Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.

A recent retrospective study assessing response to tofacitinib in adults with AA (>40% hair loss), alopecia totalis, alopecia universalis, and stable or progressive diseases for at least 6 months determined a clinical response in 50 of 65 (77%) patients, with 13 patients exhibiting a complete response.¹⁰ Patients in this study were started on tofacitinib 5 mg twice daily with the addition of adjuvant pulsed prednisone (300 mg once monthly for 3 doses) with or without doubled dosing of tofacitinib if they had a halt in hair regrowth. This study demonstrated some benefit when pulsed prednisone was combined with the daily tofacitinib therapy. However, the study emphasized the importance of maintenance therapy, as 8 patients experienced hair loss with discontinuation after previously having hair regrowth; 5 (63%) of these patients experienced regrowth with augmentation of dosing or addition of adjuvant therapy.¹⁰

Another group of investigators assessed the efficacy of tofacitinib 5 mg in 13 adolescents aged 12 to 17 years, most with alopecia universalis (46% [6/13]); 10 of 13 (77%) patients responded to treatment with a mean duration of 6.5 months. The patients who had alopecia totalis and alopecia universalis for more than 10 years were poor responders to tofacitinib, and in fact, 1 of 13 (33%) patients in the study who did not respond to therapy had disease for 12 years.¹¹ Therefore, starting tofacitinib either long-term or intermittently should be considered in children diagnosed early with severe AA, alopecia totalis, or alopecia universalis to prevent irreversible hair loss or progressive disease^12,13; however, further data are required to assess efficacy and long-term benefits of this type of regimen.

Safety Profile—Widespread use of a medication is determined not only by its efficacy profile but also its safety profile. With any medication that exhibits immunosuppressive effects, adverse events must be considered and thoroughly discussed with patients and their primary care physicians. A prospective, open-label, single-arm trial examined the efficacy and safety of tofacitinib 5 mg twice daily in the treatment of AA and its more severe forms over 3 months.¹² Of the 66 patients who completed the trial, 64% (42/66) exhibited a positive response to tofacitinib. Relapse was noted in 8.5 weeks after discontinuation of tofacitinib, reiterating the potential need for a maintenance regimen. In this study, 25.8% (17/66) of patients experienced infections as adverse events including (in decreasing order) upper respiratory tract infections, urinary tract infections, herpes zoster, conjunctivitis, bronchitis, mononucleosis, and paronychia. No reports of new or recurrent malignancy were noted. Other more constitutional adverse events were noted including headaches, abdominal pain, acne, diarrhea, fatigue, nausea, pruritus, hot flashes, cough, folliculitis, weight gain, dry eyes, and amenorrhea. One patient with a pre-existing liver condition experienced transaminitis that resolved with weight loss. There also were noted increases in low- and high-density lipoprotein levels.¹² Our patient with baseline thrombocytopenia had mild drops in platelet count that subsequently stabilized and did not result in any bleeding abnormalities.

Duration of Therapy—Tofacitinib has demonstrated some preliminary success in the management of AA, but the appropriate duration of treatment requires further investigation. Our patient has been on tofacitinib for more than 5 years. She started at a total dosage of 10 mg/d, which increased to 16 mg/d. Initial dosing with maintenance regimens needs to be established for further widespread use to maximize benefit and minimize harm.

At what point do we decide to continue or stop treatment in patients who do not respond as expected or plateau? This is another critical question; our patient had periods of slowed growth and plateauing, but knowing the risks and benefits, she continued the medication and eventually experienced improved regrowth again.

Conclusion

Throughout the literature and in our patient, tofacitinib has demonstrated efficacy in treating AA. When other conventional therapies have failed, use of tofacitinib should be considered.

Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.

A recent retrospective study assessing response to tofacitinib in adults with AA (>40% hair loss), alopecia totalis, alopecia universalis, and stable or progressive diseases for at least 6 months determined a clinical response in 50 of 65 (77%) patients, with 13 patients exhibiting a complete response.¹⁰ Patients in this study were started on tofacitinib 5 mg twice daily with the addition of adjuvant pulsed prednisone (300 mg once monthly for 3 doses) with or without doubled dosing of tofacitinib if they had a halt in hair regrowth. This study demonstrated some benefit when pulsed prednisone was combined with the daily tofacitinib therapy. However, the study emphasized the importance of maintenance therapy, as 8 patients experienced hair loss with discontinuation after previously having hair regrowth; 5 (63%) of these patients experienced regrowth with augmentation of dosing or addition of adjuvant therapy.¹⁰

Another group of investigators assessed the efficacy of tofacitinib 5 mg in 13 adolescents aged 12 to 17 years, most with alopecia universalis (46% [6/13]); 10 of 13 (77%) patients responded to treatment with a mean duration of 6.5 months. The patients who had alopecia totalis and alopecia universalis for more than 10 years were poor responders to tofacitinib, and in fact, 1 of 13 (33%) patients in the study who did not respond to therapy had disease for 12 years.¹¹ Therefore, starting tofacitinib either long-term or intermittently should be considered in children diagnosed early with severe AA, alopecia totalis, or alopecia universalis to prevent irreversible hair loss or progressive disease^12,13; however, further data are required to assess efficacy and long-term benefits of this type of regimen.

Safety Profile—Widespread use of a medication is determined not only by its efficacy profile but also its safety profile. With any medication that exhibits immunosuppressive effects, adverse events must be considered and thoroughly discussed with patients and their primary care physicians. A prospective, open-label, single-arm trial examined the efficacy and safety of tofacitinib 5 mg twice daily in the treatment of AA and its more severe forms over 3 months.¹² Of the 66 patients who completed the trial, 64% (42/66) exhibited a positive response to tofacitinib. Relapse was noted in 8.5 weeks after discontinuation of tofacitinib, reiterating the potential need for a maintenance regimen. In this study, 25.8% (17/66) of patients experienced infections as adverse events including (in decreasing order) upper respiratory tract infections, urinary tract infections, herpes zoster, conjunctivitis, bronchitis, mononucleosis, and paronychia. No reports of new or recurrent malignancy were noted. Other more constitutional adverse events were noted including headaches, abdominal pain, acne, diarrhea, fatigue, nausea, pruritus, hot flashes, cough, folliculitis, weight gain, dry eyes, and amenorrhea. One patient with a pre-existing liver condition experienced transaminitis that resolved with weight loss. There also were noted increases in low- and high-density lipoprotein levels.¹² Our patient with baseline thrombocytopenia had mild drops in platelet count that subsequently stabilized and did not result in any bleeding abnormalities.

Duration of Therapy—Tofacitinib has demonstrated some preliminary success in the management of AA, but the appropriate duration of treatment requires further investigation. Our patient has been on tofacitinib for more than 5 years. She started at a total dosage of 10 mg/d, which increased to 16 mg/d. Initial dosing with maintenance regimens needs to be established for further widespread use to maximize benefit and minimize harm.

At what point do we decide to continue or stop treatment in patients who do not respond as expected or plateau? This is another critical question; our patient had periods of slowed growth and plateauing, but knowing the risks and benefits, she continued the medication and eventually experienced improved regrowth again.

Conclusion

Throughout the literature and in our patient, tofacitinib has demonstrated efficacy in treating AA. When other conventional therapies have failed, use of tofacitinib should be considered.

Alopecia areata (AA) is an autoimmune disease that immunopathogenetically is thought to be due to breakdown of the immune privilege of the proximal hair follicle during the anagen growth phase. Alopecia areata has been reported to have a lifetime prevalence of 1.7%.¹ Recent studies have specifically identified cytotoxic CD8⁺ NKG2D⁺ T cells as being responsible for the activation of AA.^2-4 Two interleukins—IL-2 and IL-15—have been implicated to be cytotoxic sensitizers allowing CD8⁺ T cells to secrete IFN-γ and recognize autoantigens via major histocompatibility complex class I.^5,6 Janus kinases (JAKs) are enzymes that play major roles in many different molecular processes. Specifically, JAK1/3 has been determined to arbitrate IL-15 activation of receptors on CD8⁺ T cells.⁷ These cells then interact with CD4 T cells, mast cells, and other inflammatory cells to cause destruction of the hair follicle without damage to the keratinocyte and melanocyte stem cells, allowing for reversible yet relapsing hair loss.⁸

Treatment of AA is difficult, requiring patience and strict compliance while taking into account duration of disease, age at presentation, site involvement, patient expectations, cost and insurance coverage, prior therapies, and any comorbidities. At the time of this case, no US Food and Drug Administration–approved drug regimen existed for the treatment of AA, and, to date, no treatment is preventative.⁴ We present a case of a patient with alopecia universalis of 11 years’ duration that was refractory to intralesional triamcinolone, clobetasol, minoxidil, and UVB brush therapy yet was successfully treated with tofacitinib.

