Article

Important psoriatic arthritis (PsA) clinical studies published last month have focused on clinical trials. Several highly efficacious targeted therapies are now available for PsA. However, comparative effectiveness of the various drugs is less well known.

Matching adjusted indirect comparison is one method of evaluating comparative effectiveness. To compare the efficacy between bimekizumab, an interleukin (IL) 17A/F inhibitor and risankizumab, an IL-23 inhibitor, Mease et al conducted such a study using data from four phase 3 trials (BE OPTIMAL, BE COMPLETE, KEEPsAKE-1, and KEEPsAKE-2) involving patients who were biologic-naive or inadequate responders to tumour necrosis factor (TNF) inhibitors  who received bimekizumab (n = 698) or risankizumab (n = 589).¹
 

At week 52, bimekizumab led to a higher likelihood of achieving a ≥ 70% improvement in the American College of Rheumatology (ACR) response in patients who were biologic-naive and TNF inhibitor inadequate responders (TNFi-IR), compared with risankizumab. Bimekizumab also had greater odds of achieving minimal disease activity in patients who were TNFi-IR. Thus, bimekizumab may be superior to risankizumab for treating those with PsA. Randomized controlled head-to-head clinical trials are required to confirm these findings.

In regard to long-term safety and efficacy of bimekizumab, Mease et al reported that bimekizumab demonstrated consistent safety and sustained efficacy for up to 2 years in patients with PsA.² In this open-label extension (BE VITAL) of two phase 3 trials that included biologic-naive (n = 852) and TNFi-IR (n = 400) patients with PsA who were randomly assigned to receive bimekizumab, placebo with crossover to bimekizumab at week 16, or adalimumab followed by bimekizumab at week 52, no new safety signals were noted from weeks 52 to 104,. SARS-CoV-2 infection was the most common treatment-emergent adverse event. Approximately 50% of biologic-naive and TNFi-IR patients maintained a 50% or greater improvement in the ACR response.

Guselkumab, another IL-23 inhibitor, has proven efficacy in treating PsA. Curtis et al investigated the impact of early achievement of improvement with guselkumab and longer-term outcomes.³ This was a post hoc analysis of two phase 3 trials, DISCOVER-1 and DISCOVER-2, which included 1120 patients with active PsA who received guselkumab every 4 or 8 weeks (Q4W) or placebo with a crossover to guselkumab Q4W at week 24. The study demonstrated that guselkumab led to early achievement of minimal clinically important improvement (MCII) in clinical disease activity index for PsA (cDAPSA), with higher response rates at week 4 compared with placebo. Moreover, achieving early MCII in cDAPSA was associated with sustained disease control at weeks 24 and 52. Thus, guselkumab treatment achieved MCII in cDAPSA after the first dose and sustained disease control for up to 1 year. Early treatment response and a proven safety record make guselkumab an attractive treatment option for PsA.

PsA clinical trials mostly include patients with polyarthritis. Little is known about treatment efficacy for oligoarticular PsA. To address this gap in knowledge, Gossec et al reported the results of the phase 4 FOREMOST trial that included 308 patients with early (symptom duration 5 years or less) targeted therapy–naive oligoarticular PsA and were randomly assigned to receive apremilast (n = 203) or placebo (n = 105).⁴ At week 16, a higher proportion of patients receiving apremilast achieved minimal disease activity (joints response) compared with those receiving placebo. No new safety signals were reported. Apremilast is thus efficacious in treating early oligoarticular PsA as well as polyarticular PsA and psoriasis. Similar studies with other targeted therapies will help clinicians better manage early oligoarticular PsA.

References

1. Mease PJ, Warren RB, Nash P, et al. Comparative effectiveness of bimekizumab and risankizumab in patients with psoriatic arthritis at 52 weeks assessed using a matching-adjusted indirect comparison. Rheumatol Ther. 2024 Aug 9. Source
2. Mease PJ, Merola JF, Tanaka Y, et al. Safety and efficacy of bimekizumab in patients with psoriatic arthritis: 2-year results from two phase 3 studies. Rheumatol Ther. 2024 Aug 31. Source
3. Curtis JR, et al. Early improvements with guselkumab associate with sustained control of psoriatic arthritis: post hoc analyses of two phase 3 trials. Rheumatol Ther. 2024 Sep 11. Source
4. Gossec L, Coates LC, Gladman DD, et al. Treatment of early oligoarticular psoriatic arthritis with apremilast: primary outcomes at week 16 from the FOREMOST randomised controlled trial. Ann Rheum Dis. 2024 Sep 16:ard-2024-225833. Source

Important psoriatic arthritis (PsA) clinical studies published last month have focused on clinical trials. Several highly efficacious targeted therapies are now available for PsA. However, comparative effectiveness of the various drugs is less well known.

Matching adjusted indirect comparison is one method of evaluating comparative effectiveness. To compare the efficacy between bimekizumab, an interleukin (IL) 17A/F inhibitor and risankizumab, an IL-23 inhibitor, Mease et al conducted such a study using data from four phase 3 trials (BE OPTIMAL, BE COMPLETE, KEEPsAKE-1, and KEEPsAKE-2) involving patients who were biologic-naive or inadequate responders to tumour necrosis factor (TNF) inhibitors  who received bimekizumab (n = 698) or risankizumab (n = 589).¹
 

At week 52, bimekizumab led to a higher likelihood of achieving a ≥ 70% improvement in the American College of Rheumatology (ACR) response in patients who were biologic-naive and TNF inhibitor inadequate responders (TNFi-IR), compared with risankizumab. Bimekizumab also had greater odds of achieving minimal disease activity in patients who were TNFi-IR. Thus, bimekizumab may be superior to risankizumab for treating those with PsA. Randomized controlled head-to-head clinical trials are required to confirm these findings.

In regard to long-term safety and efficacy of bimekizumab, Mease et al reported that bimekizumab demonstrated consistent safety and sustained efficacy for up to 2 years in patients with PsA.² In this open-label extension (BE VITAL) of two phase 3 trials that included biologic-naive (n = 852) and TNFi-IR (n = 400) patients with PsA who were randomly assigned to receive bimekizumab, placebo with crossover to bimekizumab at week 16, or adalimumab followed by bimekizumab at week 52, no new safety signals were noted from weeks 52 to 104,. SARS-CoV-2 infection was the most common treatment-emergent adverse event. Approximately 50% of biologic-naive and TNFi-IR patients maintained a 50% or greater improvement in the ACR response.

Guselkumab, another IL-23 inhibitor, has proven efficacy in treating PsA. Curtis et al investigated the impact of early achievement of improvement with guselkumab and longer-term outcomes.³ This was a post hoc analysis of two phase 3 trials, DISCOVER-1 and DISCOVER-2, which included 1120 patients with active PsA who received guselkumab every 4 or 8 weeks (Q4W) or placebo with a crossover to guselkumab Q4W at week 24. The study demonstrated that guselkumab led to early achievement of minimal clinically important improvement (MCII) in clinical disease activity index for PsA (cDAPSA), with higher response rates at week 4 compared with placebo. Moreover, achieving early MCII in cDAPSA was associated with sustained disease control at weeks 24 and 52. Thus, guselkumab treatment achieved MCII in cDAPSA after the first dose and sustained disease control for up to 1 year. Early treatment response and a proven safety record make guselkumab an attractive treatment option for PsA.

PsA clinical trials mostly include patients with polyarthritis. Little is known about treatment efficacy for oligoarticular PsA. To address this gap in knowledge, Gossec et al reported the results of the phase 4 FOREMOST trial that included 308 patients with early (symptom duration 5 years or less) targeted therapy–naive oligoarticular PsA and were randomly assigned to receive apremilast (n = 203) or placebo (n = 105).⁴ At week 16, a higher proportion of patients receiving apremilast achieved minimal disease activity (joints response) compared with those receiving placebo. No new safety signals were reported. Apremilast is thus efficacious in treating early oligoarticular PsA as well as polyarticular PsA and psoriasis. Similar studies with other targeted therapies will help clinicians better manage early oligoarticular PsA.

References

1. Mease PJ, Warren RB, Nash P, et al. Comparative effectiveness of bimekizumab and risankizumab in patients with psoriatic arthritis at 52 weeks assessed using a matching-adjusted indirect comparison. Rheumatol Ther. 2024 Aug 9. Source
2. Mease PJ, Merola JF, Tanaka Y, et al. Safety and efficacy of bimekizumab in patients with psoriatic arthritis: 2-year results from two phase 3 studies. Rheumatol Ther. 2024 Aug 31. Source
3. Curtis JR, et al. Early improvements with guselkumab associate with sustained control of psoriatic arthritis: post hoc analyses of two phase 3 trials. Rheumatol Ther. 2024 Sep 11. Source
4. Gossec L, Coates LC, Gladman DD, et al. Treatment of early oligoarticular psoriatic arthritis with apremilast: primary outcomes at week 16 from the FOREMOST randomised controlled trial. Ann Rheum Dis. 2024 Sep 16:ard-2024-225833. Source

Important psoriatic arthritis (PsA) clinical studies published last month have focused on clinical trials. Several highly efficacious targeted therapies are now available for PsA. However, comparative effectiveness of the various drugs is less well known.

Matching adjusted indirect comparison is one method of evaluating comparative effectiveness. To compare the efficacy between bimekizumab, an interleukin (IL) 17A/F inhibitor and risankizumab, an IL-23 inhibitor, Mease et al conducted such a study using data from four phase 3 trials (BE OPTIMAL, BE COMPLETE, KEEPsAKE-1, and KEEPsAKE-2) involving patients who were biologic-naive or inadequate responders to tumour necrosis factor (TNF) inhibitors  who received bimekizumab (n = 698) or risankizumab (n = 589).¹
 

At week 52, bimekizumab led to a higher likelihood of achieving a ≥ 70% improvement in the American College of Rheumatology (ACR) response in patients who were biologic-naive and TNF inhibitor inadequate responders (TNFi-IR), compared with risankizumab. Bimekizumab also had greater odds of achieving minimal disease activity in patients who were TNFi-IR. Thus, bimekizumab may be superior to risankizumab for treating those with PsA. Randomized controlled head-to-head clinical trials are required to confirm these findings.

In regard to long-term safety and efficacy of bimekizumab, Mease et al reported that bimekizumab demonstrated consistent safety and sustained efficacy for up to 2 years in patients with PsA.² In this open-label extension (BE VITAL) of two phase 3 trials that included biologic-naive (n = 852) and TNFi-IR (n = 400) patients with PsA who were randomly assigned to receive bimekizumab, placebo with crossover to bimekizumab at week 16, or adalimumab followed by bimekizumab at week 52, no new safety signals were noted from weeks 52 to 104,. SARS-CoV-2 infection was the most common treatment-emergent adverse event. Approximately 50% of biologic-naive and TNFi-IR patients maintained a 50% or greater improvement in the ACR response.

Guselkumab, another IL-23 inhibitor, has proven efficacy in treating PsA. Curtis et al investigated the impact of early achievement of improvement with guselkumab and longer-term outcomes.³ This was a post hoc analysis of two phase 3 trials, DISCOVER-1 and DISCOVER-2, which included 1120 patients with active PsA who received guselkumab every 4 or 8 weeks (Q4W) or placebo with a crossover to guselkumab Q4W at week 24. The study demonstrated that guselkumab led to early achievement of minimal clinically important improvement (MCII) in clinical disease activity index for PsA (cDAPSA), with higher response rates at week 4 compared with placebo. Moreover, achieving early MCII in cDAPSA was associated with sustained disease control at weeks 24 and 52. Thus, guselkumab treatment achieved MCII in cDAPSA after the first dose and sustained disease control for up to 1 year. Early treatment response and a proven safety record make guselkumab an attractive treatment option for PsA.

PsA clinical trials mostly include patients with polyarthritis. Little is known about treatment efficacy for oligoarticular PsA. To address this gap in knowledge, Gossec et al reported the results of the phase 4 FOREMOST trial that included 308 patients with early (symptom duration 5 years or less) targeted therapy–naive oligoarticular PsA and were randomly assigned to receive apremilast (n = 203) or placebo (n = 105).⁴ At week 16, a higher proportion of patients receiving apremilast achieved minimal disease activity (joints response) compared with those receiving placebo. No new safety signals were reported. Apremilast is thus efficacious in treating early oligoarticular PsA as well as polyarticular PsA and psoriasis. Similar studies with other targeted therapies will help clinicians better manage early oligoarticular PsA.

References

1. Mease PJ, Warren RB, Nash P, et al. Comparative effectiveness of bimekizumab and risankizumab in patients with psoriatic arthritis at 52 weeks assessed using a matching-adjusted indirect comparison. Rheumatol Ther. 2024 Aug 9. Source
2. Mease PJ, Merola JF, Tanaka Y, et al. Safety and efficacy of bimekizumab in patients with psoriatic arthritis: 2-year results from two phase 3 studies. Rheumatol Ther. 2024 Aug 31. Source
3. Curtis JR, et al. Early improvements with guselkumab associate with sustained control of psoriatic arthritis: post hoc analyses of two phase 3 trials. Rheumatol Ther. 2024 Sep 11. Source
4. Gossec L, Coates LC, Gladman DD, et al. Treatment of early oligoarticular psoriatic arthritis with apremilast: primary outcomes at week 16 from the FOREMOST randomised controlled trial. Ann Rheum Dis. 2024 Sep 16:ard-2024-225833. Source

To the Editor:

Histopathologic analysis of debulk specimens in Mohs micrographic surgery (MMS) may augment identification of high-risk factors in cutaneous squamous cell carcinoma (cSCC), which may warrant tumor upstaging.¹ Intratumor location has not been studied when looking at these high-risk factors. Herein, we report 4 cSCCs initially categorized as well differentiated that were reclassified as moderate to poorly differentiated on analysis of debulk specimens obtained via shave removal.

