patients, with the goal of pain reduction.^2,3,7

Low- to moderate-dose corticosteroids have been shown to relieve soft-tissue swelling and decrease pain.^2,3,7 A prolonged course of steroids is not recommended, due to the risk of osteoporosis and fractures, and does not normalize bone structure.^3,7

Other options. NSAIDs, such as colchicine and indomethacin, have also been found to be effective in pain management.⁷ Treatments such as methotrexate and hydroxychloroquine may be considered for those cases that are refractory to steroids.²

Given the extent of our patient’s disease, he was referred to multiple specialists to rule out further organ involvement. He was found to have neurosarcoidosis on brain imaging and was subsequently treated with prednisone 10 mg/d. The patient is being routinely monitored for active disease at various intervals or as symptoms arise.

THE TAKEAWAY

Consideration for systemic diseases (eg, sarcoidosis) should be given to patients presenting with musculoskeletal complaints without a significant history of trauma or injury. In those with risk factors associated with a higher incidence of sarcoidosis, such as age and race, a work-up should include imaging and biopsy. Treatment (eg, corticosteroids, NSAIDs) is provided to those patients who are symptomatic, with the goal of symptom relief.³

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

The number of people with dementia globally is expected to reach 74.7 million by 2030 and 131.5 million by 2050.¹ Because dementia is progressive, many patients will exhibit severe symptoms termed behavioral crises. Deteriorating interpersonal conduct and escalating antisocial acts result in an acquired sociopathy.² Increasing cognitive impairment causes these patients to misunderstand intimate care and perceive it as a threat, often resulting in outbursts of violence against their caregivers.³

Available studies (TABLE^4-17) make evident the incidence of interpersonal violence experienced by caregivers secondary to aggressive acts by patients with dementia. This violence ranges from verbal abuse, including racial slurs, to physical abuse—sometimes resulting in significant physical injury. Aggressive behavior by patients with dementia, resulting in violence towards their caregivers or partners, stems from progressive cognitive decline, which can make optimal care difficult. Such episodes may also impair the psychological and physical well-being of caregivers, increasing their risk of depression, anxiety, and even post-traumatic stress disorder (PTSD).¹⁸ The extent of the impact is also determined by the interpretation of the abuse by the caregivers themselves. One study suggested that the perception of aggressive or violent behavior as “normal” by a caregiver reduced the overall negative effect of the interactions.⁷Our review emphasizes the unintended burden that can fall to caregivers of patients with dementia. We also address the role of primary care providers (PCPs) in identifying these instances of violence and intervening appropriately by providing safety strategies, education, resources, and support.

CASE

A 67-year-old man with a medical history of PTSD with depression, type 2 diabetes, alcohol use disorder/dependence, hypertension, and obstructive sleep apnea was brought to his PCP by his wife. She said he had recently been unable to keep appointment times, pay bills, or take his usual medications, venlafaxine and bupropion. She also said his PTSD symptoms had worsened. He was sleeping 12 to 14 hours per day and was increasingly irritable. The patient denied any concerns or changes in his behavior.

Caregivers may refuse support due to personal beliefs or values, accessibility or affordability issues, or in deference to the patient’s wishes.

The PCP administered a Saint Louis University Mental Status (SLUMS) examination to screen for cognitive impairment.¹⁹ The patient scored 14/30 (less than 20 is indicative of dementia). He was unable to complete a simple math problem, recall any items from a list of 5, count in reverse, draw a clock correctly, or recall a full story. Throughout the exam, the patient demonstrated minimal effort and was often only able to complete a task after further prompting by the examiner.

A computed tomography scan of the head revealed no signs of hemorrhage or damage. Thyroid-stimulating hormone levels and vitamin B12 levels were normal. A rapid plasma reagin test result was negative. The patient was given a diagnosis of Alzheimer disease. Donepezil was added to the patient’s medications, starting at 5 mg and then increased to 10 mg. His wife began to assist him with his tasks of daily living. His mood improved, and his wife noted he began to remember his appointments and take his medications with assistance.

However, the patient’s irritability continued to escalate. He grew paranoid and accused his wife of mismanaging their money. This pattern steadily worsened over the course of 6 months. The situation escalated until one day the patient’s wife called a mental health hotline reporting that her husband was holding her hostage and threatening to kill her with a gun. He told her, “I can do something to you, and they won’t even find a fingernail. It doesn’t have to be with a gun either.” She was counseled to try to stay calm to avoid aggravating the situation and to go to a safe place and stay there until help arrived.

His memory had worsened to the point that he could not recall any events from the previous 2 years. He was paranoid about anyone entering his home and would not allow his deteriorating roof to be repaired or his yard to be maintained. He did not shower for weeks at a time. He slept holding a rifle and accused his wife of embezzlement.

Continue to: The patient was evaluated...

The patient was evaluated by another specialist, who assessed his SLUMS score to be 18/30. He increased the patient’s donepezil dose, initiated a bupropion taper, and added sertraline to the regimen. The PCP spoke to the patient’s wife regarding options for her safety including leaving the home, hiding firearms, and calling the police in cases of interpersonal violence. The wife said she did not want to pursue these options. She expressed worry that he might be harmed if he was uncooperative with the police and said there was no one except her to take care of him.

Caregivers struggle to care for their loved ones

Instances of personal violence lead to shock, astonishment, heartbreak, and fear. Anticipation of a recurrence of violence causes many partners and caregivers to feel exhausted, because there is minimal hope for any chance of improvement. There are a few exceptions, however, as our case will show. In addition to emotional exhaustion, there is also a ­never-ending sense of self-doubt, leading many caregivers to question their ability to handle their family member.^20,21 Over time, this leads to caregiver burnout, leaving them unable to understand their family member’s aggression. The sudden loss of caregiver control in dealing with the patient may also result in the family member exhibiting behavioral changes reflecting emotional trauma. For caregivers who do not live with the patient, they may choose to make fewer or shorter visits—or not visit at all—because they fear being abused.^7,22

Caregivers of patients with dementia often feel helpless and powerless once abrupt and drastic changes in personality lead to some form of interpersonal violence. Additionally, caregivers with a poor health status are more likely to have lower physical function and experience greater caregiving stress overall.²³ Other factors increasing stress are longer years of caregiving and the severity of a patient’s dementia and functional impairment.²³

Interventions to reduce caregiver burden

Many studies have assessed the role of different interventions to reduce caregiver burden, such as teaching them problem-solving skills, increasing their knowledge of dementia, recommending social resources, providing emotional support, changing caregiver perceptions of the care situation, introducing coping strategies, relying on strengths and experiences in caregiving, help-seeking, and engaging in activity programs.^24-28 For Hispanic caregivers, a structured and self-paced online telenovela format has been effective in improving care and relieving caregiver stress.²⁹ Online positive emotion regulators helped in significantly improving quality of life and physical health in the caregivers.³⁰ In this last intervention, caregivers had 6 online sessions with a facilitator who taught them emotional regulation skills that included: noticing positive events, capitalizing on them, and feeling gratitude; practicing mindfulness; doing a positive reappraisal; acknowledging personal strengths and setting attainable goals; and performing acts of kindness. Empowerment programs have also shown significant improvement in the well-being of caregivers.³¹

Caregivers may reject support. Hindrances to caregivers accepting support can include personal factors (eg, attitude, beliefs, values), service-related issues (eg, accessibility, affordability), and relational factors (preferences of the patient).³² In the case of patients with dementia who had a higher functional status, caregivers tend to reject any form of support.³² PCPs, of course, are optimally suited to care for entire families, often having known their patients and family members for years.