Case Report

A 29-year-old otherwise-healthy woman presented to our clinic for treatment of alopecia universalis of 11 years’ duration that flared intermittently despite various treatments. Her medical history was unremarkable; however, she had a brother with alopecia universalis. She had no family history of any other autoimmune disorders. At the current presentation, the patient was known to have alopecia universalis with scant evidence of exclamation-point hairs on dermoscopy. Her treatment plan at this point consisted of intralesional triamcinolone to the active areas at 10 mg/mL every 4 weeks, plus clobetasol foam 0.05% at bedtime, minoxidil foam 5% at bedtime, and a UVB brush 3 times a week for 6 months before progressing to universalis type because of hair loss in the eyebrows and eyelashes. This treatment plan continued for 1 year with minimal improvement of the alopecia (Figure 1).

The patient was dissatisfied and wanted to discontinue therapy. Because these treatment options were exhausted with minimal benefit, the patient was then considered for treatment with tofacitinib. Baseline studies were performed, including purified protein derivative, complete blood cell count with differential, comprehensive metabolic panel, lipid profile, and liver function tests, all of which were within reference range. Insurance initially denied coverage of this therapy; a prior authorization was subsequently submitted and denied. A letter of medical necessity was then proposed, and approval for tofacitinib was finally granted. The patient was started on tofacitinib 5 mg twice daily and was monitored every 2 months with a complete blood cell count, comprehensive metabolic panel, lipid panels, and liver function tests. She had a platelet count of 112,000/μL (reference range, 150,000–450,000/μL) at baseline, and continued monitoring revealed a platelet count of 83,000 after 7 months of treatment. This platelet abnormality was evaluated by a hematologist and found to be within reference range; subsequent monitoring did not reveal any abnormalities.

Initial hair growth on the scalp was diffuse with thin, white to light brown hairs in areas of hair loss at months 1 and 2, with progressive hair growth over months 3 to 7. Eyebrow hair growth was noted beginning at month 6. One year later, only hair regrowth occurred without any adverse events (Figure 2). After 5 years of treatment, the patient had a full head of thick hair (Figure 3). The tofacitinib dosage was 5 mg twice daily at initiation, and after 1 year increased to 10 mg twice daily. Her medical insurance subsequently changed and the regimen was adjusted to an 11-mg tablet and 5-mg tablet daily. She remained on this regimen with success.

Comment

Use of JAK Inhibitors—Reports and studies have shed light on the use and efficacy of JAK inhibitors in AA (Table).^5-11 Tofacitinib is a selective JAK1/3 inhibitor that predominantly inhibits JAK3 but also inhibits JAK1, albeit to a lesser degree, which interferes with the JAK/STAT (signal transducer and activator of transcription) cascade responsible for the production, differentiation, and function of various B cells, T cells, and natural killer cells.² Although it was developed for the management of allograft rejection, tofacitinib has made headway in rheumatology for treatment of patients with moderate to severe rheumatoid arthritis who are unable to take or are not responding to methotrexate.² Since 2014, tofacitinib has been introduced to the therapeutic realm for AA but is not yet approved by the US Food and Drug Administration.^3,4

In 2014, Craiglow and King⁵ reported use of tofacitinib with dosages beginning at 10 mg/d and increasing to 15 mg/d in a patient with alopecia universalis and psoriasis. Total hair regrowth was noted after 8 months of therapy.⁵ Xing et al⁶ described 3 patients treated with ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, at an oral dose of 20 mg twice daily with near-complete hair regrowth after 5 months of treatment.⁶ Biopsies from lesions at baseline and after 3 months of therapy revealed a reduction in perifollicular T cells and in HLA class I and II expression in follicles.⁶ A patient in Italy with essential thrombocythemia and concurrent alopecia universalis was enrolled in a clinical trial with ruxolitinib and was treated with 15 mg twice daily. After 10 months of treatment, the patient had progressive hair regrowth that was sustained for more than 50 months of therapy.⁷ Baricitinib, a JAK1/2 inhibitor, was used in a 17-year-old adolescent boy to assess efficacy of the drug in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.⁸ The patient also had longstanding patch-type AA that was resistance to treatment and progressed to an ophiasis pattern even though he was on immunosuppressive therapies. He was on 12 mg of prednisone daily at the start of therapy with baricitinib 7 mg daily initially. The baricitinib regimen was titrated up to 7 mg in the morning and 4 mg in the evening, with tapering of prednisone to 3 mg daily after 6 months of initiation. Within 3 months of therapy, hair regrowth occurred, with only a resultant patch on the occipital scalp that further resolved after 6 more months of therapy, resulting in total persistent hair growth.⁸ A 40-year-old woman with moderate to severe alopecia universalis was treated with tofacitinib 5 mg twice daily, revealing near-complete hair regrowth after 4 months of treatment; regrowth of eyebrows and eyelashes also was seen.⁹ However, discontinuation of treatment resulted in hair loss. Microarray analyses of biopsy specimens of lesioned sites at baseline revealed elevated IFN-γ and cytotoxic T cell-level signatures that subsequently decreased—albeit not to normal control levels—after 4 weeks of treatment.⁹ Being that IFN-γ receptors mediate their effects through JAK1/2, JAK1/3, tofacitinib, ruxolitinib, and baricitinib seem to be in sync with the immunopathogenesis of AA and thus may be the therapy of choice in the near future.

A recent retrospective study assessing response to tofacitinib in adults with AA (>40% hair loss), alopecia totalis, alopecia universalis, and stable or progressive diseases for at least 6 months determined a clinical response in 50 of 65 (77%) patients, with 13 patients exhibiting a complete response.¹⁰ Patients in this study were started on tofacitinib 5 mg twice daily with the addition of adjuvant pulsed prednisone (300 mg once monthly for 3 doses) with or without doubled dosing of tofacitinib if they had a halt in hair regrowth. This study demonstrated some benefit when pulsed prednisone was combined with the daily tofacitinib therapy. However, the study emphasized the importance of maintenance therapy, as 8 patients experienced hair loss with discontinuation after previously having hair regrowth; 5 (63%) of these patients experienced regrowth with augmentation of dosing or addition of adjuvant therapy.¹⁰

Another group of investigators assessed the efficacy of tofacitinib 5 mg in 13 adolescents aged 12 to 17 years, most with alopecia universalis (46% [6/13]); 10 of 13 (77%) patients responded to treatment with a mean duration of 6.5 months. The patients who had alopecia totalis and alopecia universalis for more than 10 years were poor responders to tofacitinib, and in fact, 1 of 13 (33%) patients in the study who did not respond to therapy had disease for 12 years.¹¹ Therefore, starting tofacitinib either long-term or intermittently should be considered in children diagnosed early with severe AA, alopecia totalis, or alopecia universalis to prevent irreversible hair loss or progressive disease^12,13; however, further data are required to assess efficacy and long-term benefits of this type of regimen.

Safety Profile—Widespread use of a medication is determined not only by its efficacy profile but also its safety profile. With any medication that exhibits immunosuppressive effects, adverse events must be considered and thoroughly discussed with patients and their primary care physicians. A prospective, open-label, single-arm trial examined the efficacy and safety of tofacitinib 5 mg twice daily in the treatment of AA and its more severe forms over 3 months.¹² Of the 66 patients who completed the trial, 64% (42/66) exhibited a positive response to tofacitinib. Relapse was noted in 8.5 weeks after discontinuation of tofacitinib, reiterating the potential need for a maintenance regimen. In this study, 25.8% (17/66) of patients experienced infections as adverse events including (in decreasing order) upper respiratory tract infections, urinary tract infections, herpes zoster, conjunctivitis, bronchitis, mononucleosis, and paronychia. No reports of new or recurrent malignancy were noted. Other more constitutional adverse events were noted including headaches, abdominal pain, acne, diarrhea, fatigue, nausea, pruritus, hot flashes, cough, folliculitis, weight gain, dry eyes, and amenorrhea. One patient with a pre-existing liver condition experienced transaminitis that resolved with weight loss. There also were noted increases in low- and high-density lipoprotein levels.¹² Our patient with baseline thrombocytopenia had mild drops in platelet count that subsequently stabilized and did not result in any bleeding abnormalities.

