Case Letter

To the Editor:

Lichenoid drug eruptions are lichen planus–like hypersensitivity reactions induced by medications. These reactions are rare but cause irritation to the skin, as extreme pruritus is common. One review of 300 consecutive cases of drug eruptions submitted to dermatopathology revealed that 12% of cases were classified as lichenoid drug reactions.¹ Lichenoid dermatitis is characterized by extremely pruritic, scaly, eczematous or psoriasiform papules, often along the extensor surfaces and trunk.² The pruritic nature of the rash can negatively impact quality of life. Treatment typically involves discontinuation of the offending medication, although complete resolution can take months, even after the drug is stopped. Although there have been some data suggesting that topical and/or oral corticosteroids can help with resolution, the rash can persist even with steroid treatment.²

The histopathologic findings of lichenoid drug eruptions show lichen planus–like changes such as hyperkeratosis, irregular acanthosis, and lichenoid interface dermatitis. Accordingly, idiopathic lichen planus is an important differential diagnosis for lichenoid drug eruptions; however, compared to idiopathic lichen planus, lichenoid drug eruptions are more likely to be associated with eosinophils and parakeratosis.^1,3 In some cases, the histopathologic distinction between the 2 conditions is impossible, and clinical history needs to be considered to make a diagnosis.¹ Drugs known to cause lichenoid drug reactions more commonly include angiotensin-converting enzyme inhibitors, beta blockers, thiazides, gold, penicillamine, and antimalarials.² Lichenoid drug eruptions also have been documented in patients taking the second-generation nonsteroidal androgen receptor antagonist enzalutamide, which is used for the treatment of prostate cancer.⁴ More recently, the newer second-generation nonsteroidal androgen receptor antagonist apalutamide has been implicated in several cases of lichenoid drug eruptions.^5,6

We present a case of an apalutamide-induced lichenoid drug eruption that was resistant to dose reduction and required discontinuation of treatment due to the negative impact on the patient’s quality of life. Once the rash resolved, the patient transitioned to enzalutamide without any adverse events (AEs).

A 72-year-old man with a history of metastatic prostate cancer (stage IVB) presented to the dermatology clinic with a 4-month history of a dry itchy rash on the face, chest, back, and legs that had developed 2 to 3 months after oncology started him on apalutamide. The patient initially received apalutamide 240 mg/d, which was reduced by his oncologist 3 months later to 180 mg/d following the appearance of the rash. Then apalutamide was held as he awaited improvement of the rash.

One week after the apalutamide was held, the patient presented to dermatology. He reported that he had tried over-the-counter ammonium lactate 12% lotion twice daily when the rash first developed without improvement. When the apalutamide was held, oncology prescribed mupirocin ointment 2% 3 times daily which yielded minimal relief. On physical examination, widespread lichenified papules and plaques were noted on the face, chest, back, and legs (Figure 1). Dermatology initially prescribed triamcinolone ointment 0.1% twice daily. A 4-mm punch biopsy specimen of the upper back revealed a lichenoid interface dermatitis with numerous eosinophils compatible with a lichenoid hypersensitivity reaction (Figure 2). Considering the clinical and histologic findings, a diagnosis of lichenoid drug eruption secondary to apalutamide treatment was made.

Two weeks after discontinuation of the medication, the rash improved, and the patient restarted apalutamide at a dosage of 120 mg/d; however, the rash re-emerged within 1 month and was resistant to the triamcinolone ointment 0.1%. Apalutamide was again discontinued, and oncology switched the patient to enzalutamide 160 mg/d in an effort to find a medication the patient could better tolerate. Two months after starting enzalutamide, the patient had resolution of the rash and no further dermatologic complications.

Apalutamide is a second-generation nonsteroidal androgen receptor antagonist used in the treatment of nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (CSPC).⁷ It stops the spread and growth of prostate cancer cells by several different mechanisms, including competitively binding androgen receptors, preventing 5α-dihydrotestosterone from binding to androgen receptors, blocking androgen receptor nuclear translocation, impairing co-activator recruitment, and restraining androgen receptor DNA binding.⁷ The SPARTAN and TITAN phase 3 clinical trials demonstrated increased overall survival and time to progression with apalutamide in both nonmetastatic CRPC and metastatic CSPC. In both trials, the rash was shown to be an AE more commonly associated with apalutamide than placebo.^8,9

Until recently, the characteristics of apalutamide-induced drug rashes have not been well described. One literature review reported 6 cases of cutaneous apalutamide-induced drug eruptions.⁵ Four (66.7%) of these eruptions were maculopapular rashes, only 2 of which were histologically classified as lichenoid in nature. The other 2 eruptions were classified as toxic epidermal necrosis.⁵ Another study of 303 patients with prostate cancer who were treated with apalutamide recorded the frequency and time to onset of dermatologic AEs.⁶ Seventy-one (23.4%) of the patients had dermatologic AEs, and of those, only 20 (28.2%) had AEs that resulted in interruptions in apalutamide therapy (with only 5 [25.0%] requiring medication discontinuation). Thirty-two (45.1%) patients were managed with topical or oral corticosteroids or dose modification. In this study, histopathology was examined in 8 cases (one of which had 2 biopsies for a total of 9 biopsies), 7 of which were consistent with lichenoid interface dermatitis.⁶

Lichenoid interface dermatitis is a rare manifestation of an apalutamide-induced drug eruption and also has been reported secondary to treatment with enzalutamide, another second-generation nonsteroidal androgen receptor antagonist.⁴ Enzalutamide was the first second-generation nonsteroidal androgen receptor antagonist approved for the treatment of prostate cancer. It originally was approved only for metastatic CRPC after docetaxel therapy in 2012, then later was expanded to metastatic and nonmetastatic CRPC in 2012 and 2018, respectively, as well as metastatic CSPC in 2019.⁷ Because enzalutamide is from the same medication class as apalutamide and has been on the market longer for the treatment of nonmetastatic CRPC and metastatic CSPC, it is not surprising that similar drug eruptions now are being reported secondary to apalutamide use as well.

It is important for providers to consider lichenoid drug eruptions in the differential diagnosis of pruritic rashes in patients taking second-generation nonsteroidal androgen receptor antagonists such as apalutamide or enzalutamide. Although dose reduction or treatment discontinuation have been the standard of care for patients with extremely pruritic lichenoid drug eruptions secondary to these medications, these are not ideal because they are important for cancer treatment. Interestingly, after our patient’s apalutamide-induced rash resolved and he was switched to enzalutamide, he did not develop any AEs. Based on our patient’s experience, physicians could consider switching their patients to another drug of the same class, as they may be able tolerate that medication. More research is needed to determine how commonly patients tolerate a different second-generation nonsteroidal androgen receptor antagonist after not tolerating another medication from the same class.

To the Editor:

Lichenoid drug eruptions are lichen planus–like hypersensitivity reactions induced by medications. These reactions are rare but cause irritation to the skin, as extreme pruritus is common. One review of 300 consecutive cases of drug eruptions submitted to dermatopathology revealed that 12% of cases were classified as lichenoid drug reactions.¹ Lichenoid dermatitis is characterized by extremely pruritic, scaly, eczematous or psoriasiform papules, often along the extensor surfaces and trunk.² The pruritic nature of the rash can negatively impact quality of life. Treatment typically involves discontinuation of the offending medication, although complete resolution can take months, even after the drug is stopped. Although there have been some data suggesting that topical and/or oral corticosteroids can help with resolution, the rash can persist even with steroid treatment.²

The histopathologic findings of lichenoid drug eruptions show lichen planus–like changes such as hyperkeratosis, irregular acanthosis, and lichenoid interface dermatitis. Accordingly, idiopathic lichen planus is an important differential diagnosis for lichenoid drug eruptions; however, compared to idiopathic lichen planus, lichenoid drug eruptions are more likely to be associated with eosinophils and parakeratosis.^1,3 In some cases, the histopathologic distinction between the 2 conditions is impossible, and clinical history needs to be considered to make a diagnosis.¹ Drugs known to cause lichenoid drug reactions more commonly include angiotensin-converting enzyme inhibitors, beta blockers, thiazides, gold, penicillamine, and antimalarials.² Lichenoid drug eruptions also have been documented in patients taking the second-generation nonsteroidal androgen receptor antagonist enzalutamide, which is used for the treatment of prostate cancer.⁴ More recently, the newer second-generation nonsteroidal androgen receptor antagonist apalutamide has been implicated in several cases of lichenoid drug eruptions.^5,6

We present a case of an apalutamide-induced lichenoid drug eruption that was resistant to dose reduction and required discontinuation of treatment due to the negative impact on the patient’s quality of life. Once the rash resolved, the patient transitioned to enzalutamide without any adverse events (AEs).

A 72-year-old man with a history of metastatic prostate cancer (stage IVB) presented to the dermatology clinic with a 4-month history of a dry itchy rash on the face, chest, back, and legs that had developed 2 to 3 months after oncology started him on apalutamide. The patient initially received apalutamide 240 mg/d, which was reduced by his oncologist 3 months later to 180 mg/d following the appearance of the rash. Then apalutamide was held as he awaited improvement of the rash.

One week after the apalutamide was held, the patient presented to dermatology. He reported that he had tried over-the-counter ammonium lactate 12% lotion twice daily when the rash first developed without improvement. When the apalutamide was held, oncology prescribed mupirocin ointment 2% 3 times daily which yielded minimal relief. On physical examination, widespread lichenified papules and plaques were noted on the face, chest, back, and legs (Figure 1). Dermatology initially prescribed triamcinolone ointment 0.1% twice daily. A 4-mm punch biopsy specimen of the upper back revealed a lichenoid interface dermatitis with numerous eosinophils compatible with a lichenoid hypersensitivity reaction (Figure 2). Considering the clinical and histologic findings, a diagnosis of lichenoid drug eruption secondary to apalutamide treatment was made.