An 80-year-old man (patient 1) presented with a tender 2-cm erythematous plaque with dried hemorrhagic crusting on the frontal scalp. He had a history of nonmelanoma skin cancers. A biopsy revealed a ­well-differentiated cSCC, which was upgraded from a T2a tumor to T2b during MMS due to galea involvement. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells at the deep margin (Figure 1A). Given T2b staging, baseline imaging and radiation therapy were recommended.

To the Editor:

Histopathologic analysis of debulk specimens in Mohs micrographic surgery (MMS) may augment identification of high-risk factors in cutaneous squamous cell carcinoma (cSCC), which may warrant tumor upstaging.¹ Intratumor location has not been studied when looking at these high-risk factors. Herein, we report 4 cSCCs initially categorized as well differentiated that were reclassified as moderate to poorly differentiated on analysis of debulk specimens obtained via shave removal.

An 80-year-old man (patient 1) presented with a tender 2-cm erythematous plaque with dried hemorrhagic crusting on the frontal scalp. He had a history of nonmelanoma skin cancers. A biopsy revealed a ­well-differentiated cSCC, which was upgraded from a T2a tumor to T2b during MMS due to galea involvement. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells at the deep margin (Figure 1A). Given T2b staging, baseline imaging and radiation therapy were recommended.

To the Editor:

Histopathologic analysis of debulk specimens in Mohs micrographic surgery (MMS) may augment identification of high-risk factors in cutaneous squamous cell carcinoma (cSCC), which may warrant tumor upstaging.¹ Intratumor location has not been studied when looking at these high-risk factors. Herein, we report 4 cSCCs initially categorized as well differentiated that were reclassified as moderate to poorly differentiated on analysis of debulk specimens obtained via shave removal.

An 80-year-old man (patient 1) presented with a tender 2-cm erythematous plaque with dried hemorrhagic crusting on the frontal scalp. He had a history of nonmelanoma skin cancers. A biopsy revealed a ­well-differentiated cSCC, which was upgraded from a T2a tumor to T2b during MMS due to galea involvement. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells at the deep margin (Figure 1A). Given T2b staging, baseline imaging and radiation therapy were recommended.

The mango tree (Mangifera indica) produces ­nutrient-dense fruit—known colloquially as the “king of fruits”—that is widely consumed across the world. Native to southern Asia, the mango tree is a member of the Anacardiaceae family, a large family of flowering, fruit-bearing plants.¹ Many members of the Anacardiaceae family, which includes poison ivy and poison oak, are known to produce urushiol, a skin irritant associated with allergic contact dermatitis (ACD).² Interestingly, despite its widespread consumption and categorization in the Anacardiaceae family, allergic reactions to mango are comparatively rare; they occur as either immediate type I hypersensitivity reactions manifesting with rapid-onset symptoms such as urticaria, wheezing, and angioedema, or delayed type IV hypersensitivity reactions manifesting as ACD.³ Although exposure to components of the mango tree has been most characteristically linked to type IV hypersensitivity reactions, there remain fewer than 40 reported cases of mango-induced ACD since it was first described in 1939.⁴

Evaluation of ACD most commonly includes a thorough clinical assessment with diagnostic support from patch testing and histopathologic review following skin biopsy. In recent years, reflectance confocal microscopy (RCM) has shown promising potential to join the ­repertoire of diagnostic tools for ACD by enabling dynamic and high-resolution imaging of contact dermatitis in vivo.^5-10 Reflectance confocal microscopy is a noninvasive optical imaging technique that uses a low-energy diode laser to penetrate the layers of the skin. The resulting reflected light generates images that facilitate visualization of cutaneous structures to the depth of the papillary dermis.¹¹ While it is most commonly used in skin cancer diagnostics, preliminary studies also have shown an emerging role for RCM in the evaluation of eczematous and inflammatory skin disease, including contact dermatitis.^5-10 Herein, we present a unique case of mango sap–induced ACD imaged and diagnosed in real time via RCM.

Case Report

A 39-year-old woman presented to our clinic with a pruritic vesicular eruption on the right leg of 2 weeks’ duration that initially had developed within 7 days of exposure to mango tree sap (Figure 1). The patient reported having experienced similar pruritic eruptions in the past following contact with mango sap while eating mangos but denied any history of reactions from ingestion of the fruit. She also reported a history of robust reactions to poison ivy; however, a timeline specifying the order of first exposure to these irritants was unknown. She denied any personal or family history of atopic conditions.

The affected skin was imaged in real time during clinic using RCM, which showed an inflammatory infiltrate represented by dark spongiotic vesicles containing bright cells (Figure 2). Additional RCM imaging at the level of the stratum spinosum showed dark spongiotic areas with bright inflammatory cells infiltrating the vesicles, which were surrounded by normal skin showing a typical epidermal honeycomb pattern (Figure 3). These findings were diagnostic of ACD secondary to exposure to mango sap. The patient was advised to apply clobetasol cream 0.05% to the affected area. Notable improvement of the rash was noted within 10 days of treatment.

Comment

Exposure to the mango tree and its fruit is a rare cause of ACD, with few reported cases in the literature. The majority of known instances have occurred in non–mango-cultivating countries, largely the United States, although cases also have been reported in Canada, Australia, France, Japan, and Thailand.^3,12 Mango-induced contact allergy follows a roughly equal distribution between males and females and most often occurs in young adults during the third and fourth decades of life.^4,12-21 Importantly, delayed-type hypersensitivity reactions to mango can manifest as either localized or systemic ACD. Localized ACD can be induced via direct contact with the mango tree and its components or ingestion of the fruit.^3,12,22 Conversely, systemic ACD is primarily stimulated by ingestion of the fruit. In our case, the patient had no history of allergy following mango ingestion, and her ACD was prompted by isolated contact with mango sap. The time from exposure to symptom onset of known instances of mango ACD varies widely, ranging from less than 24 hours to as long as 9 days.^3,12 Diagnosis of mango-induced ACD largely is guided by clinical findings. Presenting symptoms often include an eczematous, vesicular, pruritic rash on affected areas of the skin, frequently the head, neck, and extremities. Patients also commonly present with linear papulovesicular lesions and periorbital or perioral edema.

The suspected allergens responsible for mango-induced ACD are derived from resorcinol—specifically heptadecadienyl resorcinol, heptadecenyl resorcinol, and pentadecyl resorcinol, which are collectively known as mango allergens.²³ These allergens can be found within the pulp and skin of the mango fruit as well as in the bark and leaves of the mango tree, which may explain observed allergic reactions to components of both the mango fruit and tree.¹² Similar to these resorcinol derivatives, the urushiol resin found in poison ivy and poison oak is a catechol derivative.² Importantly, both resorcinols and catechols are isomers of the same aromatic ­phenol—dihydroxybenzene. Because of these similarities, it is thought that the allergens in mangos may cross-react with urushiol in poison ivy or poison oak.²³ Alongside their shared categorization in the Anacardiaceae family, it is hypothesized that this cross-reactivity underlies the sensitization that has been noted between mango and poison ivy or poison oak exposure.^12,23,24 Thus, ACD often can occur on initial contact with the mango tree or its components, as a prior exposure to poison ivy or poison oak may serve as the inciting factor for hypersensitization. The majority of reported cases in the literature also occurred in countries where exposure to poison ivy and poison oak are common, further supporting the notion that these compounds may provide a sensitizing trigger for a future mango contact allergy.¹²

A detailed clinical history combined with adjunctive diagnostic support from patch testing and histopathology of biopsied skin lesions classically are used in the diagnosis of mango-induced ACD. Due to its ability to provide quick and noninvasive in vivo imaging of cutaneous lesions, RCM's applications have expanded to include evaluation of inflammatory skin diseases such as contact dermatitis. Many features of contact dermatitis identified via RCM are common between ACD and irritant contact dermatitis (ICD) and include disruption of the stratum corneum, parakeratosis, vesiculation, spongiosis, and exocytosis.^6,10,25 Studies also have described features shown via RCM that are unique to ACD, including vasodilation and intercellular edema, compared to more distinct targetoid keratinocytes and detached corneocytes seen in ICD.^6,10,25 Studies by Astner et al^5,6 demonstrated a wide range of sensitivity from 52% to 96% and a high specificity of RCM greater than 95% for many of the aforementioned features of contact dermatitis, including disruption of the stratum corneum, parakeratosis, spongiosis, and exocytosis. Additional studies have further strengthened these findings, demonstrating sensitivity and specificity values of 83% and 92% for contact dermatitis under RCM, respectively.²⁶ Importantly, given the similarities and potentially large overlap of features between ACD and ICD identified via RCM as well as findings seen on physical examination and histopathology, an emphasis on clinical correlation is essential when differentiating between these 2 variants of contact dermatitis. Thus, taken in consideration with clinical contexts, RCM has shown potent diagnostic accuracy and great potential to support the evaluation of ACD alongside patch testing and histopathology.

Final Thoughts

Contact allergy to the mango tree and its components is uncommon. We report a unique case of mango sap–induced ACD evaluated and diagnosed via dynamic visualization under RCM. As a noninvasive and reproducible imaging technique with resolutions comparable to histopathologic analysis, RCM is a promising tool that can be used to support the diagnostic evaluation of ACD.

The mango tree (Mangifera indica) produces ­nutrient-dense fruit—known colloquially as the “king of fruits”—that is widely consumed across the world. Native to southern Asia, the mango tree is a member of the Anacardiaceae family, a large family of flowering, fruit-bearing plants.¹ Many members of the Anacardiaceae family, which includes poison ivy and poison oak, are known to produce urushiol, a skin irritant associated with allergic contact dermatitis (ACD).² Interestingly, despite its widespread consumption and categorization in the Anacardiaceae family, allergic reactions to mango are comparatively rare; they occur as either immediate type I hypersensitivity reactions manifesting with rapid-onset symptoms such as urticaria, wheezing, and angioedema, or delayed type IV hypersensitivity reactions manifesting as ACD.³ Although exposure to components of the mango tree has been most characteristically linked to type IV hypersensitivity reactions, there remain fewer than 40 reported cases of mango-induced ACD since it was first described in 1939.⁴

Evaluation of ACD most commonly includes a thorough clinical assessment with diagnostic support from patch testing and histopathologic review following skin biopsy. In recent years, reflectance confocal microscopy (RCM) has shown promising potential to join the ­repertoire of diagnostic tools for ACD by enabling dynamic and high-resolution imaging of contact dermatitis in vivo.^5-10 Reflectance confocal microscopy is a noninvasive optical imaging technique that uses a low-energy diode laser to penetrate the layers of the skin. The resulting reflected light generates images that facilitate visualization of cutaneous structures to the depth of the papillary dermis.¹¹ While it is most commonly used in skin cancer diagnostics, preliminary studies also have shown an emerging role for RCM in the evaluation of eczematous and inflammatory skin disease, including contact dermatitis.^5-10 Herein, we present a unique case of mango sap–induced ACD imaged and diagnosed in real time via RCM.

Case Report

A 39-year-old woman presented to our clinic with a pruritic vesicular eruption on the right leg of 2 weeks’ duration that initially had developed within 7 days of exposure to mango tree sap (Figure 1). The patient reported having experienced similar pruritic eruptions in the past following contact with mango sap while eating mangos but denied any history of reactions from ingestion of the fruit. She also reported a history of robust reactions to poison ivy; however, a timeline specifying the order of first exposure to these irritants was unknown. She denied any personal or family history of atopic conditions.

The affected skin was imaged in real time during clinic using RCM, which showed an inflammatory infiltrate represented by dark spongiotic vesicles containing bright cells (Figure 2). Additional RCM imaging at the level of the stratum spinosum showed dark spongiotic areas with bright inflammatory cells infiltrating the vesicles, which were surrounded by normal skin showing a typical epidermal honeycomb pattern (Figure 3). These findings were diagnostic of ACD secondary to exposure to mango sap. The patient was advised to apply clobetasol cream 0.05% to the affected area. Notable improvement of the rash was noted within 10 days of treatment.

Comment

Exposure to the mango tree and its fruit is a rare cause of ACD, with few reported cases in the literature. The majority of known instances have occurred in non–mango-cultivating countries, largely the United States, although cases also have been reported in Canada, Australia, France, Japan, and Thailand.^3,12 Mango-induced contact allergy follows a roughly equal distribution between males and females and most often occurs in young adults during the third and fourth decades of life.^4,12-21 Importantly, delayed-type hypersensitivity reactions to mango can manifest as either localized or systemic ACD. Localized ACD can be induced via direct contact with the mango tree and its components or ingestion of the fruit.^3,12,22 Conversely, systemic ACD is primarily stimulated by ingestion of the fruit. In our case, the patient had no history of allergy following mango ingestion, and her ACD was prompted by isolated contact with mango sap. The time from exposure to symptom onset of known instances of mango ACD varies widely, ranging from less than 24 hours to as long as 9 days.^3,12 Diagnosis of mango-induced ACD largely is guided by clinical findings. Presenting symptoms often include an eczematous, vesicular, pruritic rash on affected areas of the skin, frequently the head, neck, and extremities. Patients also commonly present with linear papulovesicular lesions and periorbital or perioral edema.