Continue to: These practical tips can help

Based on our review of the literature, we recommend offering the following supports to caregivers:

• Counsel caregivers early on in a patient’s dementia that behavior changes are likely and may be unpredictable. Explain that dementia can involve changes to personality and behavior as well as memory difficulties.^33,34
• Describe resources for support, such as day programs for senior adults, insurance coverage for caregiver respite programs, and the Alzheimer’s Association (www.alz.org/). Encourage caregivers to seek general medical and mental health care for themselves. Caregivers should have opportunities and support to discuss their experiences and to be appropriately trained for the challenge of caring for a family member with dementia.³⁵
• Encourage disclosure about abrupt changes in the patient’s behavior. This invites families to discuss issues with you and may make them more comfortable with such conversations.
• Involve ancillary services (eg, social worker) to plan for a higher level of care well in advance of it becoming necessary.
• Discuss safety strategies for the caregiver, including when it is appropriate to alter a patient’s set routines such as bedtimes and mealtimes.^33,34
• Discuss when and how to involve law enforcement, if necessary.^33,34 Emphasize the importance of removing firearms from the home as a safety measure. Although federal laws do not explicitly prohibit possession of arms by patients with neurologic damage, a few states mention “organic brain syndrome” or “dementia” as conditions prohibiting use or possession of firearms.³⁶
• Suggest, as feasible, nonpharmacologic aids for the patient such as massage therapy, animal-assisted therapy, personalized interventions, music therapy, and light therapy.³⁷ Prescribe medications to the patient to aid in behavior modification when appropriate.
• Screen caregivers and family members for signs of interpersonal violence. Take notice of changes in caregiver behavior or irregularity in attending follow-up appointments.

CASE

Over the next month, the patient’s symptoms further deteriorated. His PCP recommended hospitalization, but the patient and his wife declined. Magnetic resonance imaging of the patient’s brain revealed severe confluent and patchy regions of white matter and T2 signal hyperintensity, consistent with chronic microvascular ischemic disease. An old, small, left parietal lobe infarct was also noted.

Screen caregivers and family members for signs of interpersonal violence. Take notice of changes in caregiver behavior or irregularity in attending follow-up appointments.

One month later, the patient presented to the emergency department. His symptoms were largely unchanged, but his wife indicated that she could no longer live at home due to burnout. The patient’s medications were adjusted, but he was not admitted for inpatient care. His wife said they needed help at home, but the patient opposed the idea any time that it was mentioned.

A few weeks later, the patient presented for outpatient follow-up. He was delusional, believing that the government was compelling citizens to take sertraline in order to harm their mental health. He had also begun viewing online pornography in front of his wife and attempting to remove all of his money from the bank. He was prescribed aripiprazole 15 mg, and his symptoms began to improve. Soon after, however, he threatened to kill his grandson, then took all his Lasix pills (a 7-day supply) simultaneously. The patient denied that this was a suicide attempt.

Over the course of the next month, the patient began to report hearing voices. A neuropsychological evaluation confirmed a diagnosis of dementia with psychiatric symptoms due to neurologic injury. The patient was referred to a geriatric psychiatrist and continued to be managed medically. He was assigned a multidisciplinary team comprising palliative care, social work, and care management to assist in his care and provide support to the family. His behavior improved.

Continue to: At the time of this publication...

An important step forward would be to develop an interprofessional team to aid in identifying and closely following high-risk patient– caregiver groups.

At the time of this publication, the patient’s irritability and paranoia had subsided and he had made no further threats to his family. He has allowed a home health aide into the house and has agreed to have his roof repaired. His wife still lives with him and assists him with activities of daily living.

Interprofessional teams are key

Caregiver burnout increases the risk of patient neglect or abuse, as individuals who have been the targets of aggressive behavior are more likely to leave demented patients unattended.^8,16,23 Although tools are available to screen caregivers for depression and burnout, an important step forward would be to develop an interprofessional team to aid in identifying and closely following high-risk patient–caregiver groups. This continual and varied assessment of psychosocial stressors could help prevent the development of violent interactions. These teams would allow integration with the primary health care system by frequent and effective shared communication of knowledge, development of goals, and shared decision-making.³⁸ Setting expectations, providing support, and discussing safety strategies can improve the health and welfare of caregivers and patients with dementia alike.

CORRESPONDENCE
Abu Baker Sheikh, MD, MSC 10-5550, 1 University of New Mexico, Albuquerque, NM 87131; [email protected].

The number of people with dementia globally is expected to reach 74.7 million by 2030 and 131.5 million by 2050.¹ Because dementia is progressive, many patients will exhibit severe symptoms termed behavioral crises. Deteriorating interpersonal conduct and escalating antisocial acts result in an acquired sociopathy.² Increasing cognitive impairment causes these patients to misunderstand intimate care and perceive it as a threat, often resulting in outbursts of violence against their caregivers.³

Available studies (TABLE^4-17) make evident the incidence of interpersonal violence experienced by caregivers secondary to aggressive acts by patients with dementia. This violence ranges from verbal abuse, including racial slurs, to physical abuse—sometimes resulting in significant physical injury. Aggressive behavior by patients with dementia, resulting in violence towards their caregivers or partners, stems from progressive cognitive decline, which can make optimal care difficult. Such episodes may also impair the psychological and physical well-being of caregivers, increasing their risk of depression, anxiety, and even post-traumatic stress disorder (PTSD).¹⁸ The extent of the impact is also determined by the interpretation of the abuse by the caregivers themselves. One study suggested that the perception of aggressive or violent behavior as “normal” by a caregiver reduced the overall negative effect of the interactions.⁷Our review emphasizes the unintended burden that can fall to caregivers of patients with dementia. We also address the role of primary care providers (PCPs) in identifying these instances of violence and intervening appropriately by providing safety strategies, education, resources, and support.

CASE

A 67-year-old man with a medical history of PTSD with depression, type 2 diabetes, alcohol use disorder/dependence, hypertension, and obstructive sleep apnea was brought to his PCP by his wife. She said he had recently been unable to keep appointment times, pay bills, or take his usual medications, venlafaxine and bupropion. She also said his PTSD symptoms had worsened. He was sleeping 12 to 14 hours per day and was increasingly irritable. The patient denied any concerns or changes in his behavior.

Caregivers may refuse support due to personal beliefs or values, accessibility or affordability issues, or in deference to the patient’s wishes.

The PCP administered a Saint Louis University Mental Status (SLUMS) examination to screen for cognitive impairment.¹⁹ The patient scored 14/30 (less than 20 is indicative of dementia). He was unable to complete a simple math problem, recall any items from a list of 5, count in reverse, draw a clock correctly, or recall a full story. Throughout the exam, the patient demonstrated minimal effort and was often only able to complete a task after further prompting by the examiner.

A computed tomography scan of the head revealed no signs of hemorrhage or damage. Thyroid-stimulating hormone levels and vitamin B12 levels were normal. A rapid plasma reagin test result was negative. The patient was given a diagnosis of Alzheimer disease. Donepezil was added to the patient’s medications, starting at 5 mg and then increased to 10 mg. His wife began to assist him with his tasks of daily living. His mood improved, and his wife noted he began to remember his appointments and take his medications with assistance.