Duration of Therapy—Tofacitinib has demonstrated some preliminary success in the management of AA, but the appropriate duration of treatment requires further investigation. Our patient has been on tofacitinib for more than 5 years. She started at a total dosage of 10 mg/d, which increased to 16 mg/d. Initial dosing with maintenance regimens needs to be established for further widespread use to maximize benefit and minimize harm.

At what point do we decide to continue or stop treatment in patients who do not respond as expected or plateau? This is another critical question; our patient had periods of slowed growth and plateauing, but knowing the risks and benefits, she continued the medication and eventually experienced improved regrowth again.

Conclusion

Throughout the literature and in our patient, tofacitinib has demonstrated efficacy in treating AA. When other conventional therapies have failed, use of tofacitinib should be considered.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Preoperative biopsy results in patients with esophageal adenocarcinoma (EAC) often misrepresent true tumor grade, according to a recent retrospective study.

Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.

Cleveland Clinic

“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”

While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.

Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.

To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.

For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).

“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.

Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.

These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.

“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”

The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.

Preoperative biopsy results in patients with esophageal adenocarcinoma (EAC) often misrepresent true tumor grade, according to a recent retrospective study.

Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.

Cleveland Clinic

“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”

While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.

Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.

To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.

For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).

“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.

Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.

These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.

“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”

The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.

Preoperative biopsy results in patients with esophageal adenocarcinoma (EAC) often misrepresent true tumor grade, according to a recent retrospective study.

Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.

Cleveland Clinic

“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”

While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.

Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.

To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.

For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).

“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.

Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.

These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.

“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”

The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.

TOPLINE:

Use of Janus kinase (JAK) inhibitors is associated with a nearly fourfold increase in risk of acne compared with placebo, according to an analysis of 25 JAK inhibitor studies.

METHODOLOGY:

• Acne has been reported to be an adverse effect of JAK inhibitors, but not much is known about how common acne is overall and how incidence differs between different JAK inhibitors and the disease being treated.
• For the systematic review and meta-analysis, researchers identified 25 phase 2 or 3 randomized, controlled trials that reported acne as an adverse event associated with the use of JAK inhibitors.
• The study population included 10,839 participants (54% male, 46% female).
• The primary outcome was the incidence of acne following a period of JAK inhibitor use.

TAKEAWAY:

• Overall, the risk of acne was significantly higher among those treated with JAK inhibitors in comparison with patients given placebo in a pooled analysis (odds ratio [OR], 3.83).
• The risk of acne was highest with abrocitinib (OR, 13.47), followed by baricitinib (OR, 4.96), upadacitinib (OR, 4.79), deuruxolitinib (OR, 3.30), and deucravacitinib (OR, 2.64). By JAK inhibitor class, results were as follows: JAK1-specific inhibitors (OR, 4.69), combined JAK1 and JAK2 inhibitors (OR, 3.43), and tyrosine kinase 2 inhibitors (OR, 2.64).
• In a subgroup analysis, risk of acne was higher among patients using JAK inhibitors for dermatologic conditions in comparison with those using JAK inhibitors for nondermatologic conditions (OR, 4.67 vs 1.18).
• Age and gender had no apparent impact on the effect of JAK inhibitor use on acne risk.

IN PRACTICE:

“The occurrence of acne following treatment with certain classes of JAK inhibitors is of potential concern, as this adverse effect may jeopardize treatment adherence among some patients,” the researchers wrote. More studies are needed “to characterize the underlying mechanism of acne with JAK inhibitor use and to identify best practices for treatment,” they added.

SOURCE:

The lead author was Jeremy Martinez, MPH, of Harvard Medical School, Boston. The study was published online in JAMA Dermatology.

LIMITATIONS:

The review was limited by the variable classification and reporting of acne across studies, the potential exclusion of relevant studies, and the small number of studies for certain drugs.

DISCLOSURES:

The studies were mainly funded by the pharmaceutical industry. Mr. Martinez disclosed no relevant financial relationships. Several coauthors have ties with Dexcel Pharma Technologies, AbbVie, Concert, Pfizer, 3Derm Systems, Incyte, Aclaris, Eli Lilly, Concert, Equillium, ASLAN, ACOM, and Boehringer Ingelheim.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Use of Janus kinase (JAK) inhibitors is associated with a nearly fourfold increase in risk of acne compared with placebo, according to an analysis of 25 JAK inhibitor studies.

METHODOLOGY:

• Acne has been reported to be an adverse effect of JAK inhibitors, but not much is known about how common acne is overall and how incidence differs between different JAK inhibitors and the disease being treated.
• For the systematic review and meta-analysis, researchers identified 25 phase 2 or 3 randomized, controlled trials that reported acne as an adverse event associated with the use of JAK inhibitors.
• The study population included 10,839 participants (54% male, 46% female).
• The primary outcome was the incidence of acne following a period of JAK inhibitor use.

TAKEAWAY:

• Overall, the risk of acne was significantly higher among those treated with JAK inhibitors in comparison with patients given placebo in a pooled analysis (odds ratio [OR], 3.83).
• The risk of acne was highest with abrocitinib (OR, 13.47), followed by baricitinib (OR, 4.96), upadacitinib (OR, 4.79), deuruxolitinib (OR, 3.30), and deucravacitinib (OR, 2.64). By JAK inhibitor class, results were as follows: JAK1-specific inhibitors (OR, 4.69), combined JAK1 and JAK2 inhibitors (OR, 3.43), and tyrosine kinase 2 inhibitors (OR, 2.64).
• In a subgroup analysis, risk of acne was higher among patients using JAK inhibitors for dermatologic conditions in comparison with those using JAK inhibitors for nondermatologic conditions (OR, 4.67 vs 1.18).
• Age and gender had no apparent impact on the effect of JAK inhibitor use on acne risk.

IN PRACTICE:

“The occurrence of acne following treatment with certain classes of JAK inhibitors is of potential concern, as this adverse effect may jeopardize treatment adherence among some patients,” the researchers wrote. More studies are needed “to characterize the underlying mechanism of acne with JAK inhibitor use and to identify best practices for treatment,” they added.

SOURCE:

The lead author was Jeremy Martinez, MPH, of Harvard Medical School, Boston. The study was published online in JAMA Dermatology.

LIMITATIONS:

The review was limited by the variable classification and reporting of acne across studies, the potential exclusion of relevant studies, and the small number of studies for certain drugs.

DISCLOSURES:

The studies were mainly funded by the pharmaceutical industry. Mr. Martinez disclosed no relevant financial relationships. Several coauthors have ties with Dexcel Pharma Technologies, AbbVie, Concert, Pfizer, 3Derm Systems, Incyte, Aclaris, Eli Lilly, Concert, Equillium, ASLAN, ACOM, and Boehringer Ingelheim.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Use of Janus kinase (JAK) inhibitors is associated with a nearly fourfold increase in risk of acne compared with placebo, according to an analysis of 25 JAK inhibitor studies.

METHODOLOGY:

• Acne has been reported to be an adverse effect of JAK inhibitors, but not much is known about how common acne is overall and how incidence differs between different JAK inhibitors and the disease being treated.
• For the systematic review and meta-analysis, researchers identified 25 phase 2 or 3 randomized, controlled trials that reported acne as an adverse event associated with the use of JAK inhibitors.
• The study population included 10,839 participants (54% male, 46% female).
• The primary outcome was the incidence of acne following a period of JAK inhibitor use.

TAKEAWAY:

• Overall, the risk of acne was significantly higher among those treated with JAK inhibitors in comparison with patients given placebo in a pooled analysis (odds ratio [OR], 3.83).
• The risk of acne was highest with abrocitinib (OR, 13.47), followed by baricitinib (OR, 4.96), upadacitinib (OR, 4.79), deuruxolitinib (OR, 3.30), and deucravacitinib (OR, 2.64). By JAK inhibitor class, results were as follows: JAK1-specific inhibitors (OR, 4.69), combined JAK1 and JAK2 inhibitors (OR, 3.43), and tyrosine kinase 2 inhibitors (OR, 2.64).
• In a subgroup analysis, risk of acne was higher among patients using JAK inhibitors for dermatologic conditions in comparison with those using JAK inhibitors for nondermatologic conditions (OR, 4.67 vs 1.18).
• Age and gender had no apparent impact on the effect of JAK inhibitor use on acne risk.