Two weeks after discontinuation of the medication, the rash improved, and the patient restarted apalutamide at a dosage of 120 mg/d; however, the rash re-emerged within 1 month and was resistant to the triamcinolone ointment 0.1%. Apalutamide was again discontinued, and oncology switched the patient to enzalutamide 160 mg/d in an effort to find a medication the patient could better tolerate. Two months after starting enzalutamide, the patient had resolution of the rash and no further dermatologic complications.

Apalutamide is a second-generation nonsteroidal androgen receptor antagonist used in the treatment of nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (CSPC).⁷ It stops the spread and growth of prostate cancer cells by several different mechanisms, including competitively binding androgen receptors, preventing 5α-dihydrotestosterone from binding to androgen receptors, blocking androgen receptor nuclear translocation, impairing co-activator recruitment, and restraining androgen receptor DNA binding.⁷ The SPARTAN and TITAN phase 3 clinical trials demonstrated increased overall survival and time to progression with apalutamide in both nonmetastatic CRPC and metastatic CSPC. In both trials, the rash was shown to be an AE more commonly associated with apalutamide than placebo.^8,9

Until recently, the characteristics of apalutamide-induced drug rashes have not been well described. One literature review reported 6 cases of cutaneous apalutamide-induced drug eruptions.⁵ Four (66.7%) of these eruptions were maculopapular rashes, only 2 of which were histologically classified as lichenoid in nature. The other 2 eruptions were classified as toxic epidermal necrosis.⁵ Another study of 303 patients with prostate cancer who were treated with apalutamide recorded the frequency and time to onset of dermatologic AEs.⁶ Seventy-one (23.4%) of the patients had dermatologic AEs, and of those, only 20 (28.2%) had AEs that resulted in interruptions in apalutamide therapy (with only 5 [25.0%] requiring medication discontinuation). Thirty-two (45.1%) patients were managed with topical or oral corticosteroids or dose modification. In this study, histopathology was examined in 8 cases (one of which had 2 biopsies for a total of 9 biopsies), 7 of which were consistent with lichenoid interface dermatitis.⁶

Lichenoid interface dermatitis is a rare manifestation of an apalutamide-induced drug eruption and also has been reported secondary to treatment with enzalutamide, another second-generation nonsteroidal androgen receptor antagonist.⁴ Enzalutamide was the first second-generation nonsteroidal androgen receptor antagonist approved for the treatment of prostate cancer. It originally was approved only for metastatic CRPC after docetaxel therapy in 2012, then later was expanded to metastatic and nonmetastatic CRPC in 2012 and 2018, respectively, as well as metastatic CSPC in 2019.⁷ Because enzalutamide is from the same medication class as apalutamide and has been on the market longer for the treatment of nonmetastatic CRPC and metastatic CSPC, it is not surprising that similar drug eruptions now are being reported secondary to apalutamide use as well.

It is important for providers to consider lichenoid drug eruptions in the differential diagnosis of pruritic rashes in patients taking second-generation nonsteroidal androgen receptor antagonists such as apalutamide or enzalutamide. Although dose reduction or treatment discontinuation have been the standard of care for patients with extremely pruritic lichenoid drug eruptions secondary to these medications, these are not ideal because they are important for cancer treatment. Interestingly, after our patient’s apalutamide-induced rash resolved and he was switched to enzalutamide, he did not develop any AEs. Based on our patient’s experience, physicians could consider switching their patients to another drug of the same class, as they may be able tolerate that medication. More research is needed to determine how commonly patients tolerate a different second-generation nonsteroidal androgen receptor antagonist after not tolerating another medication from the same class.

To the Editor:

Lichenoid drug eruptions are lichen planus–like hypersensitivity reactions induced by medications. These reactions are rare but cause irritation to the skin, as extreme pruritus is common. One review of 300 consecutive cases of drug eruptions submitted to dermatopathology revealed that 12% of cases were classified as lichenoid drug reactions.¹ Lichenoid dermatitis is characterized by extremely pruritic, scaly, eczematous or psoriasiform papules, often along the extensor surfaces and trunk.² The pruritic nature of the rash can negatively impact quality of life. Treatment typically involves discontinuation of the offending medication, although complete resolution can take months, even after the drug is stopped. Although there have been some data suggesting that topical and/or oral corticosteroids can help with resolution, the rash can persist even with steroid treatment.²

The histopathologic findings of lichenoid drug eruptions show lichen planus–like changes such as hyperkeratosis, irregular acanthosis, and lichenoid interface dermatitis. Accordingly, idiopathic lichen planus is an important differential diagnosis for lichenoid drug eruptions; however, compared to idiopathic lichen planus, lichenoid drug eruptions are more likely to be associated with eosinophils and parakeratosis.^1,3 In some cases, the histopathologic distinction between the 2 conditions is impossible, and clinical history needs to be considered to make a diagnosis.¹ Drugs known to cause lichenoid drug reactions more commonly include angiotensin-converting enzyme inhibitors, beta blockers, thiazides, gold, penicillamine, and antimalarials.² Lichenoid drug eruptions also have been documented in patients taking the second-generation nonsteroidal androgen receptor antagonist enzalutamide, which is used for the treatment of prostate cancer.⁴ More recently, the newer second-generation nonsteroidal androgen receptor antagonist apalutamide has been implicated in several cases of lichenoid drug eruptions.^5,6

We present a case of an apalutamide-induced lichenoid drug eruption that was resistant to dose reduction and required discontinuation of treatment due to the negative impact on the patient’s quality of life. Once the rash resolved, the patient transitioned to enzalutamide without any adverse events (AEs).

A 72-year-old man with a history of metastatic prostate cancer (stage IVB) presented to the dermatology clinic with a 4-month history of a dry itchy rash on the face, chest, back, and legs that had developed 2 to 3 months after oncology started him on apalutamide. The patient initially received apalutamide 240 mg/d, which was reduced by his oncologist 3 months later to 180 mg/d following the appearance of the rash. Then apalutamide was held as he awaited improvement of the rash.

One week after the apalutamide was held, the patient presented to dermatology. He reported that he had tried over-the-counter ammonium lactate 12% lotion twice daily when the rash first developed without improvement. When the apalutamide was held, oncology prescribed mupirocin ointment 2% 3 times daily which yielded minimal relief. On physical examination, widespread lichenified papules and plaques were noted on the face, chest, back, and legs (Figure 1). Dermatology initially prescribed triamcinolone ointment 0.1% twice daily. A 4-mm punch biopsy specimen of the upper back revealed a lichenoid interface dermatitis with numerous eosinophils compatible with a lichenoid hypersensitivity reaction (Figure 2). Considering the clinical and histologic findings, a diagnosis of lichenoid drug eruption secondary to apalutamide treatment was made.

Two weeks after discontinuation of the medication, the rash improved, and the patient restarted apalutamide at a dosage of 120 mg/d; however, the rash re-emerged within 1 month and was resistant to the triamcinolone ointment 0.1%. Apalutamide was again discontinued, and oncology switched the patient to enzalutamide 160 mg/d in an effort to find a medication the patient could better tolerate. Two months after starting enzalutamide, the patient had resolution of the rash and no further dermatologic complications.

Apalutamide is a second-generation nonsteroidal androgen receptor antagonist used in the treatment of nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (CSPC).⁷ It stops the spread and growth of prostate cancer cells by several different mechanisms, including competitively binding androgen receptors, preventing 5α-dihydrotestosterone from binding to androgen receptors, blocking androgen receptor nuclear translocation, impairing co-activator recruitment, and restraining androgen receptor DNA binding.⁷ The SPARTAN and TITAN phase 3 clinical trials demonstrated increased overall survival and time to progression with apalutamide in both nonmetastatic CRPC and metastatic CSPC. In both trials, the rash was shown to be an AE more commonly associated with apalutamide than placebo.^8,9

Until recently, the characteristics of apalutamide-induced drug rashes have not been well described. One literature review reported 6 cases of cutaneous apalutamide-induced drug eruptions.⁵ Four (66.7%) of these eruptions were maculopapular rashes, only 2 of which were histologically classified as lichenoid in nature. The other 2 eruptions were classified as toxic epidermal necrosis.⁵ Another study of 303 patients with prostate cancer who were treated with apalutamide recorded the frequency and time to onset of dermatologic AEs.⁶ Seventy-one (23.4%) of the patients had dermatologic AEs, and of those, only 20 (28.2%) had AEs that resulted in interruptions in apalutamide therapy (with only 5 [25.0%] requiring medication discontinuation). Thirty-two (45.1%) patients were managed with topical or oral corticosteroids or dose modification. In this study, histopathology was examined in 8 cases (one of which had 2 biopsies for a total of 9 biopsies), 7 of which were consistent with lichenoid interface dermatitis.⁶

Lichenoid interface dermatitis is a rare manifestation of an apalutamide-induced drug eruption and also has been reported secondary to treatment with enzalutamide, another second-generation nonsteroidal androgen receptor antagonist.⁴ Enzalutamide was the first second-generation nonsteroidal androgen receptor antagonist approved for the treatment of prostate cancer. It originally was approved only for metastatic CRPC after docetaxel therapy in 2012, then later was expanded to metastatic and nonmetastatic CRPC in 2012 and 2018, respectively, as well as metastatic CSPC in 2019.⁷ Because enzalutamide is from the same medication class as apalutamide and has been on the market longer for the treatment of nonmetastatic CRPC and metastatic CSPC, it is not surprising that similar drug eruptions now are being reported secondary to apalutamide use as well.

It is important for providers to consider lichenoid drug eruptions in the differential diagnosis of pruritic rashes in patients taking second-generation nonsteroidal androgen receptor antagonists such as apalutamide or enzalutamide. Although dose reduction or treatment discontinuation have been the standard of care for patients with extremely pruritic lichenoid drug eruptions secondary to these medications, these are not ideal because they are important for cancer treatment. Interestingly, after our patient’s apalutamide-induced rash resolved and he was switched to enzalutamide, he did not develop any AEs. Based on our patient’s experience, physicians could consider switching their patients to another drug of the same class, as they may be able tolerate that medication. More research is needed to determine how commonly patients tolerate a different second-generation nonsteroidal androgen receptor antagonist after not tolerating another medication from the same class.