However, the patient’s irritability continued to escalate. He grew paranoid and accused his wife of mismanaging their money. This pattern steadily worsened over the course of 6 months. The situation escalated until one day the patient’s wife called a mental health hotline reporting that her husband was holding her hostage and threatening to kill her with a gun. He told her, “I can do something to you, and they won’t even find a fingernail. It doesn’t have to be with a gun either.” She was counseled to try to stay calm to avoid aggravating the situation and to go to a safe place and stay there until help arrived.

His memory had worsened to the point that he could not recall any events from the previous 2 years. He was paranoid about anyone entering his home and would not allow his deteriorating roof to be repaired or his yard to be maintained. He did not shower for weeks at a time. He slept holding a rifle and accused his wife of embezzlement.

Continue to: The patient was evaluated...

The patient was evaluated by another specialist, who assessed his SLUMS score to be 18/30. He increased the patient’s donepezil dose, initiated a bupropion taper, and added sertraline to the regimen. The PCP spoke to the patient’s wife regarding options for her safety including leaving the home, hiding firearms, and calling the police in cases of interpersonal violence. The wife said she did not want to pursue these options. She expressed worry that he might be harmed if he was uncooperative with the police and said there was no one except her to take care of him.

Caregivers struggle to care for their loved ones

Instances of personal violence lead to shock, astonishment, heartbreak, and fear. Anticipation of a recurrence of violence causes many partners and caregivers to feel exhausted, because there is minimal hope for any chance of improvement. There are a few exceptions, however, as our case will show. In addition to emotional exhaustion, there is also a ­never-ending sense of self-doubt, leading many caregivers to question their ability to handle their family member.^20,21 Over time, this leads to caregiver burnout, leaving them unable to understand their family member’s aggression. The sudden loss of caregiver control in dealing with the patient may also result in the family member exhibiting behavioral changes reflecting emotional trauma. For caregivers who do not live with the patient, they may choose to make fewer or shorter visits—or not visit at all—because they fear being abused.^7,22

Caregivers of patients with dementia often feel helpless and powerless once abrupt and drastic changes in personality lead to some form of interpersonal violence. Additionally, caregivers with a poor health status are more likely to have lower physical function and experience greater caregiving stress overall.²³ Other factors increasing stress are longer years of caregiving and the severity of a patient’s dementia and functional impairment.²³

Interventions to reduce caregiver burden

Many studies have assessed the role of different interventions to reduce caregiver burden, such as teaching them problem-solving skills, increasing their knowledge of dementia, recommending social resources, providing emotional support, changing caregiver perceptions of the care situation, introducing coping strategies, relying on strengths and experiences in caregiving, help-seeking, and engaging in activity programs.^24-28 For Hispanic caregivers, a structured and self-paced online telenovela format has been effective in improving care and relieving caregiver stress.²⁹ Online positive emotion regulators helped in significantly improving quality of life and physical health in the caregivers.³⁰ In this last intervention, caregivers had 6 online sessions with a facilitator who taught them emotional regulation skills that included: noticing positive events, capitalizing on them, and feeling gratitude; practicing mindfulness; doing a positive reappraisal; acknowledging personal strengths and setting attainable goals; and performing acts of kindness. Empowerment programs have also shown significant improvement in the well-being of caregivers.³¹

Caregivers may reject support. Hindrances to caregivers accepting support can include personal factors (eg, attitude, beliefs, values), service-related issues (eg, accessibility, affordability), and relational factors (preferences of the patient).³² In the case of patients with dementia who had a higher functional status, caregivers tend to reject any form of support.³² PCPs, of course, are optimally suited to care for entire families, often having known their patients and family members for years.

Continue to: These practical tips can help

Based on our review of the literature, we recommend offering the following supports to caregivers:

• Counsel caregivers early on in a patient’s dementia that behavior changes are likely and may be unpredictable. Explain that dementia can involve changes to personality and behavior as well as memory difficulties.^33,34
• Describe resources for support, such as day programs for senior adults, insurance coverage for caregiver respite programs, and the Alzheimer’s Association (www.alz.org/). Encourage caregivers to seek general medical and mental health care for themselves. Caregivers should have opportunities and support to discuss their experiences and to be appropriately trained for the challenge of caring for a family member with dementia.³⁵
• Encourage disclosure about abrupt changes in the patient’s behavior. This invites families to discuss issues with you and may make them more comfortable with such conversations.
• Involve ancillary services (eg, social worker) to plan for a higher level of care well in advance of it becoming necessary.
• Discuss safety strategies for the caregiver, including when it is appropriate to alter a patient’s set routines such as bedtimes and mealtimes.^33,34
• Discuss when and how to involve law enforcement, if necessary.^33,34 Emphasize the importance of removing firearms from the home as a safety measure. Although federal laws do not explicitly prohibit possession of arms by patients with neurologic damage, a few states mention “organic brain syndrome” or “dementia” as conditions prohibiting use or possession of firearms.³⁶
• Suggest, as feasible, nonpharmacologic aids for the patient such as massage therapy, animal-assisted therapy, personalized interventions, music therapy, and light therapy.³⁷ Prescribe medications to the patient to aid in behavior modification when appropriate.
• Screen caregivers and family members for signs of interpersonal violence. Take notice of changes in caregiver behavior or irregularity in attending follow-up appointments.

CASE

Over the next month, the patient’s symptoms further deteriorated. His PCP recommended hospitalization, but the patient and his wife declined. Magnetic resonance imaging of the patient’s brain revealed severe confluent and patchy regions of white matter and T2 signal hyperintensity, consistent with chronic microvascular ischemic disease. An old, small, left parietal lobe infarct was also noted.

Screen caregivers and family members for signs of interpersonal violence. Take notice of changes in caregiver behavior or irregularity in attending follow-up appointments.

One month later, the patient presented to the emergency department. His symptoms were largely unchanged, but his wife indicated that she could no longer live at home due to burnout. The patient’s medications were adjusted, but he was not admitted for inpatient care. His wife said they needed help at home, but the patient opposed the idea any time that it was mentioned.

A few weeks later, the patient presented for outpatient follow-up. He was delusional, believing that the government was compelling citizens to take sertraline in order to harm their mental health. He had also begun viewing online pornography in front of his wife and attempting to remove all of his money from the bank. He was prescribed aripiprazole 15 mg, and his symptoms began to improve. Soon after, however, he threatened to kill his grandson, then took all his Lasix pills (a 7-day supply) simultaneously. The patient denied that this was a suicide attempt.

Over the course of the next month, the patient began to report hearing voices. A neuropsychological evaluation confirmed a diagnosis of dementia with psychiatric symptoms due to neurologic injury. The patient was referred to a geriatric psychiatrist and continued to be managed medically. He was assigned a multidisciplinary team comprising palliative care, social work, and care management to assist in his care and provide support to the family. His behavior improved.

Continue to: At the time of this publication...

An important step forward would be to develop an interprofessional team to aid in identifying and closely following high-risk patient– caregiver groups.

At the time of this publication, the patient’s irritability and paranoia had subsided and he had made no further threats to his family. He has allowed a home health aide into the house and has agreed to have his roof repaired. His wife still lives with him and assists him with activities of daily living.