IN PRACTICE:

“The occurrence of acne following treatment with certain classes of JAK inhibitors is of potential concern, as this adverse effect may jeopardize treatment adherence among some patients,” the researchers wrote. More studies are needed “to characterize the underlying mechanism of acne with JAK inhibitor use and to identify best practices for treatment,” they added.

SOURCE:

The lead author was Jeremy Martinez, MPH, of Harvard Medical School, Boston. The study was published online in JAMA Dermatology.

LIMITATIONS:

The review was limited by the variable classification and reporting of acne across studies, the potential exclusion of relevant studies, and the small number of studies for certain drugs.

DISCLOSURES:

The studies were mainly funded by the pharmaceutical industry. Mr. Martinez disclosed no relevant financial relationships. Several coauthors have ties with Dexcel Pharma Technologies, AbbVie, Concert, Pfizer, 3Derm Systems, Incyte, Aclaris, Eli Lilly, Concert, Equillium, ASLAN, ACOM, and Boehringer Ingelheim.
 

A version of this article appeared on Medscape.com.

SAN DIEGO – Scientists are seeing positive early results from treating relapsed/refractory T-cell blood cancers with un–gene-edited chimeric antigen receptor (CAR) T-cell therapy, a translational immunologist told colleagues at the annual meeting of the Society for Immunotherapy of Cancer. Some patients have had durable complete remission.

As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”

One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”

Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.

The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”

One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”

The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.

Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.

The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.

Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.

Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”

As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.

The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.

Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.

SAN DIEGO – Scientists are seeing positive early results from treating relapsed/refractory T-cell blood cancers with un–gene-edited chimeric antigen receptor (CAR) T-cell therapy, a translational immunologist told colleagues at the annual meeting of the Society for Immunotherapy of Cancer. Some patients have had durable complete remission.

As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”

One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”

Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.

The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”

One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”

The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.

Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.

The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.

Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.

Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”

As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.

The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.

Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.

SAN DIEGO – Scientists are seeing positive early results from treating relapsed/refractory T-cell blood cancers with un–gene-edited chimeric antigen receptor (CAR) T-cell therapy, a translational immunologist told colleagues at the annual meeting of the Society for Immunotherapy of Cancer. Some patients have had durable complete remission.

As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”

One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”

Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.

The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”

One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”

The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.

Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.

The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.

Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.

Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”

As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.

The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.

Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

CASE Pregnant woman asks about the RSV vaccine

A 28-year-old primigravid woman at 30 weeks’ gestation inquires about the new vaccine to protect her newborn baby against respiratory syncytial virus infection (RSV). Her neighbor’s daughter recently was hospitalized for the treatment of RSV, and she is understandably concerned about her own newborn. The patient is healthy, and she has never had any serious respiratory infection. She is taking no medications other than prenatal vitamins.

What advice should you give her? 

If you decide to administer this vaccine, what is the appropriate timing of administration?

Are there any maternal or fetal safety concerns related to use of this vaccine in pregnancy?
 

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. It is an enveloped, single-stranded RNA virus that is 150-300 nm in size. The virus codes for 10 virus-specific proteins. The 2 most important are the G protein, which enables the virus to attach to host cells, and the F protein, which facilitates the entry of the virus into the host cell by fusing the host and viral membranes. Two distinct subtypes exist: A and B. There is genetic variation within each subtype and between subtypes. These subtle genetic variations create the potential for reinfections, and hence, research has focused on development of a vaccine that covers both subtypes.¹

RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age. In these children, RSV is one of the most prominent causes of death, with mortality particularly marked in low- and middle-resource countries as well as in children who were born premature and/or who are immunocompromised. RSV has its greatest impact during winter epidemics in temperate climates and during the rainy seasons in tropical climates. The virus rarely is encountered in the summer.¹ Among young children, RSV primarily is transmitted via close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. The incubation period of the infection is 4 to 6 days, and viral shedding may persist for 2 weeks or longer. Most patients gradually recover within 1 to 2 weeks.¹ Adults who contract RSV usually have symptoms suggestive of a common cold; however, in older adults or those who have comorbidities, serious and potentially life-threatening lower respiratory tract infections may develop.

Recently, there have been 2 main approaches to the prevention and treatment of RSV in infants. One has been the development of monoclonal antibodies such as motavizumab, palivizumab, and nirsevimab. The other has been the development of a vaccine that could be administered to pregnant women and which could provide protection for the neonate in the early months of life.^2,3

In late August 2023, the US Food and Drug Administration (FDA) announced the approval of a new bivalent RSV prefusion F vaccine (ABRYSVO, Pfizer) intended for administration to pregnant women.⁴ Of note, previous efforts to develop whole-virus vaccines either have been ineffective or have potentiated the disease in infants who became infected; development of an effective vaccine had eluded scientists and clinicians for nearly 50 years.² Thus, the new vaccine that targets the F protein of the virus represents a major and welcomed breakthrough.

This article reviews the 3 most recent investigations that preceded the ultimate approval of this vaccine and discusses specific logistical issues related to vaccine administration.

Continue to: First step toward vaccine approval...

First step toward vaccine approval

Madhi and colleagues⁵ were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.

Intermediate step: Continued assessment of vaccine safety and immunogenicity

The next important step in the development of the RSV vaccine was a study by Simoes et al,⁶ who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.

Final step: Convincing proof of efficacy

The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.⁷ The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.

The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).

In previous reports to the FDA,⁴ the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.

Practical details

The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.⁸ There are no preservatives in the vaccine.

The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.

The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.

CASE Resolution

This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●

CASE Pregnant woman asks about the RSV vaccine

A 28-year-old primigravid woman at 30 weeks’ gestation inquires about the new vaccine to protect her newborn baby against respiratory syncytial virus infection (RSV). Her neighbor’s daughter recently was hospitalized for the treatment of RSV, and she is understandably concerned about her own newborn. The patient is healthy, and she has never had any serious respiratory infection. She is taking no medications other than prenatal vitamins.

What advice should you give her? 

If you decide to administer this vaccine, what is the appropriate timing of administration?

Are there any maternal or fetal safety concerns related to use of this vaccine in pregnancy?
 

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. It is an enveloped, single-stranded RNA virus that is 150-300 nm in size. The virus codes for 10 virus-specific proteins. The 2 most important are the G protein, which enables the virus to attach to host cells, and the F protein, which facilitates the entry of the virus into the host cell by fusing the host and viral membranes. Two distinct subtypes exist: A and B. There is genetic variation within each subtype and between subtypes. These subtle genetic variations create the potential for reinfections, and hence, research has focused on development of a vaccine that covers both subtypes.¹

RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age. In these children, RSV is one of the most prominent causes of death, with mortality particularly marked in low- and middle-resource countries as well as in children who were born premature and/or who are immunocompromised. RSV has its greatest impact during winter epidemics in temperate climates and during the rainy seasons in tropical climates. The virus rarely is encountered in the summer.¹ Among young children, RSV primarily is transmitted via close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. The incubation period of the infection is 4 to 6 days, and viral shedding may persist for 2 weeks or longer. Most patients gradually recover within 1 to 2 weeks.¹ Adults who contract RSV usually have symptoms suggestive of a common cold; however, in older adults or those who have comorbidities, serious and potentially life-threatening lower respiratory tract infections may develop.

Recently, there have been 2 main approaches to the prevention and treatment of RSV in infants. One has been the development of monoclonal antibodies such as motavizumab, palivizumab, and nirsevimab. The other has been the development of a vaccine that could be administered to pregnant women and which could provide protection for the neonate in the early months of life.^2,3

In late August 2023, the US Food and Drug Administration (FDA) announced the approval of a new bivalent RSV prefusion F vaccine (ABRYSVO, Pfizer) intended for administration to pregnant women.⁴ Of note, previous efforts to develop whole-virus vaccines either have been ineffective or have potentiated the disease in infants who became infected; development of an effective vaccine had eluded scientists and clinicians for nearly 50 years.² Thus, the new vaccine that targets the F protein of the virus represents a major and welcomed breakthrough.