The suspected allergens responsible for mango-induced ACD are derived from resorcinol—specifically heptadecadienyl resorcinol, heptadecenyl resorcinol, and pentadecyl resorcinol, which are collectively known as mango allergens.²³ These allergens can be found within the pulp and skin of the mango fruit as well as in the bark and leaves of the mango tree, which may explain observed allergic reactions to components of both the mango fruit and tree.¹² Similar to these resorcinol derivatives, the urushiol resin found in poison ivy and poison oak is a catechol derivative.² Importantly, both resorcinols and catechols are isomers of the same aromatic ­phenol—dihydroxybenzene. Because of these similarities, it is thought that the allergens in mangos may cross-react with urushiol in poison ivy or poison oak.²³ Alongside their shared categorization in the Anacardiaceae family, it is hypothesized that this cross-reactivity underlies the sensitization that has been noted between mango and poison ivy or poison oak exposure.^12,23,24 Thus, ACD often can occur on initial contact with the mango tree or its components, as a prior exposure to poison ivy or poison oak may serve as the inciting factor for hypersensitization. The majority of reported cases in the literature also occurred in countries where exposure to poison ivy and poison oak are common, further supporting the notion that these compounds may provide a sensitizing trigger for a future mango contact allergy.¹²

A detailed clinical history combined with adjunctive diagnostic support from patch testing and histopathology of biopsied skin lesions classically are used in the diagnosis of mango-induced ACD. Due to its ability to provide quick and noninvasive in vivo imaging of cutaneous lesions, RCM's applications have expanded to include evaluation of inflammatory skin diseases such as contact dermatitis. Many features of contact dermatitis identified via RCM are common between ACD and irritant contact dermatitis (ICD) and include disruption of the stratum corneum, parakeratosis, vesiculation, spongiosis, and exocytosis.^6,10,25 Studies also have described features shown via RCM that are unique to ACD, including vasodilation and intercellular edema, compared to more distinct targetoid keratinocytes and detached corneocytes seen in ICD.^6,10,25 Studies by Astner et al^5,6 demonstrated a wide range of sensitivity from 52% to 96% and a high specificity of RCM greater than 95% for many of the aforementioned features of contact dermatitis, including disruption of the stratum corneum, parakeratosis, spongiosis, and exocytosis. Additional studies have further strengthened these findings, demonstrating sensitivity and specificity values of 83% and 92% for contact dermatitis under RCM, respectively.²⁶ Importantly, given the similarities and potentially large overlap of features between ACD and ICD identified via RCM as well as findings seen on physical examination and histopathology, an emphasis on clinical correlation is essential when differentiating between these 2 variants of contact dermatitis. Thus, taken in consideration with clinical contexts, RCM has shown potent diagnostic accuracy and great potential to support the evaluation of ACD alongside patch testing and histopathology.

Final Thoughts

Contact allergy to the mango tree and its components is uncommon. We report a unique case of mango sap–induced ACD evaluated and diagnosed via dynamic visualization under RCM. As a noninvasive and reproducible imaging technique with resolutions comparable to histopathologic analysis, RCM is a promising tool that can be used to support the diagnostic evaluation of ACD.

The mango tree (Mangifera indica) produces ­nutrient-dense fruit—known colloquially as the “king of fruits”—that is widely consumed across the world. Native to southern Asia, the mango tree is a member of the Anacardiaceae family, a large family of flowering, fruit-bearing plants.¹ Many members of the Anacardiaceae family, which includes poison ivy and poison oak, are known to produce urushiol, a skin irritant associated with allergic contact dermatitis (ACD).² Interestingly, despite its widespread consumption and categorization in the Anacardiaceae family, allergic reactions to mango are comparatively rare; they occur as either immediate type I hypersensitivity reactions manifesting with rapid-onset symptoms such as urticaria, wheezing, and angioedema, or delayed type IV hypersensitivity reactions manifesting as ACD.³ Although exposure to components of the mango tree has been most characteristically linked to type IV hypersensitivity reactions, there remain fewer than 40 reported cases of mango-induced ACD since it was first described in 1939.⁴

Evaluation of ACD most commonly includes a thorough clinical assessment with diagnostic support from patch testing and histopathologic review following skin biopsy. In recent years, reflectance confocal microscopy (RCM) has shown promising potential to join the ­repertoire of diagnostic tools for ACD by enabling dynamic and high-resolution imaging of contact dermatitis in vivo.^5-10 Reflectance confocal microscopy is a noninvasive optical imaging technique that uses a low-energy diode laser to penetrate the layers of the skin. The resulting reflected light generates images that facilitate visualization of cutaneous structures to the depth of the papillary dermis.¹¹ While it is most commonly used in skin cancer diagnostics, preliminary studies also have shown an emerging role for RCM in the evaluation of eczematous and inflammatory skin disease, including contact dermatitis.^5-10 Herein, we present a unique case of mango sap–induced ACD imaged and diagnosed in real time via RCM.

Case Report

A 39-year-old woman presented to our clinic with a pruritic vesicular eruption on the right leg of 2 weeks’ duration that initially had developed within 7 days of exposure to mango tree sap (Figure 1). The patient reported having experienced similar pruritic eruptions in the past following contact with mango sap while eating mangos but denied any history of reactions from ingestion of the fruit. She also reported a history of robust reactions to poison ivy; however, a timeline specifying the order of first exposure to these irritants was unknown. She denied any personal or family history of atopic conditions.

The affected skin was imaged in real time during clinic using RCM, which showed an inflammatory infiltrate represented by dark spongiotic vesicles containing bright cells (Figure 2). Additional RCM imaging at the level of the stratum spinosum showed dark spongiotic areas with bright inflammatory cells infiltrating the vesicles, which were surrounded by normal skin showing a typical epidermal honeycomb pattern (Figure 3). These findings were diagnostic of ACD secondary to exposure to mango sap. The patient was advised to apply clobetasol cream 0.05% to the affected area. Notable improvement of the rash was noted within 10 days of treatment.

Comment

Exposure to the mango tree and its fruit is a rare cause of ACD, with few reported cases in the literature. The majority of known instances have occurred in non–mango-cultivating countries, largely the United States, although cases also have been reported in Canada, Australia, France, Japan, and Thailand.^3,12 Mango-induced contact allergy follows a roughly equal distribution between males and females and most often occurs in young adults during the third and fourth decades of life.^4,12-21 Importantly, delayed-type hypersensitivity reactions to mango can manifest as either localized or systemic ACD. Localized ACD can be induced via direct contact with the mango tree and its components or ingestion of the fruit.^3,12,22 Conversely, systemic ACD is primarily stimulated by ingestion of the fruit. In our case, the patient had no history of allergy following mango ingestion, and her ACD was prompted by isolated contact with mango sap. The time from exposure to symptom onset of known instances of mango ACD varies widely, ranging from less than 24 hours to as long as 9 days.^3,12 Diagnosis of mango-induced ACD largely is guided by clinical findings. Presenting symptoms often include an eczematous, vesicular, pruritic rash on affected areas of the skin, frequently the head, neck, and extremities. Patients also commonly present with linear papulovesicular lesions and periorbital or perioral edema.

The suspected allergens responsible for mango-induced ACD are derived from resorcinol—specifically heptadecadienyl resorcinol, heptadecenyl resorcinol, and pentadecyl resorcinol, which are collectively known as mango allergens.²³ These allergens can be found within the pulp and skin of the mango fruit as well as in the bark and leaves of the mango tree, which may explain observed allergic reactions to components of both the mango fruit and tree.¹² Similar to these resorcinol derivatives, the urushiol resin found in poison ivy and poison oak is a catechol derivative.² Importantly, both resorcinols and catechols are isomers of the same aromatic ­phenol—dihydroxybenzene. Because of these similarities, it is thought that the allergens in mangos may cross-react with urushiol in poison ivy or poison oak.²³ Alongside their shared categorization in the Anacardiaceae family, it is hypothesized that this cross-reactivity underlies the sensitization that has been noted between mango and poison ivy or poison oak exposure.^12,23,24 Thus, ACD often can occur on initial contact with the mango tree or its components, as a prior exposure to poison ivy or poison oak may serve as the inciting factor for hypersensitization. The majority of reported cases in the literature also occurred in countries where exposure to poison ivy and poison oak are common, further supporting the notion that these compounds may provide a sensitizing trigger for a future mango contact allergy.¹²

A detailed clinical history combined with adjunctive diagnostic support from patch testing and histopathology of biopsied skin lesions classically are used in the diagnosis of mango-induced ACD. Due to its ability to provide quick and noninvasive in vivo imaging of cutaneous lesions, RCM's applications have expanded to include evaluation of inflammatory skin diseases such as contact dermatitis. Many features of contact dermatitis identified via RCM are common between ACD and irritant contact dermatitis (ICD) and include disruption of the stratum corneum, parakeratosis, vesiculation, spongiosis, and exocytosis.^6,10,25 Studies also have described features shown via RCM that are unique to ACD, including vasodilation and intercellular edema, compared to more distinct targetoid keratinocytes and detached corneocytes seen in ICD.^6,10,25 Studies by Astner et al^5,6 demonstrated a wide range of sensitivity from 52% to 96% and a high specificity of RCM greater than 95% for many of the aforementioned features of contact dermatitis, including disruption of the stratum corneum, parakeratosis, spongiosis, and exocytosis. Additional studies have further strengthened these findings, demonstrating sensitivity and specificity values of 83% and 92% for contact dermatitis under RCM, respectively.²⁶ Importantly, given the similarities and potentially large overlap of features between ACD and ICD identified via RCM as well as findings seen on physical examination and histopathology, an emphasis on clinical correlation is essential when differentiating between these 2 variants of contact dermatitis. Thus, taken in consideration with clinical contexts, RCM has shown potent diagnostic accuracy and great potential to support the evaluation of ACD alongside patch testing and histopathology.

Final Thoughts

Contact allergy to the mango tree and its components is uncommon. We report a unique case of mango sap–induced ACD evaluated and diagnosed via dynamic visualization under RCM. As a noninvasive and reproducible imaging technique with resolutions comparable to histopathologic analysis, RCM is a promising tool that can be used to support the diagnostic evaluation of ACD.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

THE DIAGNOSIS: Secondary Syphilis

Histopathology demonstrated a mild superficial perivascular and interstitial infiltrate composed of lymphocytes, histiocytes, and rare plasma cells with a background of extravasated erythrocytes (Figure, A). Treponema pallidum staining highlighted multiple spirochetes along the dermoepidermal junction and in the superficial dermis (Figure, B). Direct immunofluorescence was negative. Laboratory workup revealed a reactive rapid plasma reagin screen with a titer of 1:16 and positive IgG and IgM treponemal antibodies. The patient was diagnosed with secondary syphilis and was treated with a single dose of 2.4 million U of intramuscular benzathine penicillin G, with notable improvement of the rash and arthritis symptoms at 2-week follow-up.

Syphilis is a sexually transmitted infection caused by the spirochete T pallidum that progresses through active and latent stages. The incidence of both the primary and secondary stages of syphilis was at a historic low in the year 2000 and has increased annually since then.¹ Syphilis is more common in men, and men who have sex with men (MSM) are disproportionately affected. Although the incidence of syphilis in MSM has increased since 2000, rates have slowed, with slight decreases in this population between 2019 and 2020.¹ Conversely, rates among women have increased substantially in recent years, suggesting a more recent epidemic affecting heterosexual men and women.²

Classically, the primary stage of syphilis manifests as an asymptomatic papule followed by a painless ulcer (chancre) that heals spontaneously. The secondary stage of syphilis results from dissemination of T pallidum and is characterized by a wide range of mucocutaneous manifestations and prodromal symptoms. The most common cutaneous manifestation is a diffuse, nonpruritic, papulosquamous rash with red-brown scaly macules or papules on the trunk and extremities.³ The palms and soles commonly are involved. Mucosal patches, “snail-track” ulcers in the mouth, and condylomata lata are the characteristic mucosal lesions of secondary syphilis. Mucocutaneous findings typically are preceded by systemic signs including fever, malaise, myalgia, and generalized lymphadenopathy. However, syphilis is considered “the great mimicker,” with new reports of unusual presentations of the disease. In addition to papulosquamous morphologies, pustular, targetoid, psoriasiform, and noduloulcerative (also known as lues maligna) forms of syphilis have been reported.^3-5

The histopathologic features of secondary syphilis also are variable. Classically, secondary syphilis demonstrates vacuolar interface dermatitis and acanthosis with slender elongated rete ridges. Other well-known features include endothelial swelling and the presence of plasma cells in most cases.⁶ However, the histopathologic features of secondary syphilis may vary depending on the morphology of the skin eruption and when the biopsy is taken. Our patient lacked the classic histopathologic features of secondary syphilis. However, because syphilis was in the clinical differential diagnosis, a treponemal stain was ordered and confirmed the diagnosis. Immunohistochemical stains using antibodies to treponemal antigens have a reported sensitivity of 71% to 100% and are highly specific.⁷ Although the combination of endothelial swelling, interstitial inflammation, irregular acanthosis, and elongated rete ridges should raise the possibility of syphilis, a treponemal stain may be useful to identify spirochetes if clinical suspicion exists.⁸

Given our patient’s known history of GPA, leukocytoclastic vasculitis was high on the list of differential diagnoses. However, leukocytoclastic vasculitis most classically manifests as petechiae and palpable purpura, and unlike in secondary syphilis, the palms and soles are less commonly involved. Because our patient’s rash was mainly localized to the lower limbs, the differential also included 2 pigmented purpuric dermatoses (PPDs): progressive pigmentary purpura (Schamberg disease) and purpura annularis telangiectodes (Majocchi disease). Progressive pigmentary purpura is the most common manifestation of PPD and appears as cayenne pepper–colored macules that coalesce into golden brown–pigmented patches on the legs.⁹ Purpura annularis telangiectodes is another variant of PPD that manifests as pinpoint telangiectatic macules that progress to annular hyperpigmented patches with central clearing. Although PPDs frequently occur on the lower extremities, reports of plantar involvement are rare.¹⁰ Annular lichen planus manifests as violaceous papules with a clear center; however, it would be atypical for these lesions to be restricted to the feet and ankles. Palmoplantar lichen planus can mimic secondary syphilis clinically, but these cases manifest as hyperkeratotic pruritic papules on the palms and soles in contrast to the faint brown asymptomatic macules noted in our case.¹¹

Our case highlights an unusual presentation of secondary syphilis and demonstrates the challenge of diagnosing this entity on clinical presentation alone. Because this patient lacked the classic clinical and histopathologic features of secondary syphilis, a skin biopsy with positive immunohistochemical staining for treponemal antigens was necessary to make the diagnosis. Given the variability in presentation of secondary syphilis, a biopsy or serologic testing may be necessary to make a proper diagnosis.