Interprofessional teams are key

Caregiver burnout increases the risk of patient neglect or abuse, as individuals who have been the targets of aggressive behavior are more likely to leave demented patients unattended.^8,16,23 Although tools are available to screen caregivers for depression and burnout, an important step forward would be to develop an interprofessional team to aid in identifying and closely following high-risk patient–caregiver groups. This continual and varied assessment of psychosocial stressors could help prevent the development of violent interactions. These teams would allow integration with the primary health care system by frequent and effective shared communication of knowledge, development of goals, and shared decision-making.³⁸ Setting expectations, providing support, and discussing safety strategies can improve the health and welfare of caregivers and patients with dementia alike.

CORRESPONDENCE
Abu Baker Sheikh, MD, MSC 10-5550, 1 University of New Mexico, Albuquerque, NM 87131; [email protected].

The number of people with dementia globally is expected to reach 74.7 million by 2030 and 131.5 million by 2050.¹ Because dementia is progressive, many patients will exhibit severe symptoms termed behavioral crises. Deteriorating interpersonal conduct and escalating antisocial acts result in an acquired sociopathy.² Increasing cognitive impairment causes these patients to misunderstand intimate care and perceive it as a threat, often resulting in outbursts of violence against their caregivers.³

Available studies (TABLE^4-17) make evident the incidence of interpersonal violence experienced by caregivers secondary to aggressive acts by patients with dementia. This violence ranges from verbal abuse, including racial slurs, to physical abuse—sometimes resulting in significant physical injury. Aggressive behavior by patients with dementia, resulting in violence towards their caregivers or partners, stems from progressive cognitive decline, which can make optimal care difficult. Such episodes may also impair the psychological and physical well-being of caregivers, increasing their risk of depression, anxiety, and even post-traumatic stress disorder (PTSD).¹⁸ The extent of the impact is also determined by the interpretation of the abuse by the caregivers themselves. One study suggested that the perception of aggressive or violent behavior as “normal” by a caregiver reduced the overall negative effect of the interactions.⁷Our review emphasizes the unintended burden that can fall to caregivers of patients with dementia. We also address the role of primary care providers (PCPs) in identifying these instances of violence and intervening appropriately by providing safety strategies, education, resources, and support.

CASE

A 67-year-old man with a medical history of PTSD with depression, type 2 diabetes, alcohol use disorder/dependence, hypertension, and obstructive sleep apnea was brought to his PCP by his wife. She said he had recently been unable to keep appointment times, pay bills, or take his usual medications, venlafaxine and bupropion. She also said his PTSD symptoms had worsened. He was sleeping 12 to 14 hours per day and was increasingly irritable. The patient denied any concerns or changes in his behavior.

Caregivers may refuse support due to personal beliefs or values, accessibility or affordability issues, or in deference to the patient’s wishes.

The PCP administered a Saint Louis University Mental Status (SLUMS) examination to screen for cognitive impairment.¹⁹ The patient scored 14/30 (less than 20 is indicative of dementia). He was unable to complete a simple math problem, recall any items from a list of 5, count in reverse, draw a clock correctly, or recall a full story. Throughout the exam, the patient demonstrated minimal effort and was often only able to complete a task after further prompting by the examiner.

A computed tomography scan of the head revealed no signs of hemorrhage or damage. Thyroid-stimulating hormone levels and vitamin B12 levels were normal. A rapid plasma reagin test result was negative. The patient was given a diagnosis of Alzheimer disease. Donepezil was added to the patient’s medications, starting at 5 mg and then increased to 10 mg. His wife began to assist him with his tasks of daily living. His mood improved, and his wife noted he began to remember his appointments and take his medications with assistance.

However, the patient’s irritability continued to escalate. He grew paranoid and accused his wife of mismanaging their money. This pattern steadily worsened over the course of 6 months. The situation escalated until one day the patient’s wife called a mental health hotline reporting that her husband was holding her hostage and threatening to kill her with a gun. He told her, “I can do something to you, and they won’t even find a fingernail. It doesn’t have to be with a gun either.” She was counseled to try to stay calm to avoid aggravating the situation and to go to a safe place and stay there until help arrived.

His memory had worsened to the point that he could not recall any events from the previous 2 years. He was paranoid about anyone entering his home and would not allow his deteriorating roof to be repaired or his yard to be maintained. He did not shower for weeks at a time. He slept holding a rifle and accused his wife of embezzlement.

Continue to: The patient was evaluated...

The patient was evaluated by another specialist, who assessed his SLUMS score to be 18/30. He increased the patient’s donepezil dose, initiated a bupropion taper, and added sertraline to the regimen. The PCP spoke to the patient’s wife regarding options for her safety including leaving the home, hiding firearms, and calling the police in cases of interpersonal violence. The wife said she did not want to pursue these options. She expressed worry that he might be harmed if he was uncooperative with the police and said there was no one except her to take care of him.

Caregivers struggle to care for their loved ones

Instances of personal violence lead to shock, astonishment, heartbreak, and fear. Anticipation of a recurrence of violence causes many partners and caregivers to feel exhausted, because there is minimal hope for any chance of improvement. There are a few exceptions, however, as our case will show. In addition to emotional exhaustion, there is also a ­never-ending sense of self-doubt, leading many caregivers to question their ability to handle their family member.^20,21 Over time, this leads to caregiver burnout, leaving them unable to understand their family member’s aggression. The sudden loss of caregiver control in dealing with the patient may also result in the family member exhibiting behavioral changes reflecting emotional trauma. For caregivers who do not live with the patient, they may choose to make fewer or shorter visits—or not visit at all—because they fear being abused.^7,22

Caregivers of patients with dementia often feel helpless and powerless once abrupt and drastic changes in personality lead to some form of interpersonal violence. Additionally, caregivers with a poor health status are more likely to have lower physical function and experience greater caregiving stress overall.²³ Other factors increasing stress are longer years of caregiving and the severity of a patient’s dementia and functional impairment.²³

Interventions to reduce caregiver burden

Many studies have assessed the role of different interventions to reduce caregiver burden, such as teaching them problem-solving skills, increasing their knowledge of dementia, recommending social resources, providing emotional support, changing caregiver perceptions of the care situation, introducing coping strategies, relying on strengths and experiences in caregiving, help-seeking, and engaging in activity programs.^24-28 For Hispanic caregivers, a structured and self-paced online telenovela format has been effective in improving care and relieving caregiver stress.²⁹ Online positive emotion regulators helped in significantly improving quality of life and physical health in the caregivers.³⁰ In this last intervention, caregivers had 6 online sessions with a facilitator who taught them emotional regulation skills that included: noticing positive events, capitalizing on them, and feeling gratitude; practicing mindfulness; doing a positive reappraisal; acknowledging personal strengths and setting attainable goals; and performing acts of kindness. Empowerment programs have also shown significant improvement in the well-being of caregivers.³¹

Caregivers may reject support. Hindrances to caregivers accepting support can include personal factors (eg, attitude, beliefs, values), service-related issues (eg, accessibility, affordability), and relational factors (preferences of the patient).³² In the case of patients with dementia who had a higher functional status, caregivers tend to reject any form of support.³² PCPs, of course, are optimally suited to care for entire families, often having known their patients and family members for years.