To the Editor:

Scleroderma is a chronic autoimmune connective tissue disease that results in excessive collagen deposition in the skin and other organs throughout the body. On its own or in the setting of mixed connective tissue disease, scleroderma can result in systemic or localized symptoms that can limit patients’ functional capabilities, cause pain and discomfort, and reduce self-esteem—all negatively impacting patients’ quality of life.^1,2 Neck sclerosis is a common manifestation of scleroderma. There is no curative treatment for scleroderma; thus, therapy is focused on slowing disease progression and improving quality of life. We present a case of neck sclerosis in a 44-year-old woman with scleroderma that was successfully treated with botulinum toxin (BTX) type A injection, resulting in improved skin laxity and appearance with high patient satisfaction. Our case demonstrates the potential positive effects of BTX treatment in patients with features of sclerosis or fibrosis, particularly in the neck region.

A 44-year-old woman presented to the dermatology clinic for treatment of thickened neck skin with stiffness and tightness that had been present for months to years. She had a history of mixed connective tissue disease (MCTD)(positive anti-ribonucleoprotein, anti–Sjögren syndrome–related antigen, and anti-Smith antibodies) with features of scleroderma and polyarthritis. The patient currently was taking sulfasalazine for the polyarthritis; she previously had taken hydroxychloroquine but discontinued treatment due to ineffectiveness. She was not taking any topical or systemic medications for scleroderma. On physical examination, the skin on the anterior neck appeared thickened with shiny patches (Figure 1). Pinching the skin in the affected area demonstrated ­sclerosis with high tension.

The dermatologist (J.J.) discussed potential treatment options to help relax the tension in the skin of the anterior neck, including BTX injections. After receiving counsel on adverse effects, alternative treatments, and postprocedural care, the patient decided to proceed with the procedure. The anterior neck was cleansed with an alcohol swab and 37 units (range, 25–50 units) of incobotulinumtoxinA (reconstituted using 2.5-mL bacteriostatic normal saline per 100 units) was injected transdermally using a 9-point injection technique, with each injection placed approximately 1 cm apart. The approximate treatment area included the space between the sternocleidomastoid anterior edges and below the hyoid bone up to the cricothyroid membrane (anatomic zone II).

When the patient returned for follow-up 3 weeks later, she reported considerable improvement in the stiffness and appearance of the skin on the anterior neck. On physical examination, the skin of the neck appeared softened, and improved laxity was seen on pinching the skin compared to the initial presentation (Figure 2). The patient expressed satisfaction with the results and denied any adverse events following the procedure.

Mixed connective tissue disease manifests with a combination of features from various disorders—mainly lupus, scleroderma, polymyositis, and rheumatoid arthritis. It is most prevalent in females and often is diagnosed in the third decade of life.³ It is associated with positive antinuclear antibodies and human leukocyte antigen (HLA) II alleles (HLA-DR4, HLA-DR1, and HLA-DR2). Raynaud phenomenon (RP), one of the most common skin manifestations in both scleroderma and MCTD, is present in 75% to 90% of patients with MCTD.³

Scleroderma is a chronic connective tissue disorder that results in excessive collagen deposition in the skin and other organs throughout the body.⁴ Although the etiology is unknown, scleroderma develops when overactivation of the immune system leads to CD4⁺ T-lymphocyte infiltration in the skin, along with the release of profibrotic interleukins and growth factors, resulting in fibrosis.⁴ Subtypes include localized scleroderma (morphea), limited cutaneous systemic sclerosis (formerly known as CREST [calcinosis, RP, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome), diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma.⁵ Scleroderma is associated with positive antinuclear antibodies and HLA II alleles (HLA-DR2 and HLA-DR5).

On its own or in the setting of MCTD, scleroderma can result in systemic or localized symptoms. Overall, the most common symptom is RP.⁵ Localized scleroderma and limited cutaneous systemic sclerosis manifest with symptoms of the skin and underlying tissues. Diffuse cutaneous systemic sclerosis involves cutaneous and visceral symptoms, including lung, esophageal, and vascular involvement.⁶ Similar to MCTD, scleroderma is most prevalent in middle-aged females,⁷ though it occurs at a higher rate and with a more severe disease course in Black patients.⁸

A highly sensitive and specific test for scleroderma that can aid in diagnosis is the neck sign—tightening of the skin of the neck when the head extends.^9,10 In one study, the neck sign was positive in more than 90% of patients with scleroderma and negative for control patients and those with primary RP.⁹ Thus, neck sclerosis is a common manifestation of scleroderma for which patients may seek treatment.

While there is no curative treatment for scleroderma, skin manifestations can be treated with mycophenolate mofetil or methotrexate.⁵ Systemic treatments may be recommended if the patient has additional symptoms, such as azathioprine for myositis/arthritis and cyclophosphamide for interstitial lung disease.⁵ However, it is important to note that these medications are associated with risk for gastrointestinal upset, mouth sores, fatigue, or other complications.

Botulinum toxin is a bacterial protein toxin and neuromodulator that inhibits neurotransmitter release by cleaving SNARE proteins at peripheral nerve terminal junctions.¹¹ It has been used in a variety of dermatologic and nondermatologic conditions, including migraines, hyperhidrosis, contractures, scars, and overactive bladder. It also has been used in aesthetics for facial rejuvenation and minimization of wrinkle appearance. Dermatologists and rheumatologists have successfully used BTX to treat primary and secondary RP—the most common symptom of scleroderma—due to its vasodilatation properties.¹² Although our patient did not have RP, use of BTX to treat other features of scleroderma, including en coup de sabre, thoracic outlet syndrome, dyspareunia, gastroparesis, pterygium inversum unguis, and dysphagia has been documented.^13-18 An in vivo mouse study that examined the possible mechanism for BTX as a treatment in scleroderma found that BTX injections significantly decreased dermal thickness and inflammation in fibrosis (P<.05). An analysis of oxidative stress and mRNA expression showed that BTX may treat fibrosis by suppressing oxidative stress and inflammatory cells, resulting in decreased apoptosis and oxidant-induced intracellular accumulation of reactive oxygen species.¹⁹ Another animal study demonstrated the positive effects of BTX treatment for fibrosis of the bladder in rats.²⁰ In one case report, a female patient with scleroderma and facial fibrosis received perioral BTX injections for cosmetic purposes but also observed improvement in mouth constriction, demonstrating the potential efficacy of BTX for facial fibrosis.²¹

Our case demonstrates the potential positive effects of BTX treatment in patients with features of sclerosis or fibrosis, particularly in the neck region. We recommend assessing the efficacy of the initial BTX treatment after 2 to 3 weeks, with additional injections as needed to achieve the patient’s desired level of comfort and appearance at approximately 3-month intervals (aligning with the expected duration of efficacy of BTX).²² Our patient experienced considerable relief and high satisfaction with BTX treatment. Given the limitations of sclerosis treatments and the unwanted adverse-effect profile of systemic treatments, BTX injections may be a preferrable treatment option for cutaneous manifestations of ­scleroderma among patients. Future studies with larger patient populations and a control group are warranted to further explore the use of BTX for the dermatologic treatment of scleroderma.

To the Editor:

Scleroderma is a chronic autoimmune connective tissue disease that results in excessive collagen deposition in the skin and other organs throughout the body. On its own or in the setting of mixed connective tissue disease, scleroderma can result in systemic or localized symptoms that can limit patients’ functional capabilities, cause pain and discomfort, and reduce self-esteem—all negatively impacting patients’ quality of life.^1,2 Neck sclerosis is a common manifestation of scleroderma. There is no curative treatment for scleroderma; thus, therapy is focused on slowing disease progression and improving quality of life. We present a case of neck sclerosis in a 44-year-old woman with scleroderma that was successfully treated with botulinum toxin (BTX) type A injection, resulting in improved skin laxity and appearance with high patient satisfaction. Our case demonstrates the potential positive effects of BTX treatment in patients with features of sclerosis or fibrosis, particularly in the neck region.

A 44-year-old woman presented to the dermatology clinic for treatment of thickened neck skin with stiffness and tightness that had been present for months to years. She had a history of mixed connective tissue disease (MCTD)(positive anti-ribonucleoprotein, anti–Sjögren syndrome–related antigen, and anti-Smith antibodies) with features of scleroderma and polyarthritis. The patient currently was taking sulfasalazine for the polyarthritis; she previously had taken hydroxychloroquine but discontinued treatment due to ineffectiveness. She was not taking any topical or systemic medications for scleroderma. On physical examination, the skin on the anterior neck appeared thickened with shiny patches (Figure 1). Pinching the skin in the affected area demonstrated ­sclerosis with high tension.

The dermatologist (J.J.) discussed potential treatment options to help relax the tension in the skin of the anterior neck, including BTX injections. After receiving counsel on adverse effects, alternative treatments, and postprocedural care, the patient decided to proceed with the procedure. The anterior neck was cleansed with an alcohol swab and 37 units (range, 25–50 units) of incobotulinumtoxinA (reconstituted using 2.5-mL bacteriostatic normal saline per 100 units) was injected transdermally using a 9-point injection technique, with each injection placed approximately 1 cm apart. The approximate treatment area included the space between the sternocleidomastoid anterior edges and below the hyoid bone up to the cricothyroid membrane (anatomic zone II).

When the patient returned for follow-up 3 weeks later, she reported considerable improvement in the stiffness and appearance of the skin on the anterior neck. On physical examination, the skin of the neck appeared softened, and improved laxity was seen on pinching the skin compared to the initial presentation (Figure 2). The patient expressed satisfaction with the results and denied any adverse events following the procedure.