THE DIAGNOSIS: Secondary Syphilis

Histopathology demonstrated a mild superficial perivascular and interstitial infiltrate composed of lymphocytes, histiocytes, and rare plasma cells with a background of extravasated erythrocytes (Figure, A). Treponema pallidum staining highlighted multiple spirochetes along the dermoepidermal junction and in the superficial dermis (Figure, B). Direct immunofluorescence was negative. Laboratory workup revealed a reactive rapid plasma reagin screen with a titer of 1:16 and positive IgG and IgM treponemal antibodies. The patient was diagnosed with secondary syphilis and was treated with a single dose of 2.4 million U of intramuscular benzathine penicillin G, with notable improvement of the rash and arthritis symptoms at 2-week follow-up.

Syphilis is a sexually transmitted infection caused by the spirochete T pallidum that progresses through active and latent stages. The incidence of both the primary and secondary stages of syphilis was at a historic low in the year 2000 and has increased annually since then.¹ Syphilis is more common in men, and men who have sex with men (MSM) are disproportionately affected. Although the incidence of syphilis in MSM has increased since 2000, rates have slowed, with slight decreases in this population between 2019 and 2020.¹ Conversely, rates among women have increased substantially in recent years, suggesting a more recent epidemic affecting heterosexual men and women.²

Classically, the primary stage of syphilis manifests as an asymptomatic papule followed by a painless ulcer (chancre) that heals spontaneously. The secondary stage of syphilis results from dissemination of T pallidum and is characterized by a wide range of mucocutaneous manifestations and prodromal symptoms. The most common cutaneous manifestation is a diffuse, nonpruritic, papulosquamous rash with red-brown scaly macules or papules on the trunk and extremities.³ The palms and soles commonly are involved. Mucosal patches, “snail-track” ulcers in the mouth, and condylomata lata are the characteristic mucosal lesions of secondary syphilis. Mucocutaneous findings typically are preceded by systemic signs including fever, malaise, myalgia, and generalized lymphadenopathy. However, syphilis is considered “the great mimicker,” with new reports of unusual presentations of the disease. In addition to papulosquamous morphologies, pustular, targetoid, psoriasiform, and noduloulcerative (also known as lues maligna) forms of syphilis have been reported.^3-5

The histopathologic features of secondary syphilis also are variable. Classically, secondary syphilis demonstrates vacuolar interface dermatitis and acanthosis with slender elongated rete ridges. Other well-known features include endothelial swelling and the presence of plasma cells in most cases.⁶ However, the histopathologic features of secondary syphilis may vary depending on the morphology of the skin eruption and when the biopsy is taken. Our patient lacked the classic histopathologic features of secondary syphilis. However, because syphilis was in the clinical differential diagnosis, a treponemal stain was ordered and confirmed the diagnosis. Immunohistochemical stains using antibodies to treponemal antigens have a reported sensitivity of 71% to 100% and are highly specific.⁷ Although the combination of endothelial swelling, interstitial inflammation, irregular acanthosis, and elongated rete ridges should raise the possibility of syphilis, a treponemal stain may be useful to identify spirochetes if clinical suspicion exists.⁸

Given our patient’s known history of GPA, leukocytoclastic vasculitis was high on the list of differential diagnoses. However, leukocytoclastic vasculitis most classically manifests as petechiae and palpable purpura, and unlike in secondary syphilis, the palms and soles are less commonly involved. Because our patient’s rash was mainly localized to the lower limbs, the differential also included 2 pigmented purpuric dermatoses (PPDs): progressive pigmentary purpura (Schamberg disease) and purpura annularis telangiectodes (Majocchi disease). Progressive pigmentary purpura is the most common manifestation of PPD and appears as cayenne pepper–colored macules that coalesce into golden brown–pigmented patches on the legs.⁹ Purpura annularis telangiectodes is another variant of PPD that manifests as pinpoint telangiectatic macules that progress to annular hyperpigmented patches with central clearing. Although PPDs frequently occur on the lower extremities, reports of plantar involvement are rare.¹⁰ Annular lichen planus manifests as violaceous papules with a clear center; however, it would be atypical for these lesions to be restricted to the feet and ankles. Palmoplantar lichen planus can mimic secondary syphilis clinically, but these cases manifest as hyperkeratotic pruritic papules on the palms and soles in contrast to the faint brown asymptomatic macules noted in our case.¹¹

Our case highlights an unusual presentation of secondary syphilis and demonstrates the challenge of diagnosing this entity on clinical presentation alone. Because this patient lacked the classic clinical and histopathologic features of secondary syphilis, a skin biopsy with positive immunohistochemical staining for treponemal antigens was necessary to make the diagnosis. Given the variability in presentation of secondary syphilis, a biopsy or serologic testing may be necessary to make a proper diagnosis.

THE DIAGNOSIS: Secondary Syphilis

Histopathology demonstrated a mild superficial perivascular and interstitial infiltrate composed of lymphocytes, histiocytes, and rare plasma cells with a background of extravasated erythrocytes (Figure, A). Treponema pallidum staining highlighted multiple spirochetes along the dermoepidermal junction and in the superficial dermis (Figure, B). Direct immunofluorescence was negative. Laboratory workup revealed a reactive rapid plasma reagin screen with a titer of 1:16 and positive IgG and IgM treponemal antibodies. The patient was diagnosed with secondary syphilis and was treated with a single dose of 2.4 million U of intramuscular benzathine penicillin G, with notable improvement of the rash and arthritis symptoms at 2-week follow-up.

Syphilis is a sexually transmitted infection caused by the spirochete T pallidum that progresses through active and latent stages. The incidence of both the primary and secondary stages of syphilis was at a historic low in the year 2000 and has increased annually since then.¹ Syphilis is more common in men, and men who have sex with men (MSM) are disproportionately affected. Although the incidence of syphilis in MSM has increased since 2000, rates have slowed, with slight decreases in this population between 2019 and 2020.¹ Conversely, rates among women have increased substantially in recent years, suggesting a more recent epidemic affecting heterosexual men and women.²

Classically, the primary stage of syphilis manifests as an asymptomatic papule followed by a painless ulcer (chancre) that heals spontaneously. The secondary stage of syphilis results from dissemination of T pallidum and is characterized by a wide range of mucocutaneous manifestations and prodromal symptoms. The most common cutaneous manifestation is a diffuse, nonpruritic, papulosquamous rash with red-brown scaly macules or papules on the trunk and extremities.³ The palms and soles commonly are involved. Mucosal patches, “snail-track” ulcers in the mouth, and condylomata lata are the characteristic mucosal lesions of secondary syphilis. Mucocutaneous findings typically are preceded by systemic signs including fever, malaise, myalgia, and generalized lymphadenopathy. However, syphilis is considered “the great mimicker,” with new reports of unusual presentations of the disease. In addition to papulosquamous morphologies, pustular, targetoid, psoriasiform, and noduloulcerative (also known as lues maligna) forms of syphilis have been reported.^3-5

The histopathologic features of secondary syphilis also are variable. Classically, secondary syphilis demonstrates vacuolar interface dermatitis and acanthosis with slender elongated rete ridges. Other well-known features include endothelial swelling and the presence of plasma cells in most cases.⁶ However, the histopathologic features of secondary syphilis may vary depending on the morphology of the skin eruption and when the biopsy is taken. Our patient lacked the classic histopathologic features of secondary syphilis. However, because syphilis was in the clinical differential diagnosis, a treponemal stain was ordered and confirmed the diagnosis. Immunohistochemical stains using antibodies to treponemal antigens have a reported sensitivity of 71% to 100% and are highly specific.⁷ Although the combination of endothelial swelling, interstitial inflammation, irregular acanthosis, and elongated rete ridges should raise the possibility of syphilis, a treponemal stain may be useful to identify spirochetes if clinical suspicion exists.⁸

Given our patient’s known history of GPA, leukocytoclastic vasculitis was high on the list of differential diagnoses. However, leukocytoclastic vasculitis most classically manifests as petechiae and palpable purpura, and unlike in secondary syphilis, the palms and soles are less commonly involved. Because our patient’s rash was mainly localized to the lower limbs, the differential also included 2 pigmented purpuric dermatoses (PPDs): progressive pigmentary purpura (Schamberg disease) and purpura annularis telangiectodes (Majocchi disease). Progressive pigmentary purpura is the most common manifestation of PPD and appears as cayenne pepper–colored macules that coalesce into golden brown–pigmented patches on the legs.⁹ Purpura annularis telangiectodes is another variant of PPD that manifests as pinpoint telangiectatic macules that progress to annular hyperpigmented patches with central clearing. Although PPDs frequently occur on the lower extremities, reports of plantar involvement are rare.¹⁰ Annular lichen planus manifests as violaceous papules with a clear center; however, it would be atypical for these lesions to be restricted to the feet and ankles. Palmoplantar lichen planus can mimic secondary syphilis clinically, but these cases manifest as hyperkeratotic pruritic papules on the palms and soles in contrast to the faint brown asymptomatic macules noted in our case.¹¹

Our case highlights an unusual presentation of secondary syphilis and demonstrates the challenge of diagnosing this entity on clinical presentation alone. Because this patient lacked the classic clinical and histopathologic features of secondary syphilis, a skin biopsy with positive immunohistochemical staining for treponemal antigens was necessary to make the diagnosis. Given the variability in presentation of secondary syphilis, a biopsy or serologic testing may be necessary to make a proper diagnosis.

As we move further into the 21st century, technology continues to revolutionize various facets of our lives. Healthcare is a prime example. Advances in technology have dramatically reshaped the way we develop medications, diagnose diseases, and enhance patient care. The rise of artificial intelligence (AI) and the widespread adoption of digital health technologies have marked a significant milestone in improving the quality of care. AI, with its ability to leverage algorithms, deep learning, and machine learning to process data, make decisions, and perform tasks autonomously, is becoming an integral part of modern society. It is embedded in various technologies that we rely on daily, from smartphones and smart home devices to content recommendations on streaming services and social media platforms.

In healthcare, AI has applications in numerous fields, such as radiology. AI streamlines processes such as organizing patient appointments, optimizing radiation protocols for safety and efficiency, and enhancing the documentation process through advanced image analysis. AI technology plays an integral role in imaging tasks like image enhancement, lesion detection, and precise measurement. In difficult-to-interpret radiologic studies, such as some mammography images, it can be a crucial aid to the radiologist. Additionally, the use of AI has significantly improved remote patient monitoring that enables healthcare professionals to monitor and assess patient conditions without needing in-person visits. Remote patient monitoring gained prominence during the COVID-19 pandemic and continues to be a valuable tool in post pandemic care. Study results have highlighted that AI-driven ambient dictation tools have increased provider engagement with patients during consultations while reducing the time spent documenting in electronic health records.

Like many other medical specialties, headache medicine also uses AI. Most prominently, AI has been used in models and engines in assisting with headache diagnoses. A noteworthy example of AI in headache medicine is the development of an online, computer-based diagnostic engine (CDE) by Rapoport et al, called BonTriage. This tool is designed to diagnose headaches by employing a rule set based on the International Classification of Headache Disorders-3 (ICHD-3) criteria for primary headache disorders while also evaluating secondary headaches and medication overuse headaches. By leveraging machine learning, the CDE has the potential to streamline the diagnostic process, reducing the number of questions needed to reach a diagnosis and making the experience more efficient. This information can then be printed as a PDF file and taken by the patient to a healthcare professional for further discussion, fostering a more accurate, fluid, and conversational consultation.

A study was conducted to evaluate the accuracy of the CDE. Participants were randomly assigned to 1 of 2 sequences: (1) using the CDE followed by a structured standard interview with a headache specialist using the same ICHD-3 criteria or (2) starting with the structured standard interview followed by the CDE. The results demonstrated nearly perfect agreement in diagnosing migraine and probable migraine between the CDE and structured standard interview (κ = 0.82, 95% CI: 0.74, 0.90). The CDE demonstrated a diagnostic accuracy of 91.6% (95% CI: 86.9%, 95.0%), a sensitivity rate of 89.0% (95% CI: 82.5%, 93.7%), and a specificity rate of 97.0% (95% CI: 89.5%, 99.6%).

A diagnostic engine such as this can save time that clinicians spend on documentation and allow more time for discussion with the patient. For instance, a patient can take the printout received from the CDE to an appointment; the printout gives a detailed history plus information about social and psychological issues, a list of medications taken, and results of previous testing. The CDE system was originally designed to help patients see a specialist in the environment of a nationwide lack of headache specialists. There are currently 45 million patients with headaches who are seeking treatment with only around 550 certified headache specialists in the United States. The CDE printed information can help a patient obtain a consultation from a clinician quickly and start evaluation and treatment earlier. This expert online consultation is currently free of charge.

Kwon et al developed a machine learning–based model designed to automatically classify headache disorders using data from a questionnaire. Their model was able to predict diagnoses for conditions such as migraine, tension-type headaches, trigeminal autonomic cephalalgia, epicranial headache, and thunderclap headaches. The model was trained on data from 2162 patients, all diagnosed by headache specialists, and achieved an overall accuracy of 81%, with a sensitivity of 88% and a specificity of 95% for diagnosing migraines. However, the model’s performance was less robust when applied to other headache disorders.

Katsuki et al developed an AI model to help non specialists accurately diagnose headaches. This model analyzed 17 variables and was trained on data from 2800 patients, with additional testing and refinement using data from another 200 patients. To evaluate its effectiveness, 2 groups of non-headache specialists each assessed 50 patients: 1 group relied solely on their expertise, while the other used the AI model. The group without AI assistance achieved an overall accuracy of 46% (κ = 0.21), while the group using the AI model significantly improved, reaching an overall accuracy of 83.2% (κ = 0.68).

Building on their work with AI for diagnosing headaches, Katsuki et al conducted a study using a smartphone application that tracked user-reported headache events alongside local weather data. The AI model revealed that lower barometric pressure, higher humidity, and increased rainfall were linked to the onset of headache attacks. The application also identified triggers for headaches in specific weather patterns, such as a drop in barometric pressure noted 6 hours before headache onset. The application of AI in monitoring weather changes could be crucial, especially given concerns that the rising frequency of severe weather events due to climate change may be exacerbating the severity and burden of migraine. Additionally, recent post hoc analyses of fremanezumab clinical trials have provided further evidence that weather changes can trigger headaches.