This article reviews the 3 most recent investigations that preceded the ultimate approval of this vaccine and discusses specific logistical issues related to vaccine administration.

Continue to: First step toward vaccine approval...

First step toward vaccine approval

Madhi and colleagues⁵ were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.

Intermediate step: Continued assessment of vaccine safety and immunogenicity

The next important step in the development of the RSV vaccine was a study by Simoes et al,⁶ who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.

Final step: Convincing proof of efficacy

The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.⁷ The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.

The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).

In previous reports to the FDA,⁴ the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.

Practical details

The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.⁸ There are no preservatives in the vaccine.

The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.

The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.

CASE Resolution

This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●

CASE Pregnant woman asks about the RSV vaccine

A 28-year-old primigravid woman at 30 weeks’ gestation inquires about the new vaccine to protect her newborn baby against respiratory syncytial virus infection (RSV). Her neighbor’s daughter recently was hospitalized for the treatment of RSV, and she is understandably concerned about her own newborn. The patient is healthy, and she has never had any serious respiratory infection. She is taking no medications other than prenatal vitamins.

What advice should you give her? 

If you decide to administer this vaccine, what is the appropriate timing of administration?

Are there any maternal or fetal safety concerns related to use of this vaccine in pregnancy?
 

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. It is an enveloped, single-stranded RNA virus that is 150-300 nm in size. The virus codes for 10 virus-specific proteins. The 2 most important are the G protein, which enables the virus to attach to host cells, and the F protein, which facilitates the entry of the virus into the host cell by fusing the host and viral membranes. Two distinct subtypes exist: A and B. There is genetic variation within each subtype and between subtypes. These subtle genetic variations create the potential for reinfections, and hence, research has focused on development of a vaccine that covers both subtypes.¹

RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age. In these children, RSV is one of the most prominent causes of death, with mortality particularly marked in low- and middle-resource countries as well as in children who were born premature and/or who are immunocompromised. RSV has its greatest impact during winter epidemics in temperate climates and during the rainy seasons in tropical climates. The virus rarely is encountered in the summer.¹ Among young children, RSV primarily is transmitted via close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. The incubation period of the infection is 4 to 6 days, and viral shedding may persist for 2 weeks or longer. Most patients gradually recover within 1 to 2 weeks.¹ Adults who contract RSV usually have symptoms suggestive of a common cold; however, in older adults or those who have comorbidities, serious and potentially life-threatening lower respiratory tract infections may develop.

Recently, there have been 2 main approaches to the prevention and treatment of RSV in infants. One has been the development of monoclonal antibodies such as motavizumab, palivizumab, and nirsevimab. The other has been the development of a vaccine that could be administered to pregnant women and which could provide protection for the neonate in the early months of life.^2,3

In late August 2023, the US Food and Drug Administration (FDA) announced the approval of a new bivalent RSV prefusion F vaccine (ABRYSVO, Pfizer) intended for administration to pregnant women.⁴ Of note, previous efforts to develop whole-virus vaccines either have been ineffective or have potentiated the disease in infants who became infected; development of an effective vaccine had eluded scientists and clinicians for nearly 50 years.² Thus, the new vaccine that targets the F protein of the virus represents a major and welcomed breakthrough.

This article reviews the 3 most recent investigations that preceded the ultimate approval of this vaccine and discusses specific logistical issues related to vaccine administration.

Continue to: First step toward vaccine approval...

First step toward vaccine approval

Madhi and colleagues⁵ were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.

Intermediate step: Continued assessment of vaccine safety and immunogenicity

The next important step in the development of the RSV vaccine was a study by Simoes et al,⁶ who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.

Final step: Convincing proof of efficacy

The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.⁷ The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.

The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).

In previous reports to the FDA,⁴ the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.

Practical details

The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.⁸ There are no preservatives in the vaccine.

The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.

The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.

CASE Resolution

This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●

Routine screenings for signs of cavities and gum disease by primary care clinicians may not catch patients most at risk of these conditions, according to a statement by the U.S. Preventive Services Task Force (USPSTF) that was published in JAMA.

Suggesting ways to improve oral health also may fail to engage the patients who most need the message, the group said in its statement.

The task force is not suggesting that primary care providers stop all oral health screening of adults or that they never discuss ways to improve oral health. But the current evidence of the most effective oral health screenings or enhancement strategies in primary care settings received an “I” rating, for “Inconclusive.” The highest ranking a screening can receive is an “A” or “B,” which indicate that there is strong evidence for conducting a screening, while a “C” would indicate that clinicians could rarely provide a screening, and a “D” would indicate not to, given the current evidence.

Primary care clinicians should immediately refer any patients with apparent caries or gum disease to a dentist, the USPSTF noted. But what clinicians should do for patients who have no obvious oral health problems is up for debate.

“The ‘I’ is a note about where the evidence is at this point and then a call for more research to see if we can’t get some more clarity for next time,” said John Ruiz, PhD, professor of clinical psychology at the University of Arizona, Tucson, who is a member of the task force.

More than 90% of U.S. adults may have caries, including 26% with untreated caries that can cause serious infections or tooth loss. In addition, 42% of adults have some type of gum disease. More than two-thirds of Americans aged 65 or older have gum disease, and it is the leading cause of tooth loss in this population. People earning low incomes and those who do not have health insurance or who belong to a marginalized racial or ethnic group are at greater risk of the harms of caries and gum disease.

“Oral health care is important to overall health,” and any new research on oral health screening and enhancement efforts should be demographically representative of adults affected by these conditions, Dr. Ruiz said.

In an accompanying editorial, oral health researchers from the National Institutes of Health and the University of California, San Francisco, echoed the call for representative research and encouraged closer collaboration between primary care providers and dentists to promote oral health.

“Oral health screening and referral by medical primary care clinicians can help ensure that individuals get to the dental chair to receive needed interventions that can benefit both oral and potentially overall health,” the authors wrote. “Likewise, medical challenges and oral mucosal manifestations of chronic health conditions detected at a dental visit should result in medical referral, allowing prompt evaluation and treatment.”
 

Lack of data

The USPSTF defined oral health screenings for patients older than 18 who have no obvious signs of caries or gum disease as looking at a patient’s mouth during physical exams. Additionally, clinicians might use prediction models to identify patients at greater risk of facing these problems.

Strategies to improve oral health include providing encouragement to patients to reduce intake of refined sugar, to floss and brush effectively to reduce bacteria, and to use fluoride gels, fluoride varnishes, or other kinds of sealants to make caries harder to form.

A literature review found that there has been limited analysis of primary care clinicians performing these tasks. Perhaps unsurprisingly, more such studies about dentists existed, leaving an open field for dedicated studies about what primary care clinicians should do to optimize oral health with patients.

“Clinicians, in the absence of clear guidelines, should continue to use their best judgment,” Dr. Ruiz said.

One dentist interviewed said screening could be as simple as doctors asking patients how often they brush their teeth and giving patients a toothbrush as part of the office visit.

“It all comes down to, ‘Is the person brushing their teeth?’ ” said Jennifer Hartshorn, DDS, who specializes in community and preventive dentistry at the University of Iowa, Iowa City.

“By all means look in their mouth, ask how much they are brushing, and urge them to find a dental home if at all possible,” Dr. Hartshorn said, especially for patients who smoke or have conditions such as dry mouth, which can increase the risk of oral disease.

Dr. Ruiz and Dr. Hartshorn report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Routine screenings for signs of cavities and gum disease by primary care clinicians may not catch patients most at risk of these conditions, according to a statement by the U.S. Preventive Services Task Force (USPSTF) that was published in JAMA.

Suggesting ways to improve oral health also may fail to engage the patients who most need the message, the group said in its statement.

The task force is not suggesting that primary care providers stop all oral health screening of adults or that they never discuss ways to improve oral health. But the current evidence of the most effective oral health screenings or enhancement strategies in primary care settings received an “I” rating, for “Inconclusive.” The highest ranking a screening can receive is an “A” or “B,” which indicate that there is strong evidence for conducting a screening, while a “C” would indicate that clinicians could rarely provide a screening, and a “D” would indicate not to, given the current evidence.

Primary care clinicians should immediately refer any patients with apparent caries or gum disease to a dentist, the USPSTF noted. But what clinicians should do for patients who have no obvious oral health problems is up for debate.