Mixed connective tissue disease manifests with a combination of features from various disorders—mainly lupus, scleroderma, polymyositis, and rheumatoid arthritis. It is most prevalent in females and often is diagnosed in the third decade of life.³ It is associated with positive antinuclear antibodies and human leukocyte antigen (HLA) II alleles (HLA-DR4, HLA-DR1, and HLA-DR2). Raynaud phenomenon (RP), one of the most common skin manifestations in both scleroderma and MCTD, is present in 75% to 90% of patients with MCTD.³

Scleroderma is a chronic connective tissue disorder that results in excessive collagen deposition in the skin and other organs throughout the body.⁴ Although the etiology is unknown, scleroderma develops when overactivation of the immune system leads to CD4⁺ T-lymphocyte infiltration in the skin, along with the release of profibrotic interleukins and growth factors, resulting in fibrosis.⁴ Subtypes include localized scleroderma (morphea), limited cutaneous systemic sclerosis (formerly known as CREST [calcinosis, RP, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome), diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma.⁵ Scleroderma is associated with positive antinuclear antibodies and HLA II alleles (HLA-DR2 and HLA-DR5).

On its own or in the setting of MCTD, scleroderma can result in systemic or localized symptoms. Overall, the most common symptom is RP.⁵ Localized scleroderma and limited cutaneous systemic sclerosis manifest with symptoms of the skin and underlying tissues. Diffuse cutaneous systemic sclerosis involves cutaneous and visceral symptoms, including lung, esophageal, and vascular involvement.⁶ Similar to MCTD, scleroderma is most prevalent in middle-aged females,⁷ though it occurs at a higher rate and with a more severe disease course in Black patients.⁸

A highly sensitive and specific test for scleroderma that can aid in diagnosis is the neck sign—tightening of the skin of the neck when the head extends.^9,10 In one study, the neck sign was positive in more than 90% of patients with scleroderma and negative for control patients and those with primary RP.⁹ Thus, neck sclerosis is a common manifestation of scleroderma for which patients may seek treatment.

While there is no curative treatment for scleroderma, skin manifestations can be treated with mycophenolate mofetil or methotrexate.⁵ Systemic treatments may be recommended if the patient has additional symptoms, such as azathioprine for myositis/arthritis and cyclophosphamide for interstitial lung disease.⁵ However, it is important to note that these medications are associated with risk for gastrointestinal upset, mouth sores, fatigue, or other complications.

Botulinum toxin is a bacterial protein toxin and neuromodulator that inhibits neurotransmitter release by cleaving SNARE proteins at peripheral nerve terminal junctions.¹¹ It has been used in a variety of dermatologic and nondermatologic conditions, including migraines, hyperhidrosis, contractures, scars, and overactive bladder. It also has been used in aesthetics for facial rejuvenation and minimization of wrinkle appearance. Dermatologists and rheumatologists have successfully used BTX to treat primary and secondary RP—the most common symptom of scleroderma—due to its vasodilatation properties.¹² Although our patient did not have RP, use of BTX to treat other features of scleroderma, including en coup de sabre, thoracic outlet syndrome, dyspareunia, gastroparesis, pterygium inversum unguis, and dysphagia has been documented.^13-18 An in vivo mouse study that examined the possible mechanism for BTX as a treatment in scleroderma found that BTX injections significantly decreased dermal thickness and inflammation in fibrosis (P<.05). An analysis of oxidative stress and mRNA expression showed that BTX may treat fibrosis by suppressing oxidative stress and inflammatory cells, resulting in decreased apoptosis and oxidant-induced intracellular accumulation of reactive oxygen species.¹⁹ Another animal study demonstrated the positive effects of BTX treatment for fibrosis of the bladder in rats.²⁰ In one case report, a female patient with scleroderma and facial fibrosis received perioral BTX injections for cosmetic purposes but also observed improvement in mouth constriction, demonstrating the potential efficacy of BTX for facial fibrosis.²¹

Our case demonstrates the potential positive effects of BTX treatment in patients with features of sclerosis or fibrosis, particularly in the neck region. We recommend assessing the efficacy of the initial BTX treatment after 2 to 3 weeks, with additional injections as needed to achieve the patient’s desired level of comfort and appearance at approximately 3-month intervals (aligning with the expected duration of efficacy of BTX).²² Our patient experienced considerable relief and high satisfaction with BTX treatment. Given the limitations of sclerosis treatments and the unwanted adverse-effect profile of systemic treatments, BTX injections may be a preferrable treatment option for cutaneous manifestations of ­scleroderma among patients. Future studies with larger patient populations and a control group are warranted to further explore the use of BTX for the dermatologic treatment of scleroderma.

To the Editor:

Scleroderma is a chronic autoimmune connective tissue disease that results in excessive collagen deposition in the skin and other organs throughout the body. On its own or in the setting of mixed connective tissue disease, scleroderma can result in systemic or localized symptoms that can limit patients’ functional capabilities, cause pain and discomfort, and reduce self-esteem—all negatively impacting patients’ quality of life.^1,2 Neck sclerosis is a common manifestation of scleroderma. There is no curative treatment for scleroderma; thus, therapy is focused on slowing disease progression and improving quality of life. We present a case of neck sclerosis in a 44-year-old woman with scleroderma that was successfully treated with botulinum toxin (BTX) type A injection, resulting in improved skin laxity and appearance with high patient satisfaction. Our case demonstrates the potential positive effects of BTX treatment in patients with features of sclerosis or fibrosis, particularly in the neck region.

A 44-year-old woman presented to the dermatology clinic for treatment of thickened neck skin with stiffness and tightness that had been present for months to years. She had a history of mixed connective tissue disease (MCTD)(positive anti-ribonucleoprotein, anti–Sjögren syndrome–related antigen, and anti-Smith antibodies) with features of scleroderma and polyarthritis. The patient currently was taking sulfasalazine for the polyarthritis; she previously had taken hydroxychloroquine but discontinued treatment due to ineffectiveness. She was not taking any topical or systemic medications for scleroderma. On physical examination, the skin on the anterior neck appeared thickened with shiny patches (Figure 1). Pinching the skin in the affected area demonstrated ­sclerosis with high tension.

The dermatologist (J.J.) discussed potential treatment options to help relax the tension in the skin of the anterior neck, including BTX injections. After receiving counsel on adverse effects, alternative treatments, and postprocedural care, the patient decided to proceed with the procedure. The anterior neck was cleansed with an alcohol swab and 37 units (range, 25–50 units) of incobotulinumtoxinA (reconstituted using 2.5-mL bacteriostatic normal saline per 100 units) was injected transdermally using a 9-point injection technique, with each injection placed approximately 1 cm apart. The approximate treatment area included the space between the sternocleidomastoid anterior edges and below the hyoid bone up to the cricothyroid membrane (anatomic zone II).

When the patient returned for follow-up 3 weeks later, she reported considerable improvement in the stiffness and appearance of the skin on the anterior neck. On physical examination, the skin of the neck appeared softened, and improved laxity was seen on pinching the skin compared to the initial presentation (Figure 2). The patient expressed satisfaction with the results and denied any adverse events following the procedure.

Mixed connective tissue disease manifests with a combination of features from various disorders—mainly lupus, scleroderma, polymyositis, and rheumatoid arthritis. It is most prevalent in females and often is diagnosed in the third decade of life.³ It is associated with positive antinuclear antibodies and human leukocyte antigen (HLA) II alleles (HLA-DR4, HLA-DR1, and HLA-DR2). Raynaud phenomenon (RP), one of the most common skin manifestations in both scleroderma and MCTD, is present in 75% to 90% of patients with MCTD.³

Scleroderma is a chronic connective tissue disorder that results in excessive collagen deposition in the skin and other organs throughout the body.⁴ Although the etiology is unknown, scleroderma develops when overactivation of the immune system leads to CD4⁺ T-lymphocyte infiltration in the skin, along with the release of profibrotic interleukins and growth factors, resulting in fibrosis.⁴ Subtypes include localized scleroderma (morphea), limited cutaneous systemic sclerosis (formerly known as CREST [calcinosis, RP, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome), diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma.⁵ Scleroderma is associated with positive antinuclear antibodies and HLA II alleles (HLA-DR2 and HLA-DR5).

On its own or in the setting of MCTD, scleroderma can result in systemic or localized symptoms. Overall, the most common symptom is RP.⁵ Localized scleroderma and limited cutaneous systemic sclerosis manifest with symptoms of the skin and underlying tissues. Diffuse cutaneous systemic sclerosis involves cutaneous and visceral symptoms, including lung, esophageal, and vascular involvement.⁶ Similar to MCTD, scleroderma is most prevalent in middle-aged females,⁷ though it occurs at a higher rate and with a more severe disease course in Black patients.⁸

A highly sensitive and specific test for scleroderma that can aid in diagnosis is the neck sign—tightening of the skin of the neck when the head extends.^9,10 In one study, the neck sign was positive in more than 90% of patients with scleroderma and negative for control patients and those with primary RP.⁹ Thus, neck sclerosis is a common manifestation of scleroderma for which patients may seek treatment.

While there is no curative treatment for scleroderma, skin manifestations can be treated with mycophenolate mofetil or methotrexate.⁵ Systemic treatments may be recommended if the patient has additional symptoms, such as azathioprine for myositis/arthritis and cyclophosphamide for interstitial lung disease.⁵ However, it is important to note that these medications are associated with risk for gastrointestinal upset, mouth sores, fatigue, or other complications.