Rapoport and colleagues have also developed an application called Migraine Mentor, which accurately tracks headaches, triggers, health data, and response to medication on a smartphone. The patient spends 3 minutes a day answering a few questions about their day and whether they had a headache or took any medication. At 1 or 2 months, Migraine Mentor can generate a detailed report with data and current trends that is sent to the patient, which the patient can then share with the clinician. The application also reminds patients when to document data and take medication.

However, although the use of AI in headache medicine appears promising, caution must be exercised to ensure proper results and information are disseminated. One rapidly expanding application of AI is the widely popular ChatGPT. ChatGPT, which stands for generative pretraining transformer, is a type of large language model (LLM). An LLM is a deep learning algorithm designed to recognize, translate, predict, summarize, and generate text responses based on a given prompt. This model is trained on an extensive dataset that includes a diverse array of books, articles, and websites, exposing it to various language structures and styles. This training enables ChatGPT to generate responses that closely mimic human communication. LLMs are being used more and more in medicine to assist with generating patient documentation and educational materials.

However, Dr Fred Cohen published a perspective piece detailing how LLMs (such as ChatGPT) can produce misleading and inaccurate answers. In his example, he tasked ChatGPT to describe the epidemiology of migraines in penguins; the AI model generated a well-written and highly believable manuscript titled, “Migraine Under the Ice: Understanding Headaches in Antarctica's Feathered Friends.” The manuscript highlights that migraines are more prevalent in male penguins compared to females, with the peak age of onset occurring between 4 and 5 years. Additionally, emperor and king penguins are identified as being more susceptible to developing migraines compared to other penguin species. The paper was fictitious (as no studies on migraine in penguins have been written to date), exemplifying that these models can produce nonfactual materials.

For years, technological advancements have been reshaping many aspects of life, and medicine is no exception. AI has been successfully applied to streamline medical documentation, develop new drug targets, and deepen our understanding of various diseases. The field of headache medicine now also uses AI. Recent developments show significant promise, with AI aiding in the diagnosis of migraine and other headache disorders. AI models have even been used in the identification of potential drug targets for migraine treatment. Although there are still limitations to overcome, the future of AI in headache medicine appears bright.

If you would like to read more about Dr. Cohen’s work on AI and migraine, please visit fredcohenmd.com or TikTok @fredcohenmd. 

As we move further into the 21st century, technology continues to revolutionize various facets of our lives. Healthcare is a prime example. Advances in technology have dramatically reshaped the way we develop medications, diagnose diseases, and enhance patient care. The rise of artificial intelligence (AI) and the widespread adoption of digital health technologies have marked a significant milestone in improving the quality of care. AI, with its ability to leverage algorithms, deep learning, and machine learning to process data, make decisions, and perform tasks autonomously, is becoming an integral part of modern society. It is embedded in various technologies that we rely on daily, from smartphones and smart home devices to content recommendations on streaming services and social media platforms.

In healthcare, AI has applications in numerous fields, such as radiology. AI streamlines processes such as organizing patient appointments, optimizing radiation protocols for safety and efficiency, and enhancing the documentation process through advanced image analysis. AI technology plays an integral role in imaging tasks like image enhancement, lesion detection, and precise measurement. In difficult-to-interpret radiologic studies, such as some mammography images, it can be a crucial aid to the radiologist. Additionally, the use of AI has significantly improved remote patient monitoring that enables healthcare professionals to monitor and assess patient conditions without needing in-person visits. Remote patient monitoring gained prominence during the COVID-19 pandemic and continues to be a valuable tool in post pandemic care. Study results have highlighted that AI-driven ambient dictation tools have increased provider engagement with patients during consultations while reducing the time spent documenting in electronic health records.

Like many other medical specialties, headache medicine also uses AI. Most prominently, AI has been used in models and engines in assisting with headache diagnoses. A noteworthy example of AI in headache medicine is the development of an online, computer-based diagnostic engine (CDE) by Rapoport et al, called BonTriage. This tool is designed to diagnose headaches by employing a rule set based on the International Classification of Headache Disorders-3 (ICHD-3) criteria for primary headache disorders while also evaluating secondary headaches and medication overuse headaches. By leveraging machine learning, the CDE has the potential to streamline the diagnostic process, reducing the number of questions needed to reach a diagnosis and making the experience more efficient. This information can then be printed as a PDF file and taken by the patient to a healthcare professional for further discussion, fostering a more accurate, fluid, and conversational consultation.

A study was conducted to evaluate the accuracy of the CDE. Participants were randomly assigned to 1 of 2 sequences: (1) using the CDE followed by a structured standard interview with a headache specialist using the same ICHD-3 criteria or (2) starting with the structured standard interview followed by the CDE. The results demonstrated nearly perfect agreement in diagnosing migraine and probable migraine between the CDE and structured standard interview (κ = 0.82, 95% CI: 0.74, 0.90). The CDE demonstrated a diagnostic accuracy of 91.6% (95% CI: 86.9%, 95.0%), a sensitivity rate of 89.0% (95% CI: 82.5%, 93.7%), and a specificity rate of 97.0% (95% CI: 89.5%, 99.6%).

A diagnostic engine such as this can save time that clinicians spend on documentation and allow more time for discussion with the patient. For instance, a patient can take the printout received from the CDE to an appointment; the printout gives a detailed history plus information about social and psychological issues, a list of medications taken, and results of previous testing. The CDE system was originally designed to help patients see a specialist in the environment of a nationwide lack of headache specialists. There are currently 45 million patients with headaches who are seeking treatment with only around 550 certified headache specialists in the United States. The CDE printed information can help a patient obtain a consultation from a clinician quickly and start evaluation and treatment earlier. This expert online consultation is currently free of charge.

Kwon et al developed a machine learning–based model designed to automatically classify headache disorders using data from a questionnaire. Their model was able to predict diagnoses for conditions such as migraine, tension-type headaches, trigeminal autonomic cephalalgia, epicranial headache, and thunderclap headaches. The model was trained on data from 2162 patients, all diagnosed by headache specialists, and achieved an overall accuracy of 81%, with a sensitivity of 88% and a specificity of 95% for diagnosing migraines. However, the model’s performance was less robust when applied to other headache disorders.

Katsuki et al developed an AI model to help non specialists accurately diagnose headaches. This model analyzed 17 variables and was trained on data from 2800 patients, with additional testing and refinement using data from another 200 patients. To evaluate its effectiveness, 2 groups of non-headache specialists each assessed 50 patients: 1 group relied solely on their expertise, while the other used the AI model. The group without AI assistance achieved an overall accuracy of 46% (κ = 0.21), while the group using the AI model significantly improved, reaching an overall accuracy of 83.2% (κ = 0.68).

Building on their work with AI for diagnosing headaches, Katsuki et al conducted a study using a smartphone application that tracked user-reported headache events alongside local weather data. The AI model revealed that lower barometric pressure, higher humidity, and increased rainfall were linked to the onset of headache attacks. The application also identified triggers for headaches in specific weather patterns, such as a drop in barometric pressure noted 6 hours before headache onset. The application of AI in monitoring weather changes could be crucial, especially given concerns that the rising frequency of severe weather events due to climate change may be exacerbating the severity and burden of migraine. Additionally, recent post hoc analyses of fremanezumab clinical trials have provided further evidence that weather changes can trigger headaches.

Rapoport and colleagues have also developed an application called Migraine Mentor, which accurately tracks headaches, triggers, health data, and response to medication on a smartphone. The patient spends 3 minutes a day answering a few questions about their day and whether they had a headache or took any medication. At 1 or 2 months, Migraine Mentor can generate a detailed report with data and current trends that is sent to the patient, which the patient can then share with the clinician. The application also reminds patients when to document data and take medication.

However, although the use of AI in headache medicine appears promising, caution must be exercised to ensure proper results and information are disseminated. One rapidly expanding application of AI is the widely popular ChatGPT. ChatGPT, which stands for generative pretraining transformer, is a type of large language model (LLM). An LLM is a deep learning algorithm designed to recognize, translate, predict, summarize, and generate text responses based on a given prompt. This model is trained on an extensive dataset that includes a diverse array of books, articles, and websites, exposing it to various language structures and styles. This training enables ChatGPT to generate responses that closely mimic human communication. LLMs are being used more and more in medicine to assist with generating patient documentation and educational materials.

However, Dr Fred Cohen published a perspective piece detailing how LLMs (such as ChatGPT) can produce misleading and inaccurate answers. In his example, he tasked ChatGPT to describe the epidemiology of migraines in penguins; the AI model generated a well-written and highly believable manuscript titled, “Migraine Under the Ice: Understanding Headaches in Antarctica's Feathered Friends.” The manuscript highlights that migraines are more prevalent in male penguins compared to females, with the peak age of onset occurring between 4 and 5 years. Additionally, emperor and king penguins are identified as being more susceptible to developing migraines compared to other penguin species. The paper was fictitious (as no studies on migraine in penguins have been written to date), exemplifying that these models can produce nonfactual materials.

For years, technological advancements have been reshaping many aspects of life, and medicine is no exception. AI has been successfully applied to streamline medical documentation, develop new drug targets, and deepen our understanding of various diseases. The field of headache medicine now also uses AI. Recent developments show significant promise, with AI aiding in the diagnosis of migraine and other headache disorders. AI models have even been used in the identification of potential drug targets for migraine treatment. Although there are still limitations to overcome, the future of AI in headache medicine appears bright.

If you would like to read more about Dr. Cohen’s work on AI and migraine, please visit fredcohenmd.com or TikTok @fredcohenmd. 

As we move further into the 21st century, technology continues to revolutionize various facets of our lives. Healthcare is a prime example. Advances in technology have dramatically reshaped the way we develop medications, diagnose diseases, and enhance patient care. The rise of artificial intelligence (AI) and the widespread adoption of digital health technologies have marked a significant milestone in improving the quality of care. AI, with its ability to leverage algorithms, deep learning, and machine learning to process data, make decisions, and perform tasks autonomously, is becoming an integral part of modern society. It is embedded in various technologies that we rely on daily, from smartphones and smart home devices to content recommendations on streaming services and social media platforms.

In healthcare, AI has applications in numerous fields, such as radiology. AI streamlines processes such as organizing patient appointments, optimizing radiation protocols for safety and efficiency, and enhancing the documentation process through advanced image analysis. AI technology plays an integral role in imaging tasks like image enhancement, lesion detection, and precise measurement. In difficult-to-interpret radiologic studies, such as some mammography images, it can be a crucial aid to the radiologist. Additionally, the use of AI has significantly improved remote patient monitoring that enables healthcare professionals to monitor and assess patient conditions without needing in-person visits. Remote patient monitoring gained prominence during the COVID-19 pandemic and continues to be a valuable tool in post pandemic care. Study results have highlighted that AI-driven ambient dictation tools have increased provider engagement with patients during consultations while reducing the time spent documenting in electronic health records.

Like many other medical specialties, headache medicine also uses AI. Most prominently, AI has been used in models and engines in assisting with headache diagnoses. A noteworthy example of AI in headache medicine is the development of an online, computer-based diagnostic engine (CDE) by Rapoport et al, called BonTriage. This tool is designed to diagnose headaches by employing a rule set based on the International Classification of Headache Disorders-3 (ICHD-3) criteria for primary headache disorders while also evaluating secondary headaches and medication overuse headaches. By leveraging machine learning, the CDE has the potential to streamline the diagnostic process, reducing the number of questions needed to reach a diagnosis and making the experience more efficient. This information can then be printed as a PDF file and taken by the patient to a healthcare professional for further discussion, fostering a more accurate, fluid, and conversational consultation.

A study was conducted to evaluate the accuracy of the CDE. Participants were randomly assigned to 1 of 2 sequences: (1) using the CDE followed by a structured standard interview with a headache specialist using the same ICHD-3 criteria or (2) starting with the structured standard interview followed by the CDE. The results demonstrated nearly perfect agreement in diagnosing migraine and probable migraine between the CDE and structured standard interview (κ = 0.82, 95% CI: 0.74, 0.90). The CDE demonstrated a diagnostic accuracy of 91.6% (95% CI: 86.9%, 95.0%), a sensitivity rate of 89.0% (95% CI: 82.5%, 93.7%), and a specificity rate of 97.0% (95% CI: 89.5%, 99.6%).

A diagnostic engine such as this can save time that clinicians spend on documentation and allow more time for discussion with the patient. For instance, a patient can take the printout received from the CDE to an appointment; the printout gives a detailed history plus information about social and psychological issues, a list of medications taken, and results of previous testing. The CDE system was originally designed to help patients see a specialist in the environment of a nationwide lack of headache specialists. There are currently 45 million patients with headaches who are seeking treatment with only around 550 certified headache specialists in the United States. The CDE printed information can help a patient obtain a consultation from a clinician quickly and start evaluation and treatment earlier. This expert online consultation is currently free of charge.

Kwon et al developed a machine learning–based model designed to automatically classify headache disorders using data from a questionnaire. Their model was able to predict diagnoses for conditions such as migraine, tension-type headaches, trigeminal autonomic cephalalgia, epicranial headache, and thunderclap headaches. The model was trained on data from 2162 patients, all diagnosed by headache specialists, and achieved an overall accuracy of 81%, with a sensitivity of 88% and a specificity of 95% for diagnosing migraines. However, the model’s performance was less robust when applied to other headache disorders.

Katsuki et al developed an AI model to help non specialists accurately diagnose headaches. This model analyzed 17 variables and was trained on data from 2800 patients, with additional testing and refinement using data from another 200 patients. To evaluate its effectiveness, 2 groups of non-headache specialists each assessed 50 patients: 1 group relied solely on their expertise, while the other used the AI model. The group without AI assistance achieved an overall accuracy of 46% (κ = 0.21), while the group using the AI model significantly improved, reaching an overall accuracy of 83.2% (κ = 0.68).