Continue to: These practical tips can help

Based on our review of the literature, we recommend offering the following supports to caregivers:

• Counsel caregivers early on in a patient’s dementia that behavior changes are likely and may be unpredictable. Explain that dementia can involve changes to personality and behavior as well as memory difficulties.^33,34
• Describe resources for support, such as day programs for senior adults, insurance coverage for caregiver respite programs, and the Alzheimer’s Association (www.alz.org/). Encourage caregivers to seek general medical and mental health care for themselves. Caregivers should have opportunities and support to discuss their experiences and to be appropriately trained for the challenge of caring for a family member with dementia.³⁵
• Encourage disclosure about abrupt changes in the patient’s behavior. This invites families to discuss issues with you and may make them more comfortable with such conversations.
• Involve ancillary services (eg, social worker) to plan for a higher level of care well in advance of it becoming necessary.
• Discuss safety strategies for the caregiver, including when it is appropriate to alter a patient’s set routines such as bedtimes and mealtimes.^33,34
• Discuss when and how to involve law enforcement, if necessary.^33,34 Emphasize the importance of removing firearms from the home as a safety measure. Although federal laws do not explicitly prohibit possession of arms by patients with neurologic damage, a few states mention “organic brain syndrome” or “dementia” as conditions prohibiting use or possession of firearms.³⁶
• Suggest, as feasible, nonpharmacologic aids for the patient such as massage therapy, animal-assisted therapy, personalized interventions, music therapy, and light therapy.³⁷ Prescribe medications to the patient to aid in behavior modification when appropriate.
• Screen caregivers and family members for signs of interpersonal violence. Take notice of changes in caregiver behavior or irregularity in attending follow-up appointments.

CASE

Over the next month, the patient’s symptoms further deteriorated. His PCP recommended hospitalization, but the patient and his wife declined. Magnetic resonance imaging of the patient’s brain revealed severe confluent and patchy regions of white matter and T2 signal hyperintensity, consistent with chronic microvascular ischemic disease. An old, small, left parietal lobe infarct was also noted.

Screen caregivers and family members for signs of interpersonal violence. Take notice of changes in caregiver behavior or irregularity in attending follow-up appointments.

One month later, the patient presented to the emergency department. His symptoms were largely unchanged, but his wife indicated that she could no longer live at home due to burnout. The patient’s medications were adjusted, but he was not admitted for inpatient care. His wife said they needed help at home, but the patient opposed the idea any time that it was mentioned.

A few weeks later, the patient presented for outpatient follow-up. He was delusional, believing that the government was compelling citizens to take sertraline in order to harm their mental health. He had also begun viewing online pornography in front of his wife and attempting to remove all of his money from the bank. He was prescribed aripiprazole 15 mg, and his symptoms began to improve. Soon after, however, he threatened to kill his grandson, then took all his Lasix pills (a 7-day supply) simultaneously. The patient denied that this was a suicide attempt.

Over the course of the next month, the patient began to report hearing voices. A neuropsychological evaluation confirmed a diagnosis of dementia with psychiatric symptoms due to neurologic injury. The patient was referred to a geriatric psychiatrist and continued to be managed medically. He was assigned a multidisciplinary team comprising palliative care, social work, and care management to assist in his care and provide support to the family. His behavior improved.

Continue to: At the time of this publication...

An important step forward would be to develop an interprofessional team to aid in identifying and closely following high-risk patient– caregiver groups.

At the time of this publication, the patient’s irritability and paranoia had subsided and he had made no further threats to his family. He has allowed a home health aide into the house and has agreed to have his roof repaired. His wife still lives with him and assists him with activities of daily living.

Interprofessional teams are key

Caregiver burnout increases the risk of patient neglect or abuse, as individuals who have been the targets of aggressive behavior are more likely to leave demented patients unattended.^8,16,23 Although tools are available to screen caregivers for depression and burnout, an important step forward would be to develop an interprofessional team to aid in identifying and closely following high-risk patient–caregiver groups. This continual and varied assessment of psychosocial stressors could help prevent the development of violent interactions. These teams would allow integration with the primary health care system by frequent and effective shared communication of knowledge, development of goals, and shared decision-making.³⁸ Setting expectations, providing support, and discussing safety strategies can improve the health and welfare of caregivers and patients with dementia alike.

CORRESPONDENCE
Abu Baker Sheikh, MD, MSC 10-5550, 1 University of New Mexico, Albuquerque, NM 87131; [email protected].

Discussion of a common cause of dyspepsia was missing from your September article, “Dyspepsia: A stepwise approach to evaluation and management” (J Fam Pract. 2021;70:320-325). After more than 25 years of practice, I have found that most people with dyspepsia have hypochlorhydria¹—a condition that results in the inability to produce adequate amounts of hydrochloric acid, or stomach acid. With lower amounts of stomach acid, food does not break down but ferments instead, producing gas and discomfort.

I use a simple test to diagnose patients with hypochlorhydria. The patient takes a capsule of hydrochloric acid directly after eating a meal; failure to experience epigastric burning within 30 minutes of ingesting the capsule indicates a need for additional stomach acid with a meal. If they do experience a burning sensation within 30 minutes, it indicates they do not need additional stomach acid. The burning sensation is relieved by drinking 2 teaspoons of baking soda in 4 oz of water to neutralize the excess acid.

In my experience, most people who take the test do not experience a sense of burning. I find that once these patients with hypochlorhydria start taking betaine hydrochloride with their meals, they no longer need the many over-the-counter or prescription antacids and their dyspepsia disappears. Many of my patients find that after a few months, they begin to experience burning and can discontinue the supplement, without facing a return of their dyspepsia.

Marianne Rothschild, MD
Mount Airy, MD

1. Iwai W, Abe Y, Iijima K, et al. Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients. J Gastoenterol. 2012;48:214-221. doi: 10.1007/s00535-012-0634-8

Editor’s note

After reading Dr. Rothschild’s letter, I decided to do a little digging to find out if there is any research evidence to support her approach to dyspepsia. I carefully searched PubMed and found only 2 observational studies showing an association between dyspepsia and hypochlorhydria. There are no randomized trials of dyspepsia treatment with hydrochloric acid to support her clinical observations. Placebo effect? Until there is a good, randomized trial, we will not know. But who would have guessed that H pylori causes peptic ulcers?

John Hickner, MD, MSc
Editor-in-Chief, The Journal of Family Practice

Discussion of a common cause of dyspepsia was missing from your September article, “Dyspepsia: A stepwise approach to evaluation and management” (J Fam Pract. 2021;70:320-325). After more than 25 years of practice, I have found that most people with dyspepsia have hypochlorhydria¹—a condition that results in the inability to produce adequate amounts of hydrochloric acid, or stomach acid. With lower amounts of stomach acid, food does not break down but ferments instead, producing gas and discomfort.

I use a simple test to diagnose patients with hypochlorhydria. The patient takes a capsule of hydrochloric acid directly after eating a meal; failure to experience epigastric burning within 30 minutes of ingesting the capsule indicates a need for additional stomach acid with a meal. If they do experience a burning sensation within 30 minutes, it indicates they do not need additional stomach acid. The burning sensation is relieved by drinking 2 teaspoons of baking soda in 4 oz of water to neutralize the excess acid.

In my experience, most people who take the test do not experience a sense of burning. I find that once these patients with hypochlorhydria start taking betaine hydrochloride with their meals, they no longer need the many over-the-counter or prescription antacids and their dyspepsia disappears. Many of my patients find that after a few months, they begin to experience burning and can discontinue the supplement, without facing a return of their dyspepsia.

Marianne Rothschild, MD
Mount Airy, MD

1. Iwai W, Abe Y, Iijima K, et al. Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients. J Gastoenterol. 2012;48:214-221. doi: 10.1007/s00535-012-0634-8

Editor’s note

After reading Dr. Rothschild’s letter, I decided to do a little digging to find out if there is any research evidence to support her approach to dyspepsia. I carefully searched PubMed and found only 2 observational studies showing an association between dyspepsia and hypochlorhydria. There are no randomized trials of dyspepsia treatment with hydrochloric acid to support her clinical observations. Placebo effect? Until there is a good, randomized trial, we will not know. But who would have guessed that H pylori causes peptic ulcers?

