Case Reports

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; Leara@ccf.org

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; Leara@ccf.org

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; Leara@ccf.org

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

INTRODUCTION

Urinary bladder is an extremely rare site of extrapulmonary small cell cancer (EPSCC). Unlike small cell lung cancer (SCLC), there is no clear guideline for prophylactic cranial irradiation (PCI) for EPSCC. In this case report and literature review, we discuss small cell cancer of urinary bladder (SCCUB) and the role of PCI in SCCUB.

CASE PRESENTATION

A 74-year-old male presented with gross hematuria and an unremarkable physical examination. CT showed 1.7 cm right anterolateral bladder wall thickening. Cystoscopy revealed a 2-3 cm high-grade bladder lesion. Pathology from transurethral resection of the tumor was consistent with T1N0M0 small cell carcinoma. MRI brain and FDG-PET showed no extravesical disease. Patient received four cycles of neoadjuvant carboplatin/etoposide per his preference as he wanted to protect his hearing due to his profession followed by radical cystoprostatectomy. Post-op pathology showed clear margins. We decided to forego PCI in favor of interval surveillance with MRI and follow- up images remain negative for distant metastases.

DISCUSSION

EPSCC accounts for 2.5-5% of all SCC, very rare in male genitourinary tract. Treatment approach is derived from SCLC, guided by extent of disease and patient’s functional status. Role of PCI in EPSCC has not been clearly described, and even less evidence is available for SCCUB. From a review of eleven studies in PubMed for the role of PCI in SCCUB or EPSCC, we found that SCCUB has lower incidence of brain metastases than SCLC. One study suggested that SCCUB arises from totipotent cells in the submucosa, unlike Kulchitsky cell origin of SCLC. This difference might explain the difference in their metastatic behavior. With this background, PCI is not routinely recommended for limited- stage SCCUB. There might still be a role for PCI in extensive SCCUB with high metastatic burden. More studies are needed to update the guidelines for the role of PCI for these tumors.

CONCLUSIONS

Per this literature review, PCI is not routinely recommended for SCCUB, likely due to different cells of origin compared to SCLC. Future studies should focus on characterizing differences in their metastatic behavior and updating guidelines for PCI for SCCUB.

INTRODUCTION

Urinary bladder is an extremely rare site of extrapulmonary small cell cancer (EPSCC). Unlike small cell lung cancer (SCLC), there is no clear guideline for prophylactic cranial irradiation (PCI) for EPSCC. In this case report and literature review, we discuss small cell cancer of urinary bladder (SCCUB) and the role of PCI in SCCUB.

CASE PRESENTATION

A 74-year-old male presented with gross hematuria and an unremarkable physical examination. CT showed 1.7 cm right anterolateral bladder wall thickening. Cystoscopy revealed a 2-3 cm high-grade bladder lesion. Pathology from transurethral resection of the tumor was consistent with T1N0M0 small cell carcinoma. MRI brain and FDG-PET showed no extravesical disease. Patient received four cycles of neoadjuvant carboplatin/etoposide per his preference as he wanted to protect his hearing due to his profession followed by radical cystoprostatectomy. Post-op pathology showed clear margins. We decided to forego PCI in favor of interval surveillance with MRI and follow- up images remain negative for distant metastases.

DISCUSSION

EPSCC accounts for 2.5-5% of all SCC, very rare in male genitourinary tract. Treatment approach is derived from SCLC, guided by extent of disease and patient’s functional status. Role of PCI in EPSCC has not been clearly described, and even less evidence is available for SCCUB. From a review of eleven studies in PubMed for the role of PCI in SCCUB or EPSCC, we found that SCCUB has lower incidence of brain metastases than SCLC. One study suggested that SCCUB arises from totipotent cells in the submucosa, unlike Kulchitsky cell origin of SCLC. This difference might explain the difference in their metastatic behavior. With this background, PCI is not routinely recommended for limited- stage SCCUB. There might still be a role for PCI in extensive SCCUB with high metastatic burden. More studies are needed to update the guidelines for the role of PCI for these tumors.

CONCLUSIONS

Per this literature review, PCI is not routinely recommended for SCCUB, likely due to different cells of origin compared to SCLC. Future studies should focus on characterizing differences in their metastatic behavior and updating guidelines for PCI for SCCUB.

INTRODUCTION

Urinary bladder is an extremely rare site of extrapulmonary small cell cancer (EPSCC). Unlike small cell lung cancer (SCLC), there is no clear guideline for prophylactic cranial irradiation (PCI) for EPSCC. In this case report and literature review, we discuss small cell cancer of urinary bladder (SCCUB) and the role of PCI in SCCUB.

CASE PRESENTATION

A 74-year-old male presented with gross hematuria and an unremarkable physical examination. CT showed 1.7 cm right anterolateral bladder wall thickening. Cystoscopy revealed a 2-3 cm high-grade bladder lesion. Pathology from transurethral resection of the tumor was consistent with T1N0M0 small cell carcinoma. MRI brain and FDG-PET showed no extravesical disease. Patient received four cycles of neoadjuvant carboplatin/etoposide per his preference as he wanted to protect his hearing due to his profession followed by radical cystoprostatectomy. Post-op pathology showed clear margins. We decided to forego PCI in favor of interval surveillance with MRI and follow- up images remain negative for distant metastases.

DISCUSSION

EPSCC accounts for 2.5-5% of all SCC, very rare in male genitourinary tract. Treatment approach is derived from SCLC, guided by extent of disease and patient’s functional status. Role of PCI in EPSCC has not been clearly described, and even less evidence is available for SCCUB. From a review of eleven studies in PubMed for the role of PCI in SCCUB or EPSCC, we found that SCCUB has lower incidence of brain metastases than SCLC. One study suggested that SCCUB arises from totipotent cells in the submucosa, unlike Kulchitsky cell origin of SCLC. This difference might explain the difference in their metastatic behavior. With this background, PCI is not routinely recommended for limited- stage SCCUB. There might still be a role for PCI in extensive SCCUB with high metastatic burden. More studies are needed to update the guidelines for the role of PCI for these tumors.

CONCLUSIONS

Per this literature review, PCI is not routinely recommended for SCCUB, likely due to different cells of origin compared to SCLC. Future studies should focus on characterizing differences in their metastatic behavior and updating guidelines for PCI for SCCUB.