“The ‘I’ is a note about where the evidence is at this point and then a call for more research to see if we can’t get some more clarity for next time,” said John Ruiz, PhD, professor of clinical psychology at the University of Arizona, Tucson, who is a member of the task force.

More than 90% of U.S. adults may have caries, including 26% with untreated caries that can cause serious infections or tooth loss. In addition, 42% of adults have some type of gum disease. More than two-thirds of Americans aged 65 or older have gum disease, and it is the leading cause of tooth loss in this population. People earning low incomes and those who do not have health insurance or who belong to a marginalized racial or ethnic group are at greater risk of the harms of caries and gum disease.

“Oral health care is important to overall health,” and any new research on oral health screening and enhancement efforts should be demographically representative of adults affected by these conditions, Dr. Ruiz said.

In an accompanying editorial, oral health researchers from the National Institutes of Health and the University of California, San Francisco, echoed the call for representative research and encouraged closer collaboration between primary care providers and dentists to promote oral health.

“Oral health screening and referral by medical primary care clinicians can help ensure that individuals get to the dental chair to receive needed interventions that can benefit both oral and potentially overall health,” the authors wrote. “Likewise, medical challenges and oral mucosal manifestations of chronic health conditions detected at a dental visit should result in medical referral, allowing prompt evaluation and treatment.”
 

Lack of data

The USPSTF defined oral health screenings for patients older than 18 who have no obvious signs of caries or gum disease as looking at a patient’s mouth during physical exams. Additionally, clinicians might use prediction models to identify patients at greater risk of facing these problems.

Strategies to improve oral health include providing encouragement to patients to reduce intake of refined sugar, to floss and brush effectively to reduce bacteria, and to use fluoride gels, fluoride varnishes, or other kinds of sealants to make caries harder to form.

A literature review found that there has been limited analysis of primary care clinicians performing these tasks. Perhaps unsurprisingly, more such studies about dentists existed, leaving an open field for dedicated studies about what primary care clinicians should do to optimize oral health with patients.

“Clinicians, in the absence of clear guidelines, should continue to use their best judgment,” Dr. Ruiz said.

One dentist interviewed said screening could be as simple as doctors asking patients how often they brush their teeth and giving patients a toothbrush as part of the office visit.

“It all comes down to, ‘Is the person brushing their teeth?’ ” said Jennifer Hartshorn, DDS, who specializes in community and preventive dentistry at the University of Iowa, Iowa City.

“By all means look in their mouth, ask how much they are brushing, and urge them to find a dental home if at all possible,” Dr. Hartshorn said, especially for patients who smoke or have conditions such as dry mouth, which can increase the risk of oral disease.

Dr. Ruiz and Dr. Hartshorn report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Routine screenings for signs of cavities and gum disease by primary care clinicians may not catch patients most at risk of these conditions, according to a statement by the U.S. Preventive Services Task Force (USPSTF) that was published in JAMA.

Suggesting ways to improve oral health also may fail to engage the patients who most need the message, the group said in its statement.

The task force is not suggesting that primary care providers stop all oral health screening of adults or that they never discuss ways to improve oral health. But the current evidence of the most effective oral health screenings or enhancement strategies in primary care settings received an “I” rating, for “Inconclusive.” The highest ranking a screening can receive is an “A” or “B,” which indicate that there is strong evidence for conducting a screening, while a “C” would indicate that clinicians could rarely provide a screening, and a “D” would indicate not to, given the current evidence.

Primary care clinicians should immediately refer any patients with apparent caries or gum disease to a dentist, the USPSTF noted. But what clinicians should do for patients who have no obvious oral health problems is up for debate.

“The ‘I’ is a note about where the evidence is at this point and then a call for more research to see if we can’t get some more clarity for next time,” said John Ruiz, PhD, professor of clinical psychology at the University of Arizona, Tucson, who is a member of the task force.

More than 90% of U.S. adults may have caries, including 26% with untreated caries that can cause serious infections or tooth loss. In addition, 42% of adults have some type of gum disease. More than two-thirds of Americans aged 65 or older have gum disease, and it is the leading cause of tooth loss in this population. People earning low incomes and those who do not have health insurance or who belong to a marginalized racial or ethnic group are at greater risk of the harms of caries and gum disease.

“Oral health care is important to overall health,” and any new research on oral health screening and enhancement efforts should be demographically representative of adults affected by these conditions, Dr. Ruiz said.

In an accompanying editorial, oral health researchers from the National Institutes of Health and the University of California, San Francisco, echoed the call for representative research and encouraged closer collaboration between primary care providers and dentists to promote oral health.

“Oral health screening and referral by medical primary care clinicians can help ensure that individuals get to the dental chair to receive needed interventions that can benefit both oral and potentially overall health,” the authors wrote. “Likewise, medical challenges and oral mucosal manifestations of chronic health conditions detected at a dental visit should result in medical referral, allowing prompt evaluation and treatment.”
 

Lack of data

The USPSTF defined oral health screenings for patients older than 18 who have no obvious signs of caries or gum disease as looking at a patient’s mouth during physical exams. Additionally, clinicians might use prediction models to identify patients at greater risk of facing these problems.

Strategies to improve oral health include providing encouragement to patients to reduce intake of refined sugar, to floss and brush effectively to reduce bacteria, and to use fluoride gels, fluoride varnishes, or other kinds of sealants to make caries harder to form.

A literature review found that there has been limited analysis of primary care clinicians performing these tasks. Perhaps unsurprisingly, more such studies about dentists existed, leaving an open field for dedicated studies about what primary care clinicians should do to optimize oral health with patients.

“Clinicians, in the absence of clear guidelines, should continue to use their best judgment,” Dr. Ruiz said.

One dentist interviewed said screening could be as simple as doctors asking patients how often they brush their teeth and giving patients a toothbrush as part of the office visit.

“It all comes down to, ‘Is the person brushing their teeth?’ ” said Jennifer Hartshorn, DDS, who specializes in community and preventive dentistry at the University of Iowa, Iowa City.

“By all means look in their mouth, ask how much they are brushing, and urge them to find a dental home if at all possible,” Dr. Hartshorn said, especially for patients who smoke or have conditions such as dry mouth, which can increase the risk of oral disease.

Dr. Ruiz and Dr. Hartshorn report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Endoscopy centers may be able to improve their adenoma detection rate (ADR) by employing report cards and ensuring that each procedure is attended by an additional observer, according to results of a recent meta-analysis.

Although multimodal interventions like extra training with periodic feedback showed some signs of improving ADR, withdrawal time monitoring was not significantly associated with a better detection rate, reported Anshul Arora, MD, of Western University, London, Ont., and colleagues.

“Given the increased risk of postcolonoscopy colorectal cancer associated with low ADR, improving [this performance metric] has become a major focus for quality improvement,” the investigators wrote in Clinical Gastroenterology and Hepatology.

They noted that “numerous strategies” have been evaluated for this purpose, which may be sorted into three groups: endoscopy unit–level interventions (i.e., system changes), procedure-targeted interventions (i.e., technique changes), and technology-based interventions.

“Of these categories, endoscopy unit–level interventions are perhaps the easiest to implement widely because they generally require fewer changes in the technical aspect of how a colonoscopy is performed,” the investigators wrote. “Thus, the objective of this study was to conduct a systematic review and meta-analysis to identify endoscopy unit–level interventions aimed at improving ADRs and their effectiveness.”

To this end, Dr. Arora and colleagues analyzed data from 34 randomized controlled trials and observational studies involving 1,501 endoscopists and 371,041 procedures. They evaluated the relationship between ADR and implementation of four interventions: a performance report card, a multimodal intervention (e.g., training sessions with periodic feedback), presence of an additional observer, and withdrawal time monitoring.

Provision of report cards was associated with the greatest improvement in ADR, at 28% (odds ratio, 1.28; 95% confidence interval, 1.13-1.45; P less than .001), followed by presence of an additional observer, which bumped ADR by 25% (OR, 1.25; 95% CI, 1.09-1.43; P = .002). The impact of multimodal interventions was “borderline significant,” the investigators wrote, with an 18% improvement in ADR (OR, 1.18; 95% CI, 1.00-1.40; P = .05). In contrast, withdrawal time monitoring showed no significant benefit (OR, 1.35; 95% CI, 0.93-1.96; P = .11).