John Hickner, MD, MSc
Editor-in-Chief, The Journal of Family Practice

Discussion of a common cause of dyspepsia was missing from your September article, “Dyspepsia: A stepwise approach to evaluation and management” (J Fam Pract. 2021;70:320-325). After more than 25 years of practice, I have found that most people with dyspepsia have hypochlorhydria¹—a condition that results in the inability to produce adequate amounts of hydrochloric acid, or stomach acid. With lower amounts of stomach acid, food does not break down but ferments instead, producing gas and discomfort.

I use a simple test to diagnose patients with hypochlorhydria. The patient takes a capsule of hydrochloric acid directly after eating a meal; failure to experience epigastric burning within 30 minutes of ingesting the capsule indicates a need for additional stomach acid with a meal. If they do experience a burning sensation within 30 minutes, it indicates they do not need additional stomach acid. The burning sensation is relieved by drinking 2 teaspoons of baking soda in 4 oz of water to neutralize the excess acid.

In my experience, most people who take the test do not experience a sense of burning. I find that once these patients with hypochlorhydria start taking betaine hydrochloride with their meals, they no longer need the many over-the-counter or prescription antacids and their dyspepsia disappears. Many of my patients find that after a few months, they begin to experience burning and can discontinue the supplement, without facing a return of their dyspepsia.

Marianne Rothschild, MD
Mount Airy, MD

1. Iwai W, Abe Y, Iijima K, et al. Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients. J Gastoenterol. 2012;48:214-221. doi: 10.1007/s00535-012-0634-8

Editor’s note

After reading Dr. Rothschild’s letter, I decided to do a little digging to find out if there is any research evidence to support her approach to dyspepsia. I carefully searched PubMed and found only 2 observational studies showing an association between dyspepsia and hypochlorhydria. There are no randomized trials of dyspepsia treatment with hydrochloric acid to support her clinical observations. Placebo effect? Until there is a good, randomized trial, we will not know. But who would have guessed that H pylori causes peptic ulcers?

John Hickner, MD, MSc
Editor-in-Chief, The Journal of Family Practice

Registration is now open for the Gut Microbiota for Health (GMFH) World Summit 2022, taking place March 12-13 in Washington, D.C., and virtually.  

Organized by AGA and the European Society of Neurogastroenterology and Motility (ESNM), the GMFH World Summit is the preeminent international meeting on the gut microbiome for clinicians, dietitians and researchers. 

Now in its 10th year, the program for this year’s conference will focus on “The Gut Microbiome in Precision Nutrition and Medicine.” Join us to gain a deeper understanding of the role of the gut microbiome in precision medicine and discover personalized approaches to modulating the gut microbiome that may promote health and improve patient outcomes for a variety of disorders and diseases.

Registration is now open for the Gut Microbiota for Health (GMFH) World Summit 2022, taking place March 12-13 in Washington, D.C., and virtually.  

Organized by AGA and the European Society of Neurogastroenterology and Motility (ESNM), the GMFH World Summit is the preeminent international meeting on the gut microbiome for clinicians, dietitians and researchers. 

Now in its 10th year, the program for this year’s conference will focus on “The Gut Microbiome in Precision Nutrition and Medicine.” Join us to gain a deeper understanding of the role of the gut microbiome in precision medicine and discover personalized approaches to modulating the gut microbiome that may promote health and improve patient outcomes for a variety of disorders and diseases.

Registration is now open for the Gut Microbiota for Health (GMFH) World Summit 2022, taking place March 12-13 in Washington, D.C., and virtually.  

Organized by AGA and the European Society of Neurogastroenterology and Motility (ESNM), the GMFH World Summit is the preeminent international meeting on the gut microbiome for clinicians, dietitians and researchers. 

Now in its 10th year, the program for this year’s conference will focus on “The Gut Microbiome in Precision Nutrition and Medicine.” Join us to gain a deeper understanding of the role of the gut microbiome in precision medicine and discover personalized approaches to modulating the gut microbiome that may promote health and improve patient outcomes for a variety of disorders and diseases.

Considering the controversy surrounding functional medicine, you may be wondering why JFP published an article about it last month.¹ David Gorski, MD, PhD, FACS, a vocal critic of functional medicine, commented: “Functional medicine. It sounds so … scientific and reasonable. It’s anything but. In fact, functional medicine combines the worst features of conventional medicine with a heapin’ helpin’ of quackery.”² On its website, however, The Institute for Functional Medicine claims that “functional medicine determines how and why illness occurs and restores health by addressing the root causes of disease for each individual.”³

I suspect the truth lies somewhere in between.

Does functional medicine combine “the worst features of conventional medicine with a heapin’ helpin’ of quackery”? Or is it still in its infancy and does it deserve a wait-and-see approach?

Because functional medicine has gained a certain degree of popularity, I felt it was important for family physicians and other primary care clinicians to know enough about this alternative healing method to discuss it with patients who express interest.

In their review article in JFP, Orlando and colleagues tell us there are 7 defining characteristics of functional medicine.¹ It is patient centered rather than disease centered, uses a “systems biology” approach, considers the dynamic balance of gene-environment interactions, is personalized based on biochemical individuality, promotes organ reserve and sustained health span, sees health as a positive vitality (not merely the absence of disease), and focuses on function rather than pathology.

Most of these statements about functional medicine apply to traditional family medicine. The clinical approach stressing lifestyle changes is mainstream, not unique. The focus on digestion and the microbiome as an important determinant of health is based on interesting basic science studies and associations noted between certain microbiome profiles and diseases.

But association is not causation. So far there is scant evidence that changing the microbiome results in better health, although some preliminary case series have generated intriguing hypotheses. And there is evidence that probiotics improve some symptoms. Ongoing research into the microbiome and health will, no doubt, be illuminating. We have much to learn.

What does seem unique, but suspect, about functional medicine is its focus on biochemical testing of unproven value and the prescribing of diets and supplements based on the test results. There are no sound scientific studies showing the benefit of this approach.

I suggest you read Orlando et al’s article. Functional medicine is an interesting, mostly unproven, approach to patient care. But I will keep an open mind until we see better research that either does—or doesn’t—support the validity of its practices.

Considering the controversy surrounding functional medicine, you may be wondering why JFP published an article about it last month.¹ David Gorski, MD, PhD, FACS, a vocal critic of functional medicine, commented: “Functional medicine. It sounds so … scientific and reasonable. It’s anything but. In fact, functional medicine combines the worst features of conventional medicine with a heapin’ helpin’ of quackery.”² On its website, however, The Institute for Functional Medicine claims that “functional medicine determines how and why illness occurs and restores health by addressing the root causes of disease for each individual.”³

I suspect the truth lies somewhere in between.

Does functional medicine combine “the worst features of conventional medicine with a heapin’ helpin’ of quackery”? Or is it still in its infancy and does it deserve a wait-and-see approach?

Because functional medicine has gained a certain degree of popularity, I felt it was important for family physicians and other primary care clinicians to know enough about this alternative healing method to discuss it with patients who express interest.