Botulinum toxin is a bacterial protein toxin and neuromodulator that inhibits neurotransmitter release by cleaving SNARE proteins at peripheral nerve terminal junctions.¹¹ It has been used in a variety of dermatologic and nondermatologic conditions, including migraines, hyperhidrosis, contractures, scars, and overactive bladder. It also has been used in aesthetics for facial rejuvenation and minimization of wrinkle appearance. Dermatologists and rheumatologists have successfully used BTX to treat primary and secondary RP—the most common symptom of scleroderma—due to its vasodilatation properties.¹² Although our patient did not have RP, use of BTX to treat other features of scleroderma, including en coup de sabre, thoracic outlet syndrome, dyspareunia, gastroparesis, pterygium inversum unguis, and dysphagia has been documented.^13-18 An in vivo mouse study that examined the possible mechanism for BTX as a treatment in scleroderma found that BTX injections significantly decreased dermal thickness and inflammation in fibrosis (P<.05). An analysis of oxidative stress and mRNA expression showed that BTX may treat fibrosis by suppressing oxidative stress and inflammatory cells, resulting in decreased apoptosis and oxidant-induced intracellular accumulation of reactive oxygen species.¹⁹ Another animal study demonstrated the positive effects of BTX treatment for fibrosis of the bladder in rats.²⁰ In one case report, a female patient with scleroderma and facial fibrosis received perioral BTX injections for cosmetic purposes but also observed improvement in mouth constriction, demonstrating the potential efficacy of BTX for facial fibrosis.²¹

Our case demonstrates the potential positive effects of BTX treatment in patients with features of sclerosis or fibrosis, particularly in the neck region. We recommend assessing the efficacy of the initial BTX treatment after 2 to 3 weeks, with additional injections as needed to achieve the patient’s desired level of comfort and appearance at approximately 3-month intervals (aligning with the expected duration of efficacy of BTX).²² Our patient experienced considerable relief and high satisfaction with BTX treatment. Given the limitations of sclerosis treatments and the unwanted adverse-effect profile of systemic treatments, BTX injections may be a preferrable treatment option for cutaneous manifestations of ­scleroderma among patients. Future studies with larger patient populations and a control group are warranted to further explore the use of BTX for the dermatologic treatment of scleroderma.

To the Editor:

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome—a severe cutaneous adverse drug reaction—is characterized by a cutaneous rash and systemic upset in the form of various internal organ and hematologic disturbances. This delayed and idiosyncratic syndrome went by several names, including anticonvulsant hypersensitivity syndrome, before Bocquet et al¹ proposed the term DRESS syndrome.

Phenytoin, a hydantoin derivative used in neurology, was implicated in 41% of cases of DRESS syndrome in a study of 100 patients conducted in southern India.^2,3 While DRESS syndrome is a newer name, the clinical picture of DRESS secondary to phenytoin use remains similar in that it manifests with a morbilliform rash and systemic upset. We sought to describe the clinical and laboratory characteristics of phenytoin-induced DRESS syndrome in this case series.

The analysis included 23 patients with DRESS syndrome secondary to phenytoin use who presented to a tertiary care institution in North India between July 2021 and December 2022, satisfied the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria,⁴ and achieved a DRESS diagnostic score of more than 1. The mean age of the patients was 44 years (range, 14–74 years). There was a slight female predominance with a male to female ratio of 0.9:1. More than half of the patients (52.2% [12/23]) presented directly to the dermatology outpatient department; the remaining patients were referred from other departments (47.8% [11/23]). Patients primarily were receiving phenytoin for neurologic indications. Specific reasons included antiseizure prophylaxis following a traffic accident (34.8% [8/23]); epilepsy (26.1% [6/23]); and neoplastic (17.4% [4/23]), vascular (17.4% [4/23]), and infectious (4.3% [1/23]) causes. The mean latency period from drug intake to symptom onset was 29 days (range, 6–62 days), and the mean illness duration was 9 days (range, 1–45 days).

The majority of patients experienced pruritus (91.3% [21/23]) and fever (74.0% [17/23]), and all initially had a rash. Maculopapular morphology was seen in all patients. Erythema multiforme–like (17.4% [4/23]), erythrodermic (17.4% [4/23]), and vesicular (13.0% [3/23]) rashes also were documented (Figure 1). The trunk (100% [23/23]) and extremities (95.7% [22/23]) were involved most often, followed by the palms and soles (56.5% [13/23]). The mean total body surface area affected was 73.65%. Only 7 patients (30.4%) had mucosal ­involvement; nonhemorrhagic cheilitis was the most common manifestation.

Facial edema, a hallmark feature of DRESS syndrome, was noted in 69.6% (16/23) of patients (Figure 2). Lymphadenopathy was present in 43.5% (10/23) of patients; of those cases, the inguinal (40.0%; n=4) and cervical (30%; n=3) nodes most commonly were involved. Although DRESS syndrome can affect internal organs, this was an issue for only 2 (8.7%) patients who experienced mild hepatomegaly.

Laboratory investigations revealed a mean differential eosinophil percentage of 10.3% (reference range, 1%–4%), while the mean absolute eosinophil count was 1.0634×10⁹/L (reference range, 0.02–0.5×10⁹/L). Other hematologic findings included the mean percentages of neutrophils (60%; reference range, 50%–60%), lymphocytes (19.95%; reference range, 20%–50%), and monocytes (8.70%; reference range, 2%–8%).

Liver function tests revealed transaminitis⁵ as the most common finding, with mean aspartate aminotransferase levels of 109 U/L (reference range, 8–33 U/L), mean alanine aminotransferase of 97.9 U/L (reference range, 7–56 U/L), and mean alkaline phosphatase levels of 211.35 U/L (reference range, 44–147 U/L). Half of the patients had notable (>2 times the upper limit of normal) transaminitis.

Renal blood workup revealed slightly elevated blood urea nitrogen levels with a mean value of 28.4 mg/dL (reference range, 6–24 mg/dL), and mean serum creatinine was 0.78 mg/dL (reference range for men, 0.7–1.3 mg/dL; for women, 0.6–1.1 mg/dL).

All patients were treated with oral steroids (prednisolone 1 mg/kg/d) before tapering slowly over the following 6 to 8 weeks. The culprit drug (phenytoin) was stopped on the day of presentation. Resolution of rash and itching was seen in all patients by 3 weeks after presentation without any relapse by follow-up at 6 weeks from presentation to the hospital.

Our case series seeks to discuss the clinical and laboratory features of phenytoin-induced DRESS syndrome. Our patients had more erythrodermic and erythema multiforme–like morphologies, less mucosal involvement, more hepatic involvement, and earlier resolution.

To the Editor:

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome—a severe cutaneous adverse drug reaction—is characterized by a cutaneous rash and systemic upset in the form of various internal organ and hematologic disturbances. This delayed and idiosyncratic syndrome went by several names, including anticonvulsant hypersensitivity syndrome, before Bocquet et al¹ proposed the term DRESS syndrome.

Phenytoin, a hydantoin derivative used in neurology, was implicated in 41% of cases of DRESS syndrome in a study of 100 patients conducted in southern India.^2,3 While DRESS syndrome is a newer name, the clinical picture of DRESS secondary to phenytoin use remains similar in that it manifests with a morbilliform rash and systemic upset. We sought to describe the clinical and laboratory characteristics of phenytoin-induced DRESS syndrome in this case series.

The analysis included 23 patients with DRESS syndrome secondary to phenytoin use who presented to a tertiary care institution in North India between July 2021 and December 2022, satisfied the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria,⁴ and achieved a DRESS diagnostic score of more than 1. The mean age of the patients was 44 years (range, 14–74 years). There was a slight female predominance with a male to female ratio of 0.9:1. More than half of the patients (52.2% [12/23]) presented directly to the dermatology outpatient department; the remaining patients were referred from other departments (47.8% [11/23]). Patients primarily were receiving phenytoin for neurologic indications. Specific reasons included antiseizure prophylaxis following a traffic accident (34.8% [8/23]); epilepsy (26.1% [6/23]); and neoplastic (17.4% [4/23]), vascular (17.4% [4/23]), and infectious (4.3% [1/23]) causes. The mean latency period from drug intake to symptom onset was 29 days (range, 6–62 days), and the mean illness duration was 9 days (range, 1–45 days).

The majority of patients experienced pruritus (91.3% [21/23]) and fever (74.0% [17/23]), and all initially had a rash. Maculopapular morphology was seen in all patients. Erythema multiforme–like (17.4% [4/23]), erythrodermic (17.4% [4/23]), and vesicular (13.0% [3/23]) rashes also were documented (Figure 1). The trunk (100% [23/23]) and extremities (95.7% [22/23]) were involved most often, followed by the palms and soles (56.5% [13/23]). The mean total body surface area affected was 73.65%. Only 7 patients (30.4%) had mucosal ­involvement; nonhemorrhagic cheilitis was the most common manifestation.

Facial edema, a hallmark feature of DRESS syndrome, was noted in 69.6% (16/23) of patients (Figure 2). Lymphadenopathy was present in 43.5% (10/23) of patients; of those cases, the inguinal (40.0%; n=4) and cervical (30%; n=3) nodes most commonly were involved. Although DRESS syndrome can affect internal organs, this was an issue for only 2 (8.7%) patients who experienced mild hepatomegaly.

Laboratory investigations revealed a mean differential eosinophil percentage of 10.3% (reference range, 1%–4%), while the mean absolute eosinophil count was 1.0634×10⁹/L (reference range, 0.02–0.5×10⁹/L). Other hematologic findings included the mean percentages of neutrophils (60%; reference range, 50%–60%), lymphocytes (19.95%; reference range, 20%–50%), and monocytes (8.70%; reference range, 2%–8%).

Liver function tests revealed transaminitis⁵ as the most common finding, with mean aspartate aminotransferase levels of 109 U/L (reference range, 8–33 U/L), mean alanine aminotransferase of 97.9 U/L (reference range, 7–56 U/L), and mean alkaline phosphatase levels of 211.35 U/L (reference range, 44–147 U/L). Half of the patients had notable (>2 times the upper limit of normal) transaminitis.

Renal blood workup revealed slightly elevated blood urea nitrogen levels with a mean value of 28.4 mg/dL (reference range, 6–24 mg/dL), and mean serum creatinine was 0.78 mg/dL (reference range for men, 0.7–1.3 mg/dL; for women, 0.6–1.1 mg/dL).

All patients were treated with oral steroids (prednisolone 1 mg/kg/d) before tapering slowly over the following 6 to 8 weeks. The culprit drug (phenytoin) was stopped on the day of presentation. Resolution of rash and itching was seen in all patients by 3 weeks after presentation without any relapse by follow-up at 6 weeks from presentation to the hospital.