In their discussion, Dr. Arora and colleagues offered guidance on the use of report cards, which were associated with the greatest improvement in ADR.

“We found that benchmarking individual endoscopists against their peers was important for improving ADR performance because this was the common thread among all report card–based interventions,” they wrote. “In terms of the method of delivery for feedback, only one study used public reporting of colonoscopy quality indicators, whereas the rest delivered report cards privately to physicians. This suggests that confidential feedback did not impede self-improvement, which is desirable to avoid stigmatization of low ADR performers.”

The findings also suggest that additional observers can boost ADR without specialized training.

“[The benefit of an additional observer] may be explained by the presence of a second set of eyes to identify polyps or, more pragmatically, by the Hawthorne effect, whereby endoscopists may be more careful because they know someone else is watching the screen,” the investigators wrote. “Regardless, extra training for the observer does not seem to be necessary because the three RCTs [evaluating this intervention] all used endoscopy nurses who did not receive any additional polyp detection training. Thus, endoscopy unit nurses should be encouraged to speak up should they see a polyp the endoscopist missed.”

The investigators disclosed no conflicts of interest.

Endoscopy centers may be able to improve their adenoma detection rate (ADR) by employing report cards and ensuring that each procedure is attended by an additional observer, according to results of a recent meta-analysis.

Although multimodal interventions like extra training with periodic feedback showed some signs of improving ADR, withdrawal time monitoring was not significantly associated with a better detection rate, reported Anshul Arora, MD, of Western University, London, Ont., and colleagues.

“Given the increased risk of postcolonoscopy colorectal cancer associated with low ADR, improving [this performance metric] has become a major focus for quality improvement,” the investigators wrote in Clinical Gastroenterology and Hepatology.

They noted that “numerous strategies” have been evaluated for this purpose, which may be sorted into three groups: endoscopy unit–level interventions (i.e., system changes), procedure-targeted interventions (i.e., technique changes), and technology-based interventions.

“Of these categories, endoscopy unit–level interventions are perhaps the easiest to implement widely because they generally require fewer changes in the technical aspect of how a colonoscopy is performed,” the investigators wrote. “Thus, the objective of this study was to conduct a systematic review and meta-analysis to identify endoscopy unit–level interventions aimed at improving ADRs and their effectiveness.”

To this end, Dr. Arora and colleagues analyzed data from 34 randomized controlled trials and observational studies involving 1,501 endoscopists and 371,041 procedures. They evaluated the relationship between ADR and implementation of four interventions: a performance report card, a multimodal intervention (e.g., training sessions with periodic feedback), presence of an additional observer, and withdrawal time monitoring.

Provision of report cards was associated with the greatest improvement in ADR, at 28% (odds ratio, 1.28; 95% confidence interval, 1.13-1.45; P less than .001), followed by presence of an additional observer, which bumped ADR by 25% (OR, 1.25; 95% CI, 1.09-1.43; P = .002). The impact of multimodal interventions was “borderline significant,” the investigators wrote, with an 18% improvement in ADR (OR, 1.18; 95% CI, 1.00-1.40; P = .05). In contrast, withdrawal time monitoring showed no significant benefit (OR, 1.35; 95% CI, 0.93-1.96; P = .11).

In their discussion, Dr. Arora and colleagues offered guidance on the use of report cards, which were associated with the greatest improvement in ADR.

“We found that benchmarking individual endoscopists against their peers was important for improving ADR performance because this was the common thread among all report card–based interventions,” they wrote. “In terms of the method of delivery for feedback, only one study used public reporting of colonoscopy quality indicators, whereas the rest delivered report cards privately to physicians. This suggests that confidential feedback did not impede self-improvement, which is desirable to avoid stigmatization of low ADR performers.”

The findings also suggest that additional observers can boost ADR without specialized training.

“[The benefit of an additional observer] may be explained by the presence of a second set of eyes to identify polyps or, more pragmatically, by the Hawthorne effect, whereby endoscopists may be more careful because they know someone else is watching the screen,” the investigators wrote. “Regardless, extra training for the observer does not seem to be necessary because the three RCTs [evaluating this intervention] all used endoscopy nurses who did not receive any additional polyp detection training. Thus, endoscopy unit nurses should be encouraged to speak up should they see a polyp the endoscopist missed.”

The investigators disclosed no conflicts of interest.

Endoscopy centers may be able to improve their adenoma detection rate (ADR) by employing report cards and ensuring that each procedure is attended by an additional observer, according to results of a recent meta-analysis.

Although multimodal interventions like extra training with periodic feedback showed some signs of improving ADR, withdrawal time monitoring was not significantly associated with a better detection rate, reported Anshul Arora, MD, of Western University, London, Ont., and colleagues.

“Given the increased risk of postcolonoscopy colorectal cancer associated with low ADR, improving [this performance metric] has become a major focus for quality improvement,” the investigators wrote in Clinical Gastroenterology and Hepatology.

They noted that “numerous strategies” have been evaluated for this purpose, which may be sorted into three groups: endoscopy unit–level interventions (i.e., system changes), procedure-targeted interventions (i.e., technique changes), and technology-based interventions.

“Of these categories, endoscopy unit–level interventions are perhaps the easiest to implement widely because they generally require fewer changes in the technical aspect of how a colonoscopy is performed,” the investigators wrote. “Thus, the objective of this study was to conduct a systematic review and meta-analysis to identify endoscopy unit–level interventions aimed at improving ADRs and their effectiveness.”

To this end, Dr. Arora and colleagues analyzed data from 34 randomized controlled trials and observational studies involving 1,501 endoscopists and 371,041 procedures. They evaluated the relationship between ADR and implementation of four interventions: a performance report card, a multimodal intervention (e.g., training sessions with periodic feedback), presence of an additional observer, and withdrawal time monitoring.

Provision of report cards was associated with the greatest improvement in ADR, at 28% (odds ratio, 1.28; 95% confidence interval, 1.13-1.45; P less than .001), followed by presence of an additional observer, which bumped ADR by 25% (OR, 1.25; 95% CI, 1.09-1.43; P = .002). The impact of multimodal interventions was “borderline significant,” the investigators wrote, with an 18% improvement in ADR (OR, 1.18; 95% CI, 1.00-1.40; P = .05). In contrast, withdrawal time monitoring showed no significant benefit (OR, 1.35; 95% CI, 0.93-1.96; P = .11).

In their discussion, Dr. Arora and colleagues offered guidance on the use of report cards, which were associated with the greatest improvement in ADR.

“We found that benchmarking individual endoscopists against their peers was important for improving ADR performance because this was the common thread among all report card–based interventions,” they wrote. “In terms of the method of delivery for feedback, only one study used public reporting of colonoscopy quality indicators, whereas the rest delivered report cards privately to physicians. This suggests that confidential feedback did not impede self-improvement, which is desirable to avoid stigmatization of low ADR performers.”

The findings also suggest that additional observers can boost ADR without specialized training.

“[The benefit of an additional observer] may be explained by the presence of a second set of eyes to identify polyps or, more pragmatically, by the Hawthorne effect, whereby endoscopists may be more careful because they know someone else is watching the screen,” the investigators wrote. “Regardless, extra training for the observer does not seem to be necessary because the three RCTs [evaluating this intervention] all used endoscopy nurses who did not receive any additional polyp detection training. Thus, endoscopy unit nurses should be encouraged to speak up should they see a polyp the endoscopist missed.”

The investigators disclosed no conflicts of interest.

SAN FRANCISCO – Stopping aspirin within 1 month of implanting a drug-eluting stent (DES) for acute coronary syndrome (ACS) followed by ticagrelor monotherapy was shown to be noninferior to 12 months of dual antiplatelet therapy (DAPT) in net adverse cardiovascular and bleeding events in the T-PASS trial.

“Less than 1 month of DAPT followed by ticagrelor monotherapy met a noninferiority threshold and provided evidence of superiority to 12 months of ticagrelor-based DAPT for a 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily due to a significant reduction in bleeding events,” senior author Myeong-Ki Hong, MD, PhD, Yonsei University, Seoul, Korea, told attendees at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.

“This study provides evidence that stopping aspirin within 1 month after implantation of drug-eluting stents for ticagrelor monotherapy is a reasonable alternative to 12-month DAPT as for adverse cardiovascular and bleeding events,” Dr. Hong concluded.