In their review article in JFP, Orlando and colleagues tell us there are 7 defining characteristics of functional medicine.¹ It is patient centered rather than disease centered, uses a “systems biology” approach, considers the dynamic balance of gene-environment interactions, is personalized based on biochemical individuality, promotes organ reserve and sustained health span, sees health as a positive vitality (not merely the absence of disease), and focuses on function rather than pathology.

Most of these statements about functional medicine apply to traditional family medicine. The clinical approach stressing lifestyle changes is mainstream, not unique. The focus on digestion and the microbiome as an important determinant of health is based on interesting basic science studies and associations noted between certain microbiome profiles and diseases.

But association is not causation. So far there is scant evidence that changing the microbiome results in better health, although some preliminary case series have generated intriguing hypotheses. And there is evidence that probiotics improve some symptoms. Ongoing research into the microbiome and health will, no doubt, be illuminating. We have much to learn.

What does seem unique, but suspect, about functional medicine is its focus on biochemical testing of unproven value and the prescribing of diets and supplements based on the test results. There are no sound scientific studies showing the benefit of this approach.

I suggest you read Orlando et al’s article. Functional medicine is an interesting, mostly unproven, approach to patient care. But I will keep an open mind until we see better research that either does—or doesn’t—support the validity of its practices.

Considering the controversy surrounding functional medicine, you may be wondering why JFP published an article about it last month.¹ David Gorski, MD, PhD, FACS, a vocal critic of functional medicine, commented: “Functional medicine. It sounds so … scientific and reasonable. It’s anything but. In fact, functional medicine combines the worst features of conventional medicine with a heapin’ helpin’ of quackery.”² On its website, however, The Institute for Functional Medicine claims that “functional medicine determines how and why illness occurs and restores health by addressing the root causes of disease for each individual.”³

I suspect the truth lies somewhere in between.

Does functional medicine combine “the worst features of conventional medicine with a heapin’ helpin’ of quackery”? Or is it still in its infancy and does it deserve a wait-and-see approach?

Because functional medicine has gained a certain degree of popularity, I felt it was important for family physicians and other primary care clinicians to know enough about this alternative healing method to discuss it with patients who express interest.

In their review article in JFP, Orlando and colleagues tell us there are 7 defining characteristics of functional medicine.¹ It is patient centered rather than disease centered, uses a “systems biology” approach, considers the dynamic balance of gene-environment interactions, is personalized based on biochemical individuality, promotes organ reserve and sustained health span, sees health as a positive vitality (not merely the absence of disease), and focuses on function rather than pathology.

Most of these statements about functional medicine apply to traditional family medicine. The clinical approach stressing lifestyle changes is mainstream, not unique. The focus on digestion and the microbiome as an important determinant of health is based on interesting basic science studies and associations noted between certain microbiome profiles and diseases.

But association is not causation. So far there is scant evidence that changing the microbiome results in better health, although some preliminary case series have generated intriguing hypotheses. And there is evidence that probiotics improve some symptoms. Ongoing research into the microbiome and health will, no doubt, be illuminating. We have much to learn.

What does seem unique, but suspect, about functional medicine is its focus on biochemical testing of unproven value and the prescribing of diets and supplements based on the test results. There are no sound scientific studies showing the benefit of this approach.

I suggest you read Orlando et al’s article. Functional medicine is an interesting, mostly unproven, approach to patient care. But I will keep an open mind until we see better research that either does—or doesn’t—support the validity of its practices.

An 85-year-old man with a history of skin cancer presented to my dermatology practice (NT) for evaluation of a “pimple” on his left cheek that failed to resolve after 2 months (FIGURE). The patient noted that the lesion had grown, but that he otherwise felt well.

On examination, the lesion was plum colored, and the area was firm and nontender to palpation. The patient was referred to a plastic surgeon for an excisional biopsy to clarify the nature of the lesion.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A biopsy performed 2 weeks after the initial visit confirmed the clinical suspicion for Merkel cell carcinoma (MCC).

MCC is a cutaneous neuroendocrine malignancy. Although its name acknowledges similarities between the tumor cells and Merkel cells, it is now considered unlikely that Merkel cells are the actual cells of origin.¹

The growing cohort of ageing baby boomers and the increased number of immunosuppressed individuals in the community suggest that clinicians are now more likely to encounter MCC than in the past.

The majority of MCCs are asymptomatic despite rapid growth and are typically red or pink and occur on UV-exposed areas, as in our patient.² A cyst or acneiform lesion is the single most common diagnosis given at the time of biopsy.²

The incidence of MCC is greatest in people of advanced age and in those who are immunosuppressed. In the United States, the estimated annual incidence rate rose from 0.5 cases per 100,000 people in 2000 to 0.7 cases per 100,000 people in 2013.³ MCC increases exponentially with advancing age, from 0.1 (per 100,000) in those ages 40 to 44 years to 9.8 in those older than 85 years.³ The growing cohort of ageing baby boomers and the increased number of immunosuppressed individuals in the community suggest that clinicians are now more likely to encounter MCC than in the past.

While UV radiation is highly associated with MCC, the major causative factor is considered to be Merkel cell polyomavirus (MCPyV).¹ In fact, MCPyV has been linked to 80% of MCC cases.^1,3 Most people have positive serology for MCPyV in early childhood, but the association between MCC and old age highlights the impact of immunosuppression on MCPyV activity and MCC development.¹

Clinical suspicion is the first step in diagnosing MCC

The mnemonic AEIOU highlights the key clinical features of this aggressive tumor^2,4:

• Asymptomatic
• Expanding rapidly (often grows in less than 3 months)
• Immune suppression (eg, chronic lymphocytic leukemia, solid organ transplant patient)
• Older than 50
• UV exposure on fair skin.

If a lesion is suspected to be MCC, the next step includes biopsy so that a definitive diagnosis can be made. A firm, nontender nodule that lacks fluctuance should raise suspicion for a neoplastic process.

Continue to: The differential is broad, ranging from cysts to melanoma

The differential diagnosis for an enlarging, plum-colored nodule on sun-exposed skin includes an abscess, a ruptured or inflamed epidermoid cyst, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.

An abscess is typically tender and expands within a matter of days rather than months.

A cyst can be ruled out by the clinical appearance and lack of an overlying pore.

Basal cell carcinoma can be characterized by a rolled border and central ulceration.

Squamous cell carcinomas often exhibit a verrucous surface with marked hyperkeratosis.

Continue to: Melanoma

Melanoma manifests with brown or irregular pigmentation and may be associated with a precursor lesion.

Tx includes excision and consistent follow-up

Complete excision is the critical first step to successful therapy. Sentinel lymph node studies are typically performed because of the high incidence of lymph node metastasis. Frequent follow-up is required because of the high risk of recurrent or persistent disease.

Local recurrence usually occurs within 1 year of diagnosis in more than 40% of patients.⁵ Distant metastasis can be treated with a programmed cell death ligand 1 blocking agent (avelumab) or a programmed cell death protein 1 inhibitor (nivolumab or pembrolizumab).⁶

Our patient was referred to a regional cancer center for sentinel lymph node evaluation, where he was found to have nodal disease. The patient was put on pembrolizumab and received radiation therapy but showed only limited response. Seven months after diagnosis, he passed away from metastatic MCC.

An 85-year-old man with a history of skin cancer presented to my dermatology practice (NT) for evaluation of a “pimple” on his left cheek that failed to resolve after 2 months (FIGURE). The patient noted that the lesion had grown, but that he otherwise felt well.