Our case series seeks to discuss the clinical and laboratory features of phenytoin-induced DRESS syndrome. Our patients had more erythrodermic and erythema multiforme–like morphologies, less mucosal involvement, more hepatic involvement, and earlier resolution.

To the Editor:

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome—a severe cutaneous adverse drug reaction—is characterized by a cutaneous rash and systemic upset in the form of various internal organ and hematologic disturbances. This delayed and idiosyncratic syndrome went by several names, including anticonvulsant hypersensitivity syndrome, before Bocquet et al¹ proposed the term DRESS syndrome.

Phenytoin, a hydantoin derivative used in neurology, was implicated in 41% of cases of DRESS syndrome in a study of 100 patients conducted in southern India.^2,3 While DRESS syndrome is a newer name, the clinical picture of DRESS secondary to phenytoin use remains similar in that it manifests with a morbilliform rash and systemic upset. We sought to describe the clinical and laboratory characteristics of phenytoin-induced DRESS syndrome in this case series.

The analysis included 23 patients with DRESS syndrome secondary to phenytoin use who presented to a tertiary care institution in North India between July 2021 and December 2022, satisfied the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria,⁴ and achieved a DRESS diagnostic score of more than 1. The mean age of the patients was 44 years (range, 14–74 years). There was a slight female predominance with a male to female ratio of 0.9:1. More than half of the patients (52.2% [12/23]) presented directly to the dermatology outpatient department; the remaining patients were referred from other departments (47.8% [11/23]). Patients primarily were receiving phenytoin for neurologic indications. Specific reasons included antiseizure prophylaxis following a traffic accident (34.8% [8/23]); epilepsy (26.1% [6/23]); and neoplastic (17.4% [4/23]), vascular (17.4% [4/23]), and infectious (4.3% [1/23]) causes. The mean latency period from drug intake to symptom onset was 29 days (range, 6–62 days), and the mean illness duration was 9 days (range, 1–45 days).

The majority of patients experienced pruritus (91.3% [21/23]) and fever (74.0% [17/23]), and all initially had a rash. Maculopapular morphology was seen in all patients. Erythema multiforme–like (17.4% [4/23]), erythrodermic (17.4% [4/23]), and vesicular (13.0% [3/23]) rashes also were documented (Figure 1). The trunk (100% [23/23]) and extremities (95.7% [22/23]) were involved most often, followed by the palms and soles (56.5% [13/23]). The mean total body surface area affected was 73.65%. Only 7 patients (30.4%) had mucosal ­involvement; nonhemorrhagic cheilitis was the most common manifestation.

Facial edema, a hallmark feature of DRESS syndrome, was noted in 69.6% (16/23) of patients (Figure 2). Lymphadenopathy was present in 43.5% (10/23) of patients; of those cases, the inguinal (40.0%; n=4) and cervical (30%; n=3) nodes most commonly were involved. Although DRESS syndrome can affect internal organs, this was an issue for only 2 (8.7%) patients who experienced mild hepatomegaly.

Laboratory investigations revealed a mean differential eosinophil percentage of 10.3% (reference range, 1%–4%), while the mean absolute eosinophil count was 1.0634×10⁹/L (reference range, 0.02–0.5×10⁹/L). Other hematologic findings included the mean percentages of neutrophils (60%; reference range, 50%–60%), lymphocytes (19.95%; reference range, 20%–50%), and monocytes (8.70%; reference range, 2%–8%).

Liver function tests revealed transaminitis⁵ as the most common finding, with mean aspartate aminotransferase levels of 109 U/L (reference range, 8–33 U/L), mean alanine aminotransferase of 97.9 U/L (reference range, 7–56 U/L), and mean alkaline phosphatase levels of 211.35 U/L (reference range, 44–147 U/L). Half of the patients had notable (>2 times the upper limit of normal) transaminitis.

Renal blood workup revealed slightly elevated blood urea nitrogen levels with a mean value of 28.4 mg/dL (reference range, 6–24 mg/dL), and mean serum creatinine was 0.78 mg/dL (reference range for men, 0.7–1.3 mg/dL; for women, 0.6–1.1 mg/dL).

All patients were treated with oral steroids (prednisolone 1 mg/kg/d) before tapering slowly over the following 6 to 8 weeks. The culprit drug (phenytoin) was stopped on the day of presentation. Resolution of rash and itching was seen in all patients by 3 weeks after presentation without any relapse by follow-up at 6 weeks from presentation to the hospital.

Our case series seeks to discuss the clinical and laboratory features of phenytoin-induced DRESS syndrome. Our patients had more erythrodermic and erythema multiforme–like morphologies, less mucosal involvement, more hepatic involvement, and earlier resolution.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

A shave biopsy performed on a papulovesicular lesion on the right thigh showed an intact epidermis with minimal spongiosis and no viral cytopathic changes. There was dermal edema with a moderate superficial and deep neutrophilic infiltrate, mild karyorrhexis, and focal dermal necrosis (Figure 2). Rare acute vasculitis with intravascular fibrin was seen. Periodic acid-Schiff stain for fungi, Gram stain for bacteria, and immunostains for human herpesviruses 1 and 2 were negative.

Laboratory studies revealed neutrophil-­predominant leukocytosis (white blood cell count, 13.89×10⁹/L [reference range, 4.5–11.0×10⁹/L] with 78.2% neutrophils [reference range, 40.0%–70.0%]) as well as an elevated C-reactive protein level and erythrocyte sedimentation rate (19.98 mg/dL [reference range, <0.05 mg/dL] and 38 mm/h [reference range, 0–15 mm/h], respectively). His liver enzymes, kidney function, prothrombin time, and international normalized ratio were all normal. Urinalysis showed trace amounts of blood and protein, and urine culture was negative for pathogenic bacteria. A rapid plasma reagin test and a fifth-generation HIV antibody test were nonreactive, and bacterial blood cultures were negative for other infectious diseases. Nucleic acid amplification testing (NAAT) performed on a swab from a papulovesicular lesion was negative for human herpesviruses 1 and 2, varicella-zoster virus, orthopoxvirus, and mpox (monkeypox) virus. Based on recommendations from dermatology, NAATs for C trachomatis and N gonorrhoeae were performed on urine and on swabs from the patient’s rectum and pharynx; N gonorrhoeae was detected at the pharynx, but the other sites were negative for both bacteria. A diagnosis of DGI was made based on these results as well as the patient’s clinical presentation of fever, arthralgia, and papulovesicular skin lesions. The patient was treated with 1 g of intravenous ceftriaxone while in the hospital, but unfortunately, he was lost to follow-up and did not complete the full 1-week treatment course.

Disseminated gonococcal infection (also known as arthritis-dermatitis syndrome) is characterized by the abrupt onset of fever, skin lesions, and arthralgia in a symmetric and migratory distribution. Tenosynovitis involving the extensor tendons of the wrists, fingers, knees, and ankles (particularly the Achilles tendon) is characteristic. Skin manifestations usually include hemorrhagic vesicles and papulovesicles limited to the extremities, often with an acral distribution,^2-5 though other cutaneous lesions have been described in DGI, including macules, purpura, periurethral abscesses, multifocal cellulitis, and necrotizing fasciitis.⁷ It is important to consider DGI in a patient who presents with acute systemic symptoms and any of these cutaneous manifestations, even in the absence of joint pain.

The differential diagnosis for a patient with acute fever, joint pain, and hemorrhagic macules, pustules, or vesicopustules includes neutrophilic dermatoses; endocarditis; and infections with other Gram-negative bacteria, such as rat bite fever, Rickettsia species, enteroviruses, human herpesviruses, and mpox virus. Evaluation of a patient with suspected DGI includes skin biopsies for histopathology and tissue culture to rule out other conditions, NAATs for gonococcus and chlamydia, and N gonorrhoeae–specific cultures at all possible sites of infection, as well as possible disseminated sites such as joint aspirates, blood, or cerebrospinal fluid when appropriate.

Diagnosis of DGI can be difficult, and surveillance is limited in the United States; therefore, the risk factors are somewhat unclear and might be changing. Traditional risk factors for DGI have included immunosuppression due to terminal complement deficiency, female sex, recent menstruation, and pregnancy, but recent data have shown that male sex, HIV infection, use of methamphetamines and other drugs, and use of the monoclonal antibody eculizumab for treatment of complement disorders have been associated with DGI.^2,6-8 In the past decade, uncomplicated gonococcal infections have disproportionately affected Black patients, men who have sex with men, adults aged 20 to 25 years, and individuals living in the southern United States.¹ It is unclear if the changing demographics of patients with DGI represent true risk factors for dissemination or simply reflect the changing demographics of patients at risk for uncomplicated gonococcal infection.⁶

Dermatologic expertise in the recognition of cutaneous manifestations of DGI is particularly important due to the limitations of diagnostic tools. The organism is fastidious and difficult to grow in vitro, thus cultures for N gonorrhoeae are not sensitive and require specialized media (eg, Thayer-Martin, modified New York City, or chocolate agar medium with additional antimicrobial agents).³ Molecular assays such as NAATs are more sensitive and specific than culture but are not 100% accurate.^2,3,5 Finally, sterile sites such as joints, blood, or cerebrospinal fluid can be difficult to access, and specimens are not always available for specific microbial diagnosis; therefore, even when a gonococcal infection is identified at a mucosal source, physicians must use their clinical judgment to determine whether the mucosal infection is the cause of DGI or if the patient has a separate additional illness.