The study was published in Circulation ahead of print to coincide with the presentation.
 

Three months to 1 month

Previous trials (TICO and TWILIGHT) have shown that ticagrelor monotherapy after 3 months of DAPT can be safe and effectively prevent ischemic events after percutaneous coronary intervention (PCI) in ACS or high-risk PCI patients.

The current study aimed to investigate whether ticagrelor monotherapy after less than 1 month of DAPT was noninferior to 12 months of ticagrelor-based DAPT for preventing adverse cardiovascular and bleeding events in patients with ACS undergoing PCI with a DES implant.

T-PASS, carried out at 24 centers in Korea, enrolled ACS patients aged 19 years or older who received an ultrathin, bioresorbable polymer sirolimus-eluting stent (Orsiro, Biotronik). They were randomized 1:1 to ticagrelor monotherapy after less than 1 month of DAPT (n = 1,426) or to ticagrelor-based DAPT for 12 months (n = 1,424).

The primary outcome measure was net adverse clinical events (NACE) at 12 months, consisting of major bleeding plus major adverse cardiovascular events. All patients were included in the intention-to-treat analysis.

The study could enroll patients aged 19-80 years. It excluded anyone with active bleeding, at increased risk for bleeding, with anemia (hemoglobin ≤ 8 g/dL), platelets less than 100,000/mcL, need for oral anticoagulation therapy, current or potential pregnancy, or a life expectancy less than 1 year.

Baseline characteristics of the two groups were well balanced. The extended monotherapy and DAPT arms had an average age of 61 ± 10 years, were 84% and 83% male and had diabetes mellitus in 30% and 29%, respectively, with 74% of each group admitted via the emergency room. ST-elevation myocardial infarction occurred in 40% and 41% of patients in each group, respectively.

Results showed that stopping aspirin early was noninferior and possibly superior to 12 months of DAPT.

For the 12-month clinical outcome, fewer patients in the less than 1 month DAPT followed by ticagrelor monotherapy arm reached the primary clinical endpoint of NACE versus the ticagrelor-based 12-month DAPT arm, both in terms of noninferiority (P < .001) and superiority (P = .002). Similar results were found for the 1-month landmark analyses.

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – Stopping aspirin within 1 month of implanting a drug-eluting stent (DES) for acute coronary syndrome (ACS) followed by ticagrelor monotherapy was shown to be noninferior to 12 months of dual antiplatelet therapy (DAPT) in net adverse cardiovascular and bleeding events in the T-PASS trial.

“Less than 1 month of DAPT followed by ticagrelor monotherapy met a noninferiority threshold and provided evidence of superiority to 12 months of ticagrelor-based DAPT for a 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily due to a significant reduction in bleeding events,” senior author Myeong-Ki Hong, MD, PhD, Yonsei University, Seoul, Korea, told attendees at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.

“This study provides evidence that stopping aspirin within 1 month after implantation of drug-eluting stents for ticagrelor monotherapy is a reasonable alternative to 12-month DAPT as for adverse cardiovascular and bleeding events,” Dr. Hong concluded.

The study was published in Circulation ahead of print to coincide with the presentation.
 

Three months to 1 month

Previous trials (TICO and TWILIGHT) have shown that ticagrelor monotherapy after 3 months of DAPT can be safe and effectively prevent ischemic events after percutaneous coronary intervention (PCI) in ACS or high-risk PCI patients.

The current study aimed to investigate whether ticagrelor monotherapy after less than 1 month of DAPT was noninferior to 12 months of ticagrelor-based DAPT for preventing adverse cardiovascular and bleeding events in patients with ACS undergoing PCI with a DES implant.

T-PASS, carried out at 24 centers in Korea, enrolled ACS patients aged 19 years or older who received an ultrathin, bioresorbable polymer sirolimus-eluting stent (Orsiro, Biotronik). They were randomized 1:1 to ticagrelor monotherapy after less than 1 month of DAPT (n = 1,426) or to ticagrelor-based DAPT for 12 months (n = 1,424).

The primary outcome measure was net adverse clinical events (NACE) at 12 months, consisting of major bleeding plus major adverse cardiovascular events. All patients were included in the intention-to-treat analysis.

The study could enroll patients aged 19-80 years. It excluded anyone with active bleeding, at increased risk for bleeding, with anemia (hemoglobin ≤ 8 g/dL), platelets less than 100,000/mcL, need for oral anticoagulation therapy, current or potential pregnancy, or a life expectancy less than 1 year.

Baseline characteristics of the two groups were well balanced. The extended monotherapy and DAPT arms had an average age of 61 ± 10 years, were 84% and 83% male and had diabetes mellitus in 30% and 29%, respectively, with 74% of each group admitted via the emergency room. ST-elevation myocardial infarction occurred in 40% and 41% of patients in each group, respectively.

Results showed that stopping aspirin early was noninferior and possibly superior to 12 months of DAPT.

For the 12-month clinical outcome, fewer patients in the less than 1 month DAPT followed by ticagrelor monotherapy arm reached the primary clinical endpoint of NACE versus the ticagrelor-based 12-month DAPT arm, both in terms of noninferiority (P < .001) and superiority (P = .002). Similar results were found for the 1-month landmark analyses.

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – Stopping aspirin within 1 month of implanting a drug-eluting stent (DES) for acute coronary syndrome (ACS) followed by ticagrelor monotherapy was shown to be noninferior to 12 months of dual antiplatelet therapy (DAPT) in net adverse cardiovascular and bleeding events in the T-PASS trial.

“Less than 1 month of DAPT followed by ticagrelor monotherapy met a noninferiority threshold and provided evidence of superiority to 12 months of ticagrelor-based DAPT for a 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily due to a significant reduction in bleeding events,” senior author Myeong-Ki Hong, MD, PhD, Yonsei University, Seoul, Korea, told attendees at the Transcatheter Cardiovascular Therapeutics annual meeting, sponsored by the Cardiovascular Research Foundation.

“This study provides evidence that stopping aspirin within 1 month after implantation of drug-eluting stents for ticagrelor monotherapy is a reasonable alternative to 12-month DAPT as for adverse cardiovascular and bleeding events,” Dr. Hong concluded.

The study was published in Circulation ahead of print to coincide with the presentation.
 

Three months to 1 month

Previous trials (TICO and TWILIGHT) have shown that ticagrelor monotherapy after 3 months of DAPT can be safe and effectively prevent ischemic events after percutaneous coronary intervention (PCI) in ACS or high-risk PCI patients.

The current study aimed to investigate whether ticagrelor monotherapy after less than 1 month of DAPT was noninferior to 12 months of ticagrelor-based DAPT for preventing adverse cardiovascular and bleeding events in patients with ACS undergoing PCI with a DES implant.

T-PASS, carried out at 24 centers in Korea, enrolled ACS patients aged 19 years or older who received an ultrathin, bioresorbable polymer sirolimus-eluting stent (Orsiro, Biotronik). They were randomized 1:1 to ticagrelor monotherapy after less than 1 month of DAPT (n = 1,426) or to ticagrelor-based DAPT for 12 months (n = 1,424).

The primary outcome measure was net adverse clinical events (NACE) at 12 months, consisting of major bleeding plus major adverse cardiovascular events. All patients were included in the intention-to-treat analysis.

The study could enroll patients aged 19-80 years. It excluded anyone with active bleeding, at increased risk for bleeding, with anemia (hemoglobin ≤ 8 g/dL), platelets less than 100,000/mcL, need for oral anticoagulation therapy, current or potential pregnancy, or a life expectancy less than 1 year.

Baseline characteristics of the two groups were well balanced. The extended monotherapy and DAPT arms had an average age of 61 ± 10 years, were 84% and 83% male and had diabetes mellitus in 30% and 29%, respectively, with 74% of each group admitted via the emergency room. ST-elevation myocardial infarction occurred in 40% and 41% of patients in each group, respectively.

Results showed that stopping aspirin early was noninferior and possibly superior to 12 months of DAPT.

For the 12-month clinical outcome, fewer patients in the less than 1 month DAPT followed by ticagrelor monotherapy arm reached the primary clinical endpoint of NACE versus the ticagrelor-based 12-month DAPT arm, both in terms of noninferiority (P < .001) and superiority (P = .002). Similar results were found for the 1-month landmark analyses.

A version of this article first appeared on Medscape.com.