On examination, the lesion was plum colored, and the area was firm and nontender to palpation. The patient was referred to a plastic surgeon for an excisional biopsy to clarify the nature of the lesion.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A biopsy performed 2 weeks after the initial visit confirmed the clinical suspicion for Merkel cell carcinoma (MCC).

MCC is a cutaneous neuroendocrine malignancy. Although its name acknowledges similarities between the tumor cells and Merkel cells, it is now considered unlikely that Merkel cells are the actual cells of origin.¹

The growing cohort of ageing baby boomers and the increased number of immunosuppressed individuals in the community suggest that clinicians are now more likely to encounter MCC than in the past.

The majority of MCCs are asymptomatic despite rapid growth and are typically red or pink and occur on UV-exposed areas, as in our patient.² A cyst or acneiform lesion is the single most common diagnosis given at the time of biopsy.²

The incidence of MCC is greatest in people of advanced age and in those who are immunosuppressed. In the United States, the estimated annual incidence rate rose from 0.5 cases per 100,000 people in 2000 to 0.7 cases per 100,000 people in 2013.³ MCC increases exponentially with advancing age, from 0.1 (per 100,000) in those ages 40 to 44 years to 9.8 in those older than 85 years.³ The growing cohort of ageing baby boomers and the increased number of immunosuppressed individuals in the community suggest that clinicians are now more likely to encounter MCC than in the past.

While UV radiation is highly associated with MCC, the major causative factor is considered to be Merkel cell polyomavirus (MCPyV).¹ In fact, MCPyV has been linked to 80% of MCC cases.^1,3 Most people have positive serology for MCPyV in early childhood, but the association between MCC and old age highlights the impact of immunosuppression on MCPyV activity and MCC development.¹

Clinical suspicion is the first step in diagnosing MCC

The mnemonic AEIOU highlights the key clinical features of this aggressive tumor^2,4:

• Asymptomatic
• Expanding rapidly (often grows in less than 3 months)
• Immune suppression (eg, chronic lymphocytic leukemia, solid organ transplant patient)
• Older than 50
• UV exposure on fair skin.

If a lesion is suspected to be MCC, the next step includes biopsy so that a definitive diagnosis can be made. A firm, nontender nodule that lacks fluctuance should raise suspicion for a neoplastic process.

Continue to: The differential is broad, ranging from cysts to melanoma

The differential diagnosis for an enlarging, plum-colored nodule on sun-exposed skin includes an abscess, a ruptured or inflamed epidermoid cyst, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.

An abscess is typically tender and expands within a matter of days rather than months.

A cyst can be ruled out by the clinical appearance and lack of an overlying pore.

Basal cell carcinoma can be characterized by a rolled border and central ulceration.

Squamous cell carcinomas often exhibit a verrucous surface with marked hyperkeratosis.

Continue to: Melanoma

Melanoma manifests with brown or irregular pigmentation and may be associated with a precursor lesion.

Tx includes excision and consistent follow-up

Complete excision is the critical first step to successful therapy. Sentinel lymph node studies are typically performed because of the high incidence of lymph node metastasis. Frequent follow-up is required because of the high risk of recurrent or persistent disease.

Local recurrence usually occurs within 1 year of diagnosis in more than 40% of patients.⁵ Distant metastasis can be treated with a programmed cell death ligand 1 blocking agent (avelumab) or a programmed cell death protein 1 inhibitor (nivolumab or pembrolizumab).⁶

Our patient was referred to a regional cancer center for sentinel lymph node evaluation, where he was found to have nodal disease. The patient was put on pembrolizumab and received radiation therapy but showed only limited response. Seven months after diagnosis, he passed away from metastatic MCC.

An 85-year-old man with a history of skin cancer presented to my dermatology practice (NT) for evaluation of a “pimple” on his left cheek that failed to resolve after 2 months (FIGURE). The patient noted that the lesion had grown, but that he otherwise felt well.

On examination, the lesion was plum colored, and the area was firm and nontender to palpation. The patient was referred to a plastic surgeon for an excisional biopsy to clarify the nature of the lesion.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A biopsy performed 2 weeks after the initial visit confirmed the clinical suspicion for Merkel cell carcinoma (MCC).

MCC is a cutaneous neuroendocrine malignancy. Although its name acknowledges similarities between the tumor cells and Merkel cells, it is now considered unlikely that Merkel cells are the actual cells of origin.¹

The growing cohort of ageing baby boomers and the increased number of immunosuppressed individuals in the community suggest that clinicians are now more likely to encounter MCC than in the past.

The majority of MCCs are asymptomatic despite rapid growth and are typically red or pink and occur on UV-exposed areas, as in our patient.² A cyst or acneiform lesion is the single most common diagnosis given at the time of biopsy.²

The incidence of MCC is greatest in people of advanced age and in those who are immunosuppressed. In the United States, the estimated annual incidence rate rose from 0.5 cases per 100,000 people in 2000 to 0.7 cases per 100,000 people in 2013.³ MCC increases exponentially with advancing age, from 0.1 (per 100,000) in those ages 40 to 44 years to 9.8 in those older than 85 years.³ The growing cohort of ageing baby boomers and the increased number of immunosuppressed individuals in the community suggest that clinicians are now more likely to encounter MCC than in the past.

While UV radiation is highly associated with MCC, the major causative factor is considered to be Merkel cell polyomavirus (MCPyV).¹ In fact, MCPyV has been linked to 80% of MCC cases.^1,3 Most people have positive serology for MCPyV in early childhood, but the association between MCC and old age highlights the impact of immunosuppression on MCPyV activity and MCC development.¹

Clinical suspicion is the first step in diagnosing MCC

The mnemonic AEIOU highlights the key clinical features of this aggressive tumor^2,4:

• Asymptomatic
• Expanding rapidly (often grows in less than 3 months)
• Immune suppression (eg, chronic lymphocytic leukemia, solid organ transplant patient)
• Older than 50
• UV exposure on fair skin.

If a lesion is suspected to be MCC, the next step includes biopsy so that a definitive diagnosis can be made. A firm, nontender nodule that lacks fluctuance should raise suspicion for a neoplastic process.

Continue to: The differential is broad, ranging from cysts to melanoma

The differential diagnosis for an enlarging, plum-colored nodule on sun-exposed skin includes an abscess, a ruptured or inflamed epidermoid cyst, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.

An abscess is typically tender and expands within a matter of days rather than months.

A cyst can be ruled out by the clinical appearance and lack of an overlying pore.

Basal cell carcinoma can be characterized by a rolled border and central ulceration.

Squamous cell carcinomas often exhibit a verrucous surface with marked hyperkeratosis.

Continue to: Melanoma

Melanoma manifests with brown or irregular pigmentation and may be associated with a precursor lesion.

Tx includes excision and consistent follow-up

Complete excision is the critical first step to successful therapy. Sentinel lymph node studies are typically performed because of the high incidence of lymph node metastasis. Frequent follow-up is required because of the high risk of recurrent or persistent disease.

Local recurrence usually occurs within 1 year of diagnosis in more than 40% of patients.⁵ Distant metastasis can be treated with a programmed cell death ligand 1 blocking agent (avelumab) or a programmed cell death protein 1 inhibitor (nivolumab or pembrolizumab).⁶

Our patient was referred to a regional cancer center for sentinel lymph node evaluation, where he was found to have nodal disease. The patient was put on pembrolizumab and received radiation therapy but showed only limited response. Seven months after diagnosis, he passed away from metastatic MCC.