Building on their work with AI for diagnosing headaches, Katsuki et al conducted a study using a smartphone application that tracked user-reported headache events alongside local weather data. The AI model revealed that lower barometric pressure, higher humidity, and increased rainfall were linked to the onset of headache attacks. The application also identified triggers for headaches in specific weather patterns, such as a drop in barometric pressure noted 6 hours before headache onset. The application of AI in monitoring weather changes could be crucial, especially given concerns that the rising frequency of severe weather events due to climate change may be exacerbating the severity and burden of migraine. Additionally, recent post hoc analyses of fremanezumab clinical trials have provided further evidence that weather changes can trigger headaches.

Rapoport and colleagues have also developed an application called Migraine Mentor, which accurately tracks headaches, triggers, health data, and response to medication on a smartphone. The patient spends 3 minutes a day answering a few questions about their day and whether they had a headache or took any medication. At 1 or 2 months, Migraine Mentor can generate a detailed report with data and current trends that is sent to the patient, which the patient can then share with the clinician. The application also reminds patients when to document data and take medication.

However, although the use of AI in headache medicine appears promising, caution must be exercised to ensure proper results and information are disseminated. One rapidly expanding application of AI is the widely popular ChatGPT. ChatGPT, which stands for generative pretraining transformer, is a type of large language model (LLM). An LLM is a deep learning algorithm designed to recognize, translate, predict, summarize, and generate text responses based on a given prompt. This model is trained on an extensive dataset that includes a diverse array of books, articles, and websites, exposing it to various language structures and styles. This training enables ChatGPT to generate responses that closely mimic human communication. LLMs are being used more and more in medicine to assist with generating patient documentation and educational materials.

However, Dr Fred Cohen published a perspective piece detailing how LLMs (such as ChatGPT) can produce misleading and inaccurate answers. In his example, he tasked ChatGPT to describe the epidemiology of migraines in penguins; the AI model generated a well-written and highly believable manuscript titled, “Migraine Under the Ice: Understanding Headaches in Antarctica's Feathered Friends.” The manuscript highlights that migraines are more prevalent in male penguins compared to females, with the peak age of onset occurring between 4 and 5 years. Additionally, emperor and king penguins are identified as being more susceptible to developing migraines compared to other penguin species. The paper was fictitious (as no studies on migraine in penguins have been written to date), exemplifying that these models can produce nonfactual materials.

For years, technological advancements have been reshaping many aspects of life, and medicine is no exception. AI has been successfully applied to streamline medical documentation, develop new drug targets, and deepen our understanding of various diseases. The field of headache medicine now also uses AI. Recent developments show significant promise, with AI aiding in the diagnosis of migraine and other headache disorders. AI models have even been used in the identification of potential drug targets for migraine treatment. Although there are still limitations to overcome, the future of AI in headache medicine appears bright.

If you would like to read more about Dr. Cohen’s work on AI and migraine, please visit fredcohenmd.com or TikTok @fredcohenmd. 

Colorectal cancer (CRC) is the third-most diagnosed cancer after breast and lung cancer, and is the second leading cause of global cancer related deaths.¹ In 2023 in the United States, > 150,000 individuals were diagnosed with CRC and 52,000 died.²

Colonoscopy is an effective CRC screening method and the lone method recommended for polyp surveillance. Inadequate bowel preparation (IBP) has been estimated to occur in about 6% to 26% of colonoscopies. ^3,4 The prevalence varies based on a variety of comorbidities, including immobility, diabetes mellitus, neurologic disorders, and use of opioids, with more occurrences of IBP noted in older adult, non-English speaking, and male individuals.^4-6

The quality of bowel preparation is integral to the effectiveness of screening and surveillance colonoscopies. IBP has been associated with missed adenomas and significantly lower adenoma detection rates.^7-9 In particular, IBP is independently associated with an increased risk of CRC in the future.³ Accordingly, the US Multisociety Task Force recommends repeat colonoscopies for individuals with IBP within 1 year.¹⁰ Ensuring that these individuals receive repeat colonoscopies is an essential part of CRC prevention. The benefit of repeat colonoscopy after IBP is highlighted by a retrospective analysis from Fung and colleagues that showed 81% of repeat colonoscopies had adequate bowel preparation, with higher numbers of adenomas detected on repeat compared to initial colonoscopies.¹¹

Given the impact of bowel preparation quality on the diagnostic capability of the colonoscopy, adherence to guidelines for repeat colonoscopies in cases of IBP is paramount for effective CRC prevention. This study aims to measure the frequency of repeat colonoscopy after IBP and the factors associated with adherence to recommendations.

METHODS

Individuals who underwent colonoscopy at the Minneapolis Veterans Affairs Medical Center (MVAMC) from January 1, 2016, to October 19, 2021, were identified to allow for 400 days of follow-up from the index colonoscopy to the data collection date. During the COVID-19 pandemic, the colonoscopy procedure capacity was reduced by 50% from June 1, 2020, to December 1, 2020, delaying nonurgent procedures, including screening and surveillance colonoscopies.

Individuals who underwent colonoscopy for CRC screening or polyp surveillance, or following a positive fecal immunohistochemistry test (FIT) or virtual computed tomography colonoscopy were included. Patients with colonoscopy indications for iron deficiency anemia, gastrointestinal bleeding, disease activity assessment of inflammatory bowel disease, abdominal pain, or changes in bowel movement pattern were excluded. IBP was defined as recording a Boston Bowel Preparation Scale (BBPS) score of < 6, or < 2 in any segment, or described as poor or inadequate using the Aronchick scale.

Age, sex, race, marital status, distance to MVAMC, smoking status, comorbidities, and concurrent medication use, including antiplatelet, anticoagulation, and prescription opiates at the time of index colonoscopy were obtained from the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW) using structured query language processing of colonoscopy procedure notes to extract preparation scores and other procedure information. The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999.¹² Current smoking status was defined as any smoking activity at the time the questionnaire was administered during a routine clinic visit within 400 days from the index colonoscopy.

Only individuals who were recommended to have repeat colonoscopy within 1 year were included. The intervals of 365 days and 400 days (1 year + about 1 additional month) were used in the event that the individual had a delay in scheduling their 1-year repeat colonoscopy. For individuals who did not undergo a colonoscopy at MVAMC within 400 days, a manual chart review of all available records was performed to determine whether a colonoscopy was performed at a non-VA facility.

Patients received written instructions for bowel preparation 2 weeks prior to the procedure. The preparation included magnesium citrate and a split dose of 4 liters of polyethylene glycol. Patients were also advised to start a low-fiber diet 3 days prior to the procedure and a clear liquid diet the day before the procedure. Patients with a history of IBP or those undergoing procedures with anesthesia received an additional 2 liters for a total of 6 liters of polyethylene glycol.

Statistical analysis

Baseline characteristics were reported as mean (SD) or median and IQR for continuous variables and percentage for categorical variables. Individuals who returned for colonoscopy within 400 days were compared to those who did not identify factors associated with adherence to recommendations. The data on individuals who returned for colonoscopy within 400 days were also analyzed for additional minor delays in the timing of the repeat colonoscopy. Continuous data were compared using Mann-Whitney U tests. Categorical data were compared using X² or Fisher exact tests. Missing data were imputed from the analyses. All analyses were performed using SAS JMP Pro version 16. P < .05 was considered statistically significant.

RESULTS

There were 18,241 total colonoscopies performed between January 1, 2016, to October 19, 2021, and 13,818 colonoscopies had indications for screening for colon cancer, positive FIT, virtual colonoscopy, or surveillance. Of the 10,466 unique patients there were 5369 patients for polyp surveillance, 4054 patients for CRC screening, and 1043 patients for positive FIT or virtual colonoscopy. Of these, 571 individuals (5.5%) had IBP. Repeat colonoscopy within 1 year was recommended for 485 individuals (84.9%) who were included in this study (153 CRC screenings and 46 positive FITs) but not for 86 individuals (15.1%) (Figure 1). Among included patients, the mean (SD) age was 66.6 (7.2) years, and the majority were male (460 [94.8%]) and White (435 [89.7%]) (Table). Two hundred and forty-three (50.1%) were married.

Adherence to Recommended Interval Colonoscopy

Of the 485 patients with IBP who were recommended for follow-up colonoscopy, 287 (59.2%) had a colonoscopy within 1 year, and 198 (40.8%) did not; 17 patients (13.5%) had repeat colonoscopy within 366 to 400 days. Five (1.0%) individuals had a repeat colonoscopy the next day, and 77 (15.9%) had a repeat colonoscopy within 7 days. One hundred and twentysix (26.0%) individuals underwent no repeat colonoscopy during the study period (Figure 2).

To account for the COVID-19 pandemic, the adherence rate of repeat colonoscopy within 1 year prepandemic (January 1, 2016, to December 1, 2018) was calculated along with the adherence rate postpandemic (January 1, 2019 to the end of the study). The rates were similar: 199 of 330 (60.3%) individuals prepandemic vs 88 of 155 (56.8%) individuals postpandemic (Figure 3).

Significant Associations

Age, sex, and race were not associated with adherence to repeat colonoscopy within 1 year. Individuals living ≤ 40 miles from the endoscopy center were more likely to undergo a repeat colonoscopy within 1 year compared with those who lived > 40 miles away (61.7% vs 51.0%, P = .02). Current smoking status was associated with a lower rate of repeat colonoscopy within 1 year (25.8% vs 35.9%; P = .02). There were no differences with respect to inflammatory bowel disease diagnosis, mental health diagnosis, diabetes mellitus, cirrhosis, or medications used, including opioids, anticoagulation, and antiplatelet therapy.

Outcomes

Among individuals who had a repeat colonoscopy the day after the index colonoscopy, 53 of 56 individuals (94.6%) had adequate bowel preparation. Among individuals who had a repeat colonoscopy within 7 days, 70 of 77 (90.9%) had adequate bowel preparation. Of 287 individuals with a repeat colonoscopy within 1 year, 251 (87.5%) had adequate bowel preparation on the repeat colonoscopy. By 400 days after the index colonoscopy, 268 of 304 individuals (88.2%) had adequate bowel preparation.

In this study conducted at a large VA medical center, we found that 5.6% of individuals undergoing colonoscopies had IBP, a rate comparable to prior studies (6% to 26%).^3,4 Only 59.2% of individuals underwent repeat colonoscopies within 1 year, as recommended after an index colonoscopy with IBP. Smoking and living longer distances (> 40 miles) from the endoscopy center were associated with a decreased adherence to the repeat colonoscopy recommendation.

Current guidelines recommend repeat colonoscopy for individuals with IBP within 1 year.¹⁰ In cases of IBP, the advanced adenoma miss rate is 36% upon repeat colonoscopy within 1 year.¹³ Despite the importance of a follow-up colonoscopy, clinician adherence with this recommendation remains low.^10,14,15 However, in this study cohort, 485 of 571 individuals with IBP (84.9%) received recommendations for a repeat colonoscopy within 1 year. In the US, only 31.9% of 260,314 colonoscopies with IBP included recommendations for a follow-up colonoscopy within 1 year.¹⁴ This could be related to variations in endoscopist practice as well as patient risk factors for developing polyps, including family history of cancer and personal history of prior polyps. The findings of multiple polyps, high-risk adenomas, and cancer on the index colonoscopy also influences the endoscopist for repeat colonoscopy within 1 year.¹⁴

The timing for repeat colonoscopies within 1 year will be determined by the patients, clinicians, and available scheduling. In this study, the earlier repeat colonoscopies, especially those occurring the day after the index colonoscopy, had the highest success rate of adequate bowel preparation. In a prior study, repeating colonoscopies within the same day or the next day was also found to have a higher rate of adequate bowel preparation than repeat colonoscopies within 1 year (88.9% vs 83.5%).¹⁶

Ensuring the return of individuals with IBP for repeat colonoscopy is a challenging task. We identified that individuals who live further away from MVAMC and current smokers had a decreased probability of returning for a repeat colonoscopy. Toro and colleagues found a 68.7% return rate for a repeat colonoscopy within 1 year with individuals age ≥ 60 years, and patients who were White were less likely to proceed with a repeat colonoscopy within 1 year.¹⁷ The study did not provide data regarding smoking status or distance to the endoscopy center.¹⁷ In a prior study of veterans, the dual diagnosis of psychiatric disorders and substance abuse was associated with missed and canceled colonoscopy appointments.¹⁸ The distance to the endoscopy center has also been previously identified as a barrier to a colonoscopy following an abnormal FIT.¹⁹ Although not identified in this study due to the homogenous demographic profile, social determinants of health such as socioeconomic status, education, and insurance coverage are known barriers to cancer screening but were not evaluated in this study.²⁰

Based on the identified risk factors, we have created a model for utilizing those risk factors to identify individuals at higher risk for noncompliance (ie, those who live further away from the endoscopy center or currently smoke). These individuals are proactively offered to use an intraprocedural bowel cleansing device to achieve adequate bowel preparation or priority rescheduling for a next-day colonoscopy.

Limitations

This study was a single-center study of the veteran population, which is predominantly White and male, thus limiting generalizability. The study is also limited by minimal available data on adenoma detection and colon cancer incidence on subsequent colonoscopies.

CONCLUSIONS

The rate of IBP was 5.5% in individuals undergoing colonoscopy for colon cancer screening, surveillance, positive FIT, or computed tomography colonography. Only 59.2% of those with IBP underwent the recommended repeat colonoscopy within 1 year. Smoking and distance to the endoscopy center were associated with a decreased adherence to the repeat colonoscopy recommendation. Additional efforts are needed to ensure that individuals with IBP return for timely repeat colonoscopy.