Once a diagnosis of gonococcal infection is made, any isolated gonococcal bacteria should be tested for antimicrobial susceptibility due to rising rates of drug resistance. Since at least the 1980s, N gonorrhoeae has steadily evolved to have some degree of resistance to most antimicrobials, and epidemiologic evidence indicates that this evolution is continuing.² Current Centers for Disease Control and Prevention (CDC) recommendations are to treat uncomplicated gonococcal infections with 1 dose of ceftriaxone 500 mg intramuscularly in individuals weighing less than 150 kg (increase to 1 g in those ≥150 kg). Disseminated gonococcal infection requires more aggressive treatment with ceftriaxone 1 g intravenously or intramuscularly every 24 hours for at least 7 days and at a higher dose and for longer duration for patients with endocarditis or meningitis.² If there is notable clinical improvement after 24 to 48 hours and antimicrobial susceptibility testing confirms an oral agent is appropriate, the patient can be switched to that oral agent to complete treatment. Also, if chlamydia has not been excluded in patients with any type of gonococcal infection, they also should be treated for chlamydia with doxycycline 100 mg twice daily, per CDC guidelines.² Dermatologists should advocate for patients to be treated for DGI even if the diagnosis is clinical because of the potential for untreated or undertreated patients to progress, to develop additional antimicrobial resistant bacteria, and/or to transmit the infection to others.

This case highlights 2 important points about gonococcal infections and DGI. First, it is important to test and screen patients for gonococcal infection at genitourinary, rectal, and pharyngeal sites. Despite our patient’s report of dysuria, gonococcal infection was only detected via NAAT at the pharynx. As of 2021, CDC guidelines recommend not only testing for gonococcal infection in symptomatic patients at all mucosal sites but also screening all mucosal sites in asymptomatic individuals at high risk.² Second, dermatologists’ specialized knowledge of cutaneous manifestations provides a valuable tool in the clinical diagnosis of DGI. In this patient, it was the dermatology team’s high index of concern for DGI that led to NAAT testing at all mucosal sites and resulted in an accurate diagnosis. Ultimately, dermatologists play an important role in the diagnosis and management of DGI.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

A shave biopsy performed on a papulovesicular lesion on the right thigh showed an intact epidermis with minimal spongiosis and no viral cytopathic changes. There was dermal edema with a moderate superficial and deep neutrophilic infiltrate, mild karyorrhexis, and focal dermal necrosis (Figure 2). Rare acute vasculitis with intravascular fibrin was seen. Periodic acid-Schiff stain for fungi, Gram stain for bacteria, and immunostains for human herpesviruses 1 and 2 were negative.

Laboratory studies revealed neutrophil-­predominant leukocytosis (white blood cell count, 13.89×10⁹/L [reference range, 4.5–11.0×10⁹/L] with 78.2% neutrophils [reference range, 40.0%–70.0%]) as well as an elevated C-reactive protein level and erythrocyte sedimentation rate (19.98 mg/dL [reference range, <0.05 mg/dL] and 38 mm/h [reference range, 0–15 mm/h], respectively). His liver enzymes, kidney function, prothrombin time, and international normalized ratio were all normal. Urinalysis showed trace amounts of blood and protein, and urine culture was negative for pathogenic bacteria. A rapid plasma reagin test and a fifth-generation HIV antibody test were nonreactive, and bacterial blood cultures were negative for other infectious diseases. Nucleic acid amplification testing (NAAT) performed on a swab from a papulovesicular lesion was negative for human herpesviruses 1 and 2, varicella-zoster virus, orthopoxvirus, and mpox (monkeypox) virus. Based on recommendations from dermatology, NAATs for C trachomatis and N gonorrhoeae were performed on urine and on swabs from the patient’s rectum and pharynx; N gonorrhoeae was detected at the pharynx, but the other sites were negative for both bacteria. A diagnosis of DGI was made based on these results as well as the patient’s clinical presentation of fever, arthralgia, and papulovesicular skin lesions. The patient was treated with 1 g of intravenous ceftriaxone while in the hospital, but unfortunately, he was lost to follow-up and did not complete the full 1-week treatment course.

Disseminated gonococcal infection (also known as arthritis-dermatitis syndrome) is characterized by the abrupt onset of fever, skin lesions, and arthralgia in a symmetric and migratory distribution. Tenosynovitis involving the extensor tendons of the wrists, fingers, knees, and ankles (particularly the Achilles tendon) is characteristic. Skin manifestations usually include hemorrhagic vesicles and papulovesicles limited to the extremities, often with an acral distribution,^2-5 though other cutaneous lesions have been described in DGI, including macules, purpura, periurethral abscesses, multifocal cellulitis, and necrotizing fasciitis.⁷ It is important to consider DGI in a patient who presents with acute systemic symptoms and any of these cutaneous manifestations, even in the absence of joint pain.

The differential diagnosis for a patient with acute fever, joint pain, and hemorrhagic macules, pustules, or vesicopustules includes neutrophilic dermatoses; endocarditis; and infections with other Gram-negative bacteria, such as rat bite fever, Rickettsia species, enteroviruses, human herpesviruses, and mpox virus. Evaluation of a patient with suspected DGI includes skin biopsies for histopathology and tissue culture to rule out other conditions, NAATs for gonococcus and chlamydia, and N gonorrhoeae–specific cultures at all possible sites of infection, as well as possible disseminated sites such as joint aspirates, blood, or cerebrospinal fluid when appropriate.

Diagnosis of DGI can be difficult, and surveillance is limited in the United States; therefore, the risk factors are somewhat unclear and might be changing. Traditional risk factors for DGI have included immunosuppression due to terminal complement deficiency, female sex, recent menstruation, and pregnancy, but recent data have shown that male sex, HIV infection, use of methamphetamines and other drugs, and use of the monoclonal antibody eculizumab for treatment of complement disorders have been associated with DGI.^2,6-8 In the past decade, uncomplicated gonococcal infections have disproportionately affected Black patients, men who have sex with men, adults aged 20 to 25 years, and individuals living in the southern United States.¹ It is unclear if the changing demographics of patients with DGI represent true risk factors for dissemination or simply reflect the changing demographics of patients at risk for uncomplicated gonococcal infection.⁶

Dermatologic expertise in the recognition of cutaneous manifestations of DGI is particularly important due to the limitations of diagnostic tools. The organism is fastidious and difficult to grow in vitro, thus cultures for N gonorrhoeae are not sensitive and require specialized media (eg, Thayer-Martin, modified New York City, or chocolate agar medium with additional antimicrobial agents).³ Molecular assays such as NAATs are more sensitive and specific than culture but are not 100% accurate.^2,3,5 Finally, sterile sites such as joints, blood, or cerebrospinal fluid can be difficult to access, and specimens are not always available for specific microbial diagnosis; therefore, even when a gonococcal infection is identified at a mucosal source, physicians must use their clinical judgment to determine whether the mucosal infection is the cause of DGI or if the patient has a separate additional illness.

Once a diagnosis of gonococcal infection is made, any isolated gonococcal bacteria should be tested for antimicrobial susceptibility due to rising rates of drug resistance. Since at least the 1980s, N gonorrhoeae has steadily evolved to have some degree of resistance to most antimicrobials, and epidemiologic evidence indicates that this evolution is continuing.² Current Centers for Disease Control and Prevention (CDC) recommendations are to treat uncomplicated gonococcal infections with 1 dose of ceftriaxone 500 mg intramuscularly in individuals weighing less than 150 kg (increase to 1 g in those ≥150 kg). Disseminated gonococcal infection requires more aggressive treatment with ceftriaxone 1 g intravenously or intramuscularly every 24 hours for at least 7 days and at a higher dose and for longer duration for patients with endocarditis or meningitis.² If there is notable clinical improvement after 24 to 48 hours and antimicrobial susceptibility testing confirms an oral agent is appropriate, the patient can be switched to that oral agent to complete treatment. Also, if chlamydia has not been excluded in patients with any type of gonococcal infection, they also should be treated for chlamydia with doxycycline 100 mg twice daily, per CDC guidelines.² Dermatologists should advocate for patients to be treated for DGI even if the diagnosis is clinical because of the potential for untreated or undertreated patients to progress, to develop additional antimicrobial resistant bacteria, and/or to transmit the infection to others.

This case highlights 2 important points about gonococcal infections and DGI. First, it is important to test and screen patients for gonococcal infection at genitourinary, rectal, and pharyngeal sites. Despite our patient’s report of dysuria, gonococcal infection was only detected via NAAT at the pharynx. As of 2021, CDC guidelines recommend not only testing for gonococcal infection in symptomatic patients at all mucosal sites but also screening all mucosal sites in asymptomatic individuals at high risk.² Second, dermatologists’ specialized knowledge of cutaneous manifestations provides a valuable tool in the clinical diagnosis of DGI. In this patient, it was the dermatology team’s high index of concern for DGI that led to NAAT testing at all mucosal sites and resulted in an accurate diagnosis. Ultimately, dermatologists play an important role in the diagnosis and management of DGI.

To the Editor:

Gonococcal infections, which are caused by the sexually transmitted, gram-negative diplococcus Neisseria gonorrhoeae, are a current and increasing threat to public health. Between 2012 and 2021, the rate of gonococcal infection in the United States increased 137.8% in men and 64.9% in women,¹ with an estimated 1.5 million new gonococcal infections occurring each year in the United States as of 2021.²Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection (STI), and patients with gonococcal infection frequently are coinfected with Chlamydia trachomatis, which is the most common bacterial STI. Uncomplicated gonococcal infection (also known as gonorrhea) most commonly causes asymptomatic cervicovaginal infection in women and symptomatic urethral infection in men.² Other uncomplicated manifestations include rectal infection, which can be asymptomatic or manifest with anal pruritus, anal discharge, or tenesmus, and oropharyngeal infection, which can be asymptomatic or manifest with throat pain. If uncomplicated gonococcal infections are left untreated or are incompletely treated, serious complications including septic arthritis, myositis, osteomyelitis, myocarditis, endocarditis, and meningitis might occur.^2-5 Ascending, locally invasive infections can cause epididymitis or pelvic inflammatory disease, which is an important cause of infertility in women.^2,3 Gonococcal conjunctivitis also can occur, particularly when neonates are exposed to bacteria during vaginal delivery. Although rare, gonococcal bacteria can disseminate widely, with an estimated 0.5% to 3% of uncomplicated gonococcal infections progressing to disseminated gonococcal infection (DGI).^3-6 Because DGI can mimic other systemic conditions, including a variety of bacterial and viral infections as well as inflammatory conditions, it can be difficult to diagnose without a high index of clinical suspicion. We present a case of DGI diagnosed based on dermatologic expertise and pharyngeal molecular testing.