Colorectal cancer (CRC) is the third-most diagnosed cancer after breast and lung cancer, and is the second leading cause of global cancer related deaths.¹ In 2023 in the United States, > 150,000 individuals were diagnosed with CRC and 52,000 died.²

Colonoscopy is an effective CRC screening method and the lone method recommended for polyp surveillance. Inadequate bowel preparation (IBP) has been estimated to occur in about 6% to 26% of colonoscopies. ^3,4 The prevalence varies based on a variety of comorbidities, including immobility, diabetes mellitus, neurologic disorders, and use of opioids, with more occurrences of IBP noted in older adult, non-English speaking, and male individuals.^4-6

The quality of bowel preparation is integral to the effectiveness of screening and surveillance colonoscopies. IBP has been associated with missed adenomas and significantly lower adenoma detection rates.^7-9 In particular, IBP is independently associated with an increased risk of CRC in the future.³ Accordingly, the US Multisociety Task Force recommends repeat colonoscopies for individuals with IBP within 1 year.¹⁰ Ensuring that these individuals receive repeat colonoscopies is an essential part of CRC prevention. The benefit of repeat colonoscopy after IBP is highlighted by a retrospective analysis from Fung and colleagues that showed 81% of repeat colonoscopies had adequate bowel preparation, with higher numbers of adenomas detected on repeat compared to initial colonoscopies.¹¹

Given the impact of bowel preparation quality on the diagnostic capability of the colonoscopy, adherence to guidelines for repeat colonoscopies in cases of IBP is paramount for effective CRC prevention. This study aims to measure the frequency of repeat colonoscopy after IBP and the factors associated with adherence to recommendations.

METHODS

Individuals who underwent colonoscopy at the Minneapolis Veterans Affairs Medical Center (MVAMC) from January 1, 2016, to October 19, 2021, were identified to allow for 400 days of follow-up from the index colonoscopy to the data collection date. During the COVID-19 pandemic, the colonoscopy procedure capacity was reduced by 50% from June 1, 2020, to December 1, 2020, delaying nonurgent procedures, including screening and surveillance colonoscopies.

Individuals who underwent colonoscopy for CRC screening or polyp surveillance, or following a positive fecal immunohistochemistry test (FIT) or virtual computed tomography colonoscopy were included. Patients with colonoscopy indications for iron deficiency anemia, gastrointestinal bleeding, disease activity assessment of inflammatory bowel disease, abdominal pain, or changes in bowel movement pattern were excluded. IBP was defined as recording a Boston Bowel Preparation Scale (BBPS) score of < 6, or < 2 in any segment, or described as poor or inadequate using the Aronchick scale.

Age, sex, race, marital status, distance to MVAMC, smoking status, comorbidities, and concurrent medication use, including antiplatelet, anticoagulation, and prescription opiates at the time of index colonoscopy were obtained from the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW) using structured query language processing of colonoscopy procedure notes to extract preparation scores and other procedure information. The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999.¹² Current smoking status was defined as any smoking activity at the time the questionnaire was administered during a routine clinic visit within 400 days from the index colonoscopy.

Only individuals who were recommended to have repeat colonoscopy within 1 year were included. The intervals of 365 days and 400 days (1 year + about 1 additional month) were used in the event that the individual had a delay in scheduling their 1-year repeat colonoscopy. For individuals who did not undergo a colonoscopy at MVAMC within 400 days, a manual chart review of all available records was performed to determine whether a colonoscopy was performed at a non-VA facility.

Patients received written instructions for bowel preparation 2 weeks prior to the procedure. The preparation included magnesium citrate and a split dose of 4 liters of polyethylene glycol. Patients were also advised to start a low-fiber diet 3 days prior to the procedure and a clear liquid diet the day before the procedure. Patients with a history of IBP or those undergoing procedures with anesthesia received an additional 2 liters for a total of 6 liters of polyethylene glycol.

Statistical analysis

Baseline characteristics were reported as mean (SD) or median and IQR for continuous variables and percentage for categorical variables. Individuals who returned for colonoscopy within 400 days were compared to those who did not identify factors associated with adherence to recommendations. The data on individuals who returned for colonoscopy within 400 days were also analyzed for additional minor delays in the timing of the repeat colonoscopy. Continuous data were compared using Mann-Whitney U tests. Categorical data were compared using X² or Fisher exact tests. Missing data were imputed from the analyses. All analyses were performed using SAS JMP Pro version 16. P < .05 was considered statistically significant.

RESULTS

There were 18,241 total colonoscopies performed between January 1, 2016, to October 19, 2021, and 13,818 colonoscopies had indications for screening for colon cancer, positive FIT, virtual colonoscopy, or surveillance. Of the 10,466 unique patients there were 5369 patients for polyp surveillance, 4054 patients for CRC screening, and 1043 patients for positive FIT or virtual colonoscopy. Of these, 571 individuals (5.5%) had IBP. Repeat colonoscopy within 1 year was recommended for 485 individuals (84.9%) who were included in this study (153 CRC screenings and 46 positive FITs) but not for 86 individuals (15.1%) (Figure 1). Among included patients, the mean (SD) age was 66.6 (7.2) years, and the majority were male (460 [94.8%]) and White (435 [89.7%]) (Table). Two hundred and forty-three (50.1%) were married.

Adherence to Recommended Interval Colonoscopy

Of the 485 patients with IBP who were recommended for follow-up colonoscopy, 287 (59.2%) had a colonoscopy within 1 year, and 198 (40.8%) did not; 17 patients (13.5%) had repeat colonoscopy within 366 to 400 days. Five (1.0%) individuals had a repeat colonoscopy the next day, and 77 (15.9%) had a repeat colonoscopy within 7 days. One hundred and twentysix (26.0%) individuals underwent no repeat colonoscopy during the study period (Figure 2).

To account for the COVID-19 pandemic, the adherence rate of repeat colonoscopy within 1 year prepandemic (January 1, 2016, to December 1, 2018) was calculated along with the adherence rate postpandemic (January 1, 2019 to the end of the study). The rates were similar: 199 of 330 (60.3%) individuals prepandemic vs 88 of 155 (56.8%) individuals postpandemic (Figure 3).

Significant Associations

Age, sex, and race were not associated with adherence to repeat colonoscopy within 1 year. Individuals living ≤ 40 miles from the endoscopy center were more likely to undergo a repeat colonoscopy within 1 year compared with those who lived > 40 miles away (61.7% vs 51.0%, P = .02). Current smoking status was associated with a lower rate of repeat colonoscopy within 1 year (25.8% vs 35.9%; P = .02). There were no differences with respect to inflammatory bowel disease diagnosis, mental health diagnosis, diabetes mellitus, cirrhosis, or medications used, including opioids, anticoagulation, and antiplatelet therapy.

Outcomes

Among individuals who had a repeat colonoscopy the day after the index colonoscopy, 53 of 56 individuals (94.6%) had adequate bowel preparation. Among individuals who had a repeat colonoscopy within 7 days, 70 of 77 (90.9%) had adequate bowel preparation. Of 287 individuals with a repeat colonoscopy within 1 year, 251 (87.5%) had adequate bowel preparation on the repeat colonoscopy. By 400 days after the index colonoscopy, 268 of 304 individuals (88.2%) had adequate bowel preparation.

In this study conducted at a large VA medical center, we found that 5.6% of individuals undergoing colonoscopies had IBP, a rate comparable to prior studies (6% to 26%).^3,4 Only 59.2% of individuals underwent repeat colonoscopies within 1 year, as recommended after an index colonoscopy with IBP. Smoking and living longer distances (> 40 miles) from the endoscopy center were associated with a decreased adherence to the repeat colonoscopy recommendation.

Current guidelines recommend repeat colonoscopy for individuals with IBP within 1 year.¹⁰ In cases of IBP, the advanced adenoma miss rate is 36% upon repeat colonoscopy within 1 year.¹³ Despite the importance of a follow-up colonoscopy, clinician adherence with this recommendation remains low.^10,14,15 However, in this study cohort, 485 of 571 individuals with IBP (84.9%) received recommendations for a repeat colonoscopy within 1 year. In the US, only 31.9% of 260,314 colonoscopies with IBP included recommendations for a follow-up colonoscopy within 1 year.¹⁴ This could be related to variations in endoscopist practice as well as patient risk factors for developing polyps, including family history of cancer and personal history of prior polyps. The findings of multiple polyps, high-risk adenomas, and cancer on the index colonoscopy also influences the endoscopist for repeat colonoscopy within 1 year.¹⁴

The timing for repeat colonoscopies within 1 year will be determined by the patients, clinicians, and available scheduling. In this study, the earlier repeat colonoscopies, especially those occurring the day after the index colonoscopy, had the highest success rate of adequate bowel preparation. In a prior study, repeating colonoscopies within the same day or the next day was also found to have a higher rate of adequate bowel preparation than repeat colonoscopies within 1 year (88.9% vs 83.5%).¹⁶

Ensuring the return of individuals with IBP for repeat colonoscopy is a challenging task. We identified that individuals who live further away from MVAMC and current smokers had a decreased probability of returning for a repeat colonoscopy. Toro and colleagues found a 68.7% return rate for a repeat colonoscopy within 1 year with individuals age ≥ 60 years, and patients who were White were less likely to proceed with a repeat colonoscopy within 1 year.¹⁷ The study did not provide data regarding smoking status or distance to the endoscopy center.¹⁷ In a prior study of veterans, the dual diagnosis of psychiatric disorders and substance abuse was associated with missed and canceled colonoscopy appointments.¹⁸ The distance to the endoscopy center has also been previously identified as a barrier to a colonoscopy following an abnormal FIT.¹⁹ Although not identified in this study due to the homogenous demographic profile, social determinants of health such as socioeconomic status, education, and insurance coverage are known barriers to cancer screening but were not evaluated in this study.²⁰

Based on the identified risk factors, we have created a model for utilizing those risk factors to identify individuals at higher risk for noncompliance (ie, those who live further away from the endoscopy center or currently smoke). These individuals are proactively offered to use an intraprocedural bowel cleansing device to achieve adequate bowel preparation or priority rescheduling for a next-day colonoscopy.

Limitations

This study was a single-center study of the veteran population, which is predominantly White and male, thus limiting generalizability. The study is also limited by minimal available data on adenoma detection and colon cancer incidence on subsequent colonoscopies.

CONCLUSIONS

The rate of IBP was 5.5% in individuals undergoing colonoscopy for colon cancer screening, surveillance, positive FIT, or computed tomography colonography. Only 59.2% of those with IBP underwent the recommended repeat colonoscopy within 1 year. Smoking and distance to the endoscopy center were associated with a decreased adherence to the repeat colonoscopy recommendation. Additional efforts are needed to ensure that individuals with IBP return for timely repeat colonoscopy.

Colorectal cancer (CRC) is the third-most diagnosed cancer after breast and lung cancer, and is the second leading cause of global cancer related deaths.¹ In 2023 in the United States, > 150,000 individuals were diagnosed with CRC and 52,000 died.²

Colonoscopy is an effective CRC screening method and the lone method recommended for polyp surveillance. Inadequate bowel preparation (IBP) has been estimated to occur in about 6% to 26% of colonoscopies. ^3,4 The prevalence varies based on a variety of comorbidities, including immobility, diabetes mellitus, neurologic disorders, and use of opioids, with more occurrences of IBP noted in older adult, non-English speaking, and male individuals.^4-6

The quality of bowel preparation is integral to the effectiveness of screening and surveillance colonoscopies. IBP has been associated with missed adenomas and significantly lower adenoma detection rates.^7-9 In particular, IBP is independently associated with an increased risk of CRC in the future.³ Accordingly, the US Multisociety Task Force recommends repeat colonoscopies for individuals with IBP within 1 year.¹⁰ Ensuring that these individuals receive repeat colonoscopies is an essential part of CRC prevention. The benefit of repeat colonoscopy after IBP is highlighted by a retrospective analysis from Fung and colleagues that showed 81% of repeat colonoscopies had adequate bowel preparation, with higher numbers of adenomas detected on repeat compared to initial colonoscopies.¹¹

Given the impact of bowel preparation quality on the diagnostic capability of the colonoscopy, adherence to guidelines for repeat colonoscopies in cases of IBP is paramount for effective CRC prevention. This study aims to measure the frequency of repeat colonoscopy after IBP and the factors associated with adherence to recommendations.

METHODS

Individuals who underwent colonoscopy at the Minneapolis Veterans Affairs Medical Center (MVAMC) from January 1, 2016, to October 19, 2021, were identified to allow for 400 days of follow-up from the index colonoscopy to the data collection date. During the COVID-19 pandemic, the colonoscopy procedure capacity was reduced by 50% from June 1, 2020, to December 1, 2020, delaying nonurgent procedures, including screening and surveillance colonoscopies.

Individuals who underwent colonoscopy for CRC screening or polyp surveillance, or following a positive fecal immunohistochemistry test (FIT) or virtual computed tomography colonoscopy were included. Patients with colonoscopy indications for iron deficiency anemia, gastrointestinal bleeding, disease activity assessment of inflammatory bowel disease, abdominal pain, or changes in bowel movement pattern were excluded. IBP was defined as recording a Boston Bowel Preparation Scale (BBPS) score of < 6, or < 2 in any segment, or described as poor or inadequate using the Aronchick scale.

Age, sex, race, marital status, distance to MVAMC, smoking status, comorbidities, and concurrent medication use, including antiplatelet, anticoagulation, and prescription opiates at the time of index colonoscopy were obtained from the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW) using structured query language processing of colonoscopy procedure notes to extract preparation scores and other procedure information. The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999.¹² Current smoking status was defined as any smoking activity at the time the questionnaire was administered during a routine clinic visit within 400 days from the index colonoscopy.

Only individuals who were recommended to have repeat colonoscopy within 1 year were included. The intervals of 365 days and 400 days (1 year + about 1 additional month) were used in the event that the individual had a delay in scheduling their 1-year repeat colonoscopy. For individuals who did not undergo a colonoscopy at MVAMC within 400 days, a manual chart review of all available records was performed to determine whether a colonoscopy was performed at a non-VA facility.

Patients received written instructions for bowel preparation 2 weeks prior to the procedure. The preparation included magnesium citrate and a split dose of 4 liters of polyethylene glycol. Patients were also advised to start a low-fiber diet 3 days prior to the procedure and a clear liquid diet the day before the procedure. Patients with a history of IBP or those undergoing procedures with anesthesia received an additional 2 liters for a total of 6 liters of polyethylene glycol.

Statistical analysis

Baseline characteristics were reported as mean (SD) or median and IQR for continuous variables and percentage for categorical variables. Individuals who returned for colonoscopy within 400 days were compared to those who did not identify factors associated with adherence to recommendations. The data on individuals who returned for colonoscopy within 400 days were also analyzed for additional minor delays in the timing of the repeat colonoscopy. Continuous data were compared using Mann-Whitney U tests. Categorical data were compared using X² or Fisher exact tests. Missing data were imputed from the analyses. All analyses were performed using SAS JMP Pro version 16. P < .05 was considered statistically significant.

RESULTS

There were 18,241 total colonoscopies performed between January 1, 2016, to October 19, 2021, and 13,818 colonoscopies had indications for screening for colon cancer, positive FIT, virtual colonoscopy, or surveillance. Of the 10,466 unique patients there were 5369 patients for polyp surveillance, 4054 patients for CRC screening, and 1043 patients for positive FIT or virtual colonoscopy. Of these, 571 individuals (5.5%) had IBP. Repeat colonoscopy within 1 year was recommended for 485 individuals (84.9%) who were included in this study (153 CRC screenings and 46 positive FITs) but not for 86 individuals (15.1%) (Figure 1). Among included patients, the mean (SD) age was 66.6 (7.2) years, and the majority were male (460 [94.8%]) and White (435 [89.7%]) (Table). Two hundred and forty-three (50.1%) were married.

Adherence to Recommended Interval Colonoscopy

Of the 485 patients with IBP who were recommended for follow-up colonoscopy, 287 (59.2%) had a colonoscopy within 1 year, and 198 (40.8%) did not; 17 patients (13.5%) had repeat colonoscopy within 366 to 400 days. Five (1.0%) individuals had a repeat colonoscopy the next day, and 77 (15.9%) had a repeat colonoscopy within 7 days. One hundred and twentysix (26.0%) individuals underwent no repeat colonoscopy during the study period (Figure 2).

To account for the COVID-19 pandemic, the adherence rate of repeat colonoscopy within 1 year prepandemic (January 1, 2016, to December 1, 2018) was calculated along with the adherence rate postpandemic (January 1, 2019 to the end of the study). The rates were similar: 199 of 330 (60.3%) individuals prepandemic vs 88 of 155 (56.8%) individuals postpandemic (Figure 3).

Significant Associations

Age, sex, and race were not associated with adherence to repeat colonoscopy within 1 year. Individuals living ≤ 40 miles from the endoscopy center were more likely to undergo a repeat colonoscopy within 1 year compared with those who lived > 40 miles away (61.7% vs 51.0%, P = .02). Current smoking status was associated with a lower rate of repeat colonoscopy within 1 year (25.8% vs 35.9%; P = .02). There were no differences with respect to inflammatory bowel disease diagnosis, mental health diagnosis, diabetes mellitus, cirrhosis, or medications used, including opioids, anticoagulation, and antiplatelet therapy.

Outcomes

Among individuals who had a repeat colonoscopy the day after the index colonoscopy, 53 of 56 individuals (94.6%) had adequate bowel preparation. Among individuals who had a repeat colonoscopy within 7 days, 70 of 77 (90.9%) had adequate bowel preparation. Of 287 individuals with a repeat colonoscopy within 1 year, 251 (87.5%) had adequate bowel preparation on the repeat colonoscopy. By 400 days after the index colonoscopy, 268 of 304 individuals (88.2%) had adequate bowel preparation.

In this study conducted at a large VA medical center, we found that 5.6% of individuals undergoing colonoscopies had IBP, a rate comparable to prior studies (6% to 26%).^3,4 Only 59.2% of individuals underwent repeat colonoscopies within 1 year, as recommended after an index colonoscopy with IBP. Smoking and living longer distances (> 40 miles) from the endoscopy center were associated with a decreased adherence to the repeat colonoscopy recommendation.

Current guidelines recommend repeat colonoscopy for individuals with IBP within 1 year.¹⁰ In cases of IBP, the advanced adenoma miss rate is 36% upon repeat colonoscopy within 1 year.¹³ Despite the importance of a follow-up colonoscopy, clinician adherence with this recommendation remains low.^10,14,15 However, in this study cohort, 485 of 571 individuals with IBP (84.9%) received recommendations for a repeat colonoscopy within 1 year. In the US, only 31.9% of 260,314 colonoscopies with IBP included recommendations for a follow-up colonoscopy within 1 year.¹⁴ This could be related to variations in endoscopist practice as well as patient risk factors for developing polyps, including family history of cancer and personal history of prior polyps. The findings of multiple polyps, high-risk adenomas, and cancer on the index colonoscopy also influences the endoscopist for repeat colonoscopy within 1 year.¹⁴

The timing for repeat colonoscopies within 1 year will be determined by the patients, clinicians, and available scheduling. In this study, the earlier repeat colonoscopies, especially those occurring the day after the index colonoscopy, had the highest success rate of adequate bowel preparation. In a prior study, repeating colonoscopies within the same day or the next day was also found to have a higher rate of adequate bowel preparation than repeat colonoscopies within 1 year (88.9% vs 83.5%).¹⁶

Ensuring the return of individuals with IBP for repeat colonoscopy is a challenging task. We identified that individuals who live further away from MVAMC and current smokers had a decreased probability of returning for a repeat colonoscopy. Toro and colleagues found a 68.7% return rate for a repeat colonoscopy within 1 year with individuals age ≥ 60 years, and patients who were White were less likely to proceed with a repeat colonoscopy within 1 year.¹⁷ The study did not provide data regarding smoking status or distance to the endoscopy center.¹⁷ In a prior study of veterans, the dual diagnosis of psychiatric disorders and substance abuse was associated with missed and canceled colonoscopy appointments.¹⁸ The distance to the endoscopy center has also been previously identified as a barrier to a colonoscopy following an abnormal FIT.¹⁹ Although not identified in this study due to the homogenous demographic profile, social determinants of health such as socioeconomic status, education, and insurance coverage are known barriers to cancer screening but were not evaluated in this study.²⁰

Based on the identified risk factors, we have created a model for utilizing those risk factors to identify individuals at higher risk for noncompliance (ie, those who live further away from the endoscopy center or currently smoke). These individuals are proactively offered to use an intraprocedural bowel cleansing device to achieve adequate bowel preparation or priority rescheduling for a next-day colonoscopy.

Limitations

This study was a single-center study of the veteran population, which is predominantly White and male, thus limiting generalizability. The study is also limited by minimal available data on adenoma detection and colon cancer incidence on subsequent colonoscopies.

CONCLUSIONS

The rate of IBP was 5.5% in individuals undergoing colonoscopy for colon cancer screening, surveillance, positive FIT, or computed tomography colonography. Only 59.2% of those with IBP underwent the recommended repeat colonoscopy within 1 year. Smoking and distance to the endoscopy center were associated with a decreased adherence to the repeat colonoscopy recommendation. Additional efforts are needed to ensure that individuals with IBP return for timely repeat colonoscopy.

Key clinical point: Nearly two out of three patients with psoriatic arthritis (PsA) had clinically significant central sensitization (CS), with the severity of psoriasis, anxiety level, and sleep quality being independent predictors of worse CS Inventory (CSI) scores.

Major finding: Overall, 65.1% patients had clinically significant CS, with a CSI score ≥ 40, with the severity of psoriasis and disease activity scores for PsA being positively associated with CSI scores (correlation coefficient 0.393-0.652; P < .001). The Psoriasis Area Severity Index (odds ratio [OR] 9.70; P = .017), General Anxiety Disorder-7 (OR 2.89; P = .014), and Insomnia Severity Index (OR 5.56; P = .041) scores were independent predictors of CS.

Study details: This cross-sectional observational study included 103 patients with PsA (age 18-75 years) with a mean CSI score of 45.4.

Disclosures: This study did not receive any financial support. The authors declared no conflicts of interest.

Source: Kaya MN, Tecer D, Kılıç Ö, et al. Impact of central sensitization on clinical and functional aspects of psoriatic arthritis. Medicina. 2024;60(9):1449 (Sept 4). Source

Key clinical point: Nearly two out of three patients with psoriatic arthritis (PsA) had clinically significant central sensitization (CS), with the severity of psoriasis, anxiety level, and sleep quality being independent predictors of worse CS Inventory (CSI) scores.

Major finding: Overall, 65.1% patients had clinically significant CS, with a CSI score ≥ 40, with the severity of psoriasis and disease activity scores for PsA being positively associated with CSI scores (correlation coefficient 0.393-0.652; P < .001). The Psoriasis Area Severity Index (odds ratio [OR] 9.70; P = .017), General Anxiety Disorder-7 (OR 2.89; P = .014), and Insomnia Severity Index (OR 5.56; P = .041) scores were independent predictors of CS.

Study details: This cross-sectional observational study included 103 patients with PsA (age 18-75 years) with a mean CSI score of 45.4.

Disclosures: This study did not receive any financial support. The authors declared no conflicts of interest.

Source: Kaya MN, Tecer D, Kılıç Ö, et al. Impact of central sensitization on clinical and functional aspects of psoriatic arthritis. Medicina. 2024;60(9):1449 (Sept 4). Source

Key clinical point: Nearly two out of three patients with psoriatic arthritis (PsA) had clinically significant central sensitization (CS), with the severity of psoriasis, anxiety level, and sleep quality being independent predictors of worse CS Inventory (CSI) scores.

Major finding: Overall, 65.1% patients had clinically significant CS, with a CSI score ≥ 40, with the severity of psoriasis and disease activity scores for PsA being positively associated with CSI scores (correlation coefficient 0.393-0.652; P < .001). The Psoriasis Area Severity Index (odds ratio [OR] 9.70; P = .017), General Anxiety Disorder-7 (OR 2.89; P = .014), and Insomnia Severity Index (OR 5.56; P = .041) scores were independent predictors of CS.

Study details: This cross-sectional observational study included 103 patients with PsA (age 18-75 years) with a mean CSI score of 45.4.

Disclosures: This study did not receive any financial support. The authors declared no conflicts of interest.

Source: Kaya MN, Tecer D, Kılıç Ö, et al. Impact of central sensitization on clinical and functional aspects of psoriatic arthritis. Medicina. 2024;60(9):1449 (Sept 4). Source

Key clinical point: Bimekizumab demonstrated consistent safety and sustained efficacy for up to 2 years in patients with psoriatic arthritis (PsA) who were biologic-naive or inadequately responsive to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: From weeks 52 to 104, the incidence of treatment emergent adverse events (TEAE) was consistent with previous studies, with no new safety signals. SARS-CoV2 infection (18.6 per 100 patient-years) was the most common TEAE. Approximately 50% biologic-naive and TNFi-IR patients maintained a ≥50% improvement in the American College of Rheumatology response.

Study details: This open-label extension (BE-VITAL) of two phase 3 trials included biologic-naive (n = 852) and TNFi-IR (n = 400) patients with PsA who were randomly assigned to receive bimekizumab, placebo with crossover to bimekizumab at week 16, or adalimumab followed by bimekizumab at week 52.

Disclosures: This study was sponsored by UCB Pharma. Five authors declared being employees or shareholders of UCB Pharma. LC Coates declared being an editorial board member of Rheumatology and Therapy. Other authors declared having ties with various sources, including UCB.

Source: Mease PJ, Merola JF, Tanaka Y, et al. Safety and efficacy of bimekizumab in patients with psoriatic arthritis: 2-year results from two phase 3 studies. Rheumatol Ther. 2024 (Aug 31). doi: 10.1007/s40744-024-00708-8 Source

Key clinical point: Bimekizumab demonstrated consistent safety and sustained efficacy for up to 2 years in patients with psoriatic arthritis (PsA) who were biologic-naive or inadequately responsive to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: From weeks 52 to 104, the incidence of treatment emergent adverse events (TEAE) was consistent with previous studies, with no new safety signals. SARS-CoV2 infection (18.6 per 100 patient-years) was the most common TEAE. Approximately 50% biologic-naive and TNFi-IR patients maintained a ≥50% improvement in the American College of Rheumatology response.

Study details: This open-label extension (BE-VITAL) of two phase 3 trials included biologic-naive (n = 852) and TNFi-IR (n = 400) patients with PsA who were randomly assigned to receive bimekizumab, placebo with crossover to bimekizumab at week 16, or adalimumab followed by bimekizumab at week 52.

Disclosures: This study was sponsored by UCB Pharma. Five authors declared being employees or shareholders of UCB Pharma. LC Coates declared being an editorial board member of Rheumatology and Therapy. Other authors declared having ties with various sources, including UCB.

Source: Mease PJ, Merola JF, Tanaka Y, et al. Safety and efficacy of bimekizumab in patients with psoriatic arthritis: 2-year results from two phase 3 studies. Rheumatol Ther. 2024 (Aug 31). doi: 10.1007/s40744-024-00708-8 Source

Key clinical point: Bimekizumab demonstrated consistent safety and sustained efficacy for up to 2 years in patients with psoriatic arthritis (PsA) who were biologic-naive or inadequately responsive to tumor necrosis factor inhibitors (TNFi-IR).

Major finding: From weeks 52 to 104, the incidence of treatment emergent adverse events (TEAE) was consistent with previous studies, with no new safety signals. SARS-CoV2 infection (18.6 per 100 patient-years) was the most common TEAE. Approximately 50% biologic-naive and TNFi-IR patients maintained a ≥50% improvement in the American College of Rheumatology response.

Study details: This open-label extension (BE-VITAL) of two phase 3 trials included biologic-naive (n = 852) and TNFi-IR (n = 400) patients with PsA who were randomly assigned to receive bimekizumab, placebo with crossover to bimekizumab at week 16, or adalimumab followed by bimekizumab at week 52.

Disclosures: This study was sponsored by UCB Pharma. Five authors declared being employees or shareholders of UCB Pharma. LC Coates declared being an editorial board member of Rheumatology and Therapy. Other authors declared having ties with various sources, including UCB.

Source: Mease PJ, Merola JF, Tanaka Y, et al. Safety and efficacy of bimekizumab in patients with psoriatic arthritis: 2-year results from two phase 3 studies. Rheumatol Ther. 2024 (Aug 31). doi: 10.1007/s40744-024-00708-8 Source