A 30-year-old man presented to the emergency department with a rash on the extremeities as well as emesis, fever, sore throat, and severe arthralgia in the wrists, hands, knees, and feet of 2 days’ duration. The patient also had experienced several months of dysuria. He reported daily use of the recreational drug ketamine, multiple new male sexual partners, and unprotected oral and receptive anal sex in recent months. He denied any history of STIs. Physical examination demonstrated tender edematous wrists and fingers, papulovesicles on erythematous bases on the palms, and purpuric macules scattered on the legs (Figure 1). The patient also had tonsillar edema with notable white tonsillar exudate.

A shave biopsy performed on a papulovesicular lesion on the right thigh showed an intact epidermis with minimal spongiosis and no viral cytopathic changes. There was dermal edema with a moderate superficial and deep neutrophilic infiltrate, mild karyorrhexis, and focal dermal necrosis (Figure 2). Rare acute vasculitis with intravascular fibrin was seen. Periodic acid-Schiff stain for fungi, Gram stain for bacteria, and immunostains for human herpesviruses 1 and 2 were negative.

Laboratory studies revealed neutrophil-­predominant leukocytosis (white blood cell count, 13.89×10⁹/L [reference range, 4.5–11.0×10⁹/L] with 78.2% neutrophils [reference range, 40.0%–70.0%]) as well as an elevated C-reactive protein level and erythrocyte sedimentation rate (19.98 mg/dL [reference range, <0.05 mg/dL] and 38 mm/h [reference range, 0–15 mm/h], respectively). His liver enzymes, kidney function, prothrombin time, and international normalized ratio were all normal. Urinalysis showed trace amounts of blood and protein, and urine culture was negative for pathogenic bacteria. A rapid plasma reagin test and a fifth-generation HIV antibody test were nonreactive, and bacterial blood cultures were negative for other infectious diseases. Nucleic acid amplification testing (NAAT) performed on a swab from a papulovesicular lesion was negative for human herpesviruses 1 and 2, varicella-zoster virus, orthopoxvirus, and mpox (monkeypox) virus. Based on recommendations from dermatology, NAATs for C trachomatis and N gonorrhoeae were performed on urine and on swabs from the patient’s rectum and pharynx; N gonorrhoeae was detected at the pharynx, but the other sites were negative for both bacteria. A diagnosis of DGI was made based on these results as well as the patient’s clinical presentation of fever, arthralgia, and papulovesicular skin lesions. The patient was treated with 1 g of intravenous ceftriaxone while in the hospital, but unfortunately, he was lost to follow-up and did not complete the full 1-week treatment course.

Disseminated gonococcal infection (also known as arthritis-dermatitis syndrome) is characterized by the abrupt onset of fever, skin lesions, and arthralgia in a symmetric and migratory distribution. Tenosynovitis involving the extensor tendons of the wrists, fingers, knees, and ankles (particularly the Achilles tendon) is characteristic. Skin manifestations usually include hemorrhagic vesicles and papulovesicles limited to the extremities, often with an acral distribution,^2-5 though other cutaneous lesions have been described in DGI, including macules, purpura, periurethral abscesses, multifocal cellulitis, and necrotizing fasciitis.⁷ It is important to consider DGI in a patient who presents with acute systemic symptoms and any of these cutaneous manifestations, even in the absence of joint pain.

The differential diagnosis for a patient with acute fever, joint pain, and hemorrhagic macules, pustules, or vesicopustules includes neutrophilic dermatoses; endocarditis; and infections with other Gram-negative bacteria, such as rat bite fever, Rickettsia species, enteroviruses, human herpesviruses, and mpox virus. Evaluation of a patient with suspected DGI includes skin biopsies for histopathology and tissue culture to rule out other conditions, NAATs for gonococcus and chlamydia, and N gonorrhoeae–specific cultures at all possible sites of infection, as well as possible disseminated sites such as joint aspirates, blood, or cerebrospinal fluid when appropriate.

Diagnosis of DGI can be difficult, and surveillance is limited in the United States; therefore, the risk factors are somewhat unclear and might be changing. Traditional risk factors for DGI have included immunosuppression due to terminal complement deficiency, female sex, recent menstruation, and pregnancy, but recent data have shown that male sex, HIV infection, use of methamphetamines and other drugs, and use of the monoclonal antibody eculizumab for treatment of complement disorders have been associated with DGI.^2,6-8 In the past decade, uncomplicated gonococcal infections have disproportionately affected Black patients, men who have sex with men, adults aged 20 to 25 years, and individuals living in the southern United States.¹ It is unclear if the changing demographics of patients with DGI represent true risk factors for dissemination or simply reflect the changing demographics of patients at risk for uncomplicated gonococcal infection.⁶

Dermatologic expertise in the recognition of cutaneous manifestations of DGI is particularly important due to the limitations of diagnostic tools. The organism is fastidious and difficult to grow in vitro, thus cultures for N gonorrhoeae are not sensitive and require specialized media (eg, Thayer-Martin, modified New York City, or chocolate agar medium with additional antimicrobial agents).³ Molecular assays such as NAATs are more sensitive and specific than culture but are not 100% accurate.^2,3,5 Finally, sterile sites such as joints, blood, or cerebrospinal fluid can be difficult to access, and specimens are not always available for specific microbial diagnosis; therefore, even when a gonococcal infection is identified at a mucosal source, physicians must use their clinical judgment to determine whether the mucosal infection is the cause of DGI or if the patient has a separate additional illness.

Once a diagnosis of gonococcal infection is made, any isolated gonococcal bacteria should be tested for antimicrobial susceptibility due to rising rates of drug resistance. Since at least the 1980s, N gonorrhoeae has steadily evolved to have some degree of resistance to most antimicrobials, and epidemiologic evidence indicates that this evolution is continuing.² Current Centers for Disease Control and Prevention (CDC) recommendations are to treat uncomplicated gonococcal infections with 1 dose of ceftriaxone 500 mg intramuscularly in individuals weighing less than 150 kg (increase to 1 g in those ≥150 kg). Disseminated gonococcal infection requires more aggressive treatment with ceftriaxone 1 g intravenously or intramuscularly every 24 hours for at least 7 days and at a higher dose and for longer duration for patients with endocarditis or meningitis.² If there is notable clinical improvement after 24 to 48 hours and antimicrobial susceptibility testing confirms an oral agent is appropriate, the patient can be switched to that oral agent to complete treatment. Also, if chlamydia has not been excluded in patients with any type of gonococcal infection, they also should be treated for chlamydia with doxycycline 100 mg twice daily, per CDC guidelines.² Dermatologists should advocate for patients to be treated for DGI even if the diagnosis is clinical because of the potential for untreated or undertreated patients to progress, to develop additional antimicrobial resistant bacteria, and/or to transmit the infection to others.

This case highlights 2 important points about gonococcal infections and DGI. First, it is important to test and screen patients for gonococcal infection at genitourinary, rectal, and pharyngeal sites. Despite our patient’s report of dysuria, gonococcal infection was only detected via NAAT at the pharynx. As of 2021, CDC guidelines recommend not only testing for gonococcal infection in symptomatic patients at all mucosal sites but also screening all mucosal sites in asymptomatic individuals at high risk.² Second, dermatologists’ specialized knowledge of cutaneous manifestations provides a valuable tool in the clinical diagnosis of DGI. In this patient, it was the dermatology team’s high index of concern for DGI that led to NAAT testing at all mucosal sites and resulted in an accurate diagnosis. Ultimately, dermatologists play an important role in the diagnosis and management of DGI.

To the Editor:

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

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

A 75-year-old man (patient 2) presented with a 2-cm erythematous plaque on the left vertex scalp with hemorrhagic crusting, yellow scale, and purulent drainage. He had a history of cSCCs. A biopsy revealed ­well-differentiated invasive cSCC, which was upgraded from a T2a tumor to T2b during MMS due to tumor extension beyond the subcutaneous fat. Examination of the second Mohs stage revealed moderately differentiated cSCC, with the least-differentiated cells at the deep margin, infiltration beyond the subcutaneous fat, and perineural invasion (Figure 1B). Given T2b staging, baseline imaging and radiation therapy were recommended.

An 86-year-old woman (patient 3) presented with a tender 2.4-cm plum-colored nodule on the right lower leg. She had a history of basal cell carcinoma. A biopsy revealed a well-differentiated invasive cSCC staged at T2a. Debulk analysis revealed moderately differentiated cSCC, with the least-differentiated cells at the deep margin, though the staging remained the same (Figure 1C).

An 82-year-old man (patient 4) presented with a ­2.7-cm ulcerated nodule with adjacent scaling on the vertex scalp. He had no history of skin cancer. A biopsy revealed a well-differentiated cSCC (Figure 2) that was upgraded from a T2a tumor to T2b during MMS due to tumor extension beyond the subcutaneous fat. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells with single-cell ­extension at the deep margin in the galea (Figure 1D). Given T2b staging, baseline imaging and radiation therapy were recommended.

Tumor differentiation is a factor included in the Brigham and Women’s Hospital staging system, and intratumor variability can be clinically relevant for tumor staging.¹ Specifically, cSCCs may exhibit intratumor heterogeneity in which predominantly well-differentiated tumors contain focal areas of poorer differentiation.² This intratumor heterogeneity complicates estimation of tumor risk, as a well-differentiated tumor on biopsy may exhibit poor differentiation at a deeper margin. Our cases highlight that the cells at the deeper margin indeed can show poorer differentiation or other higher-risk tumor features. Thus, the most clinically relevant cells for tumor staging and prognostication may not be visible on initial biopsy, underscoring the utility of close examination of the deep layer of the debulk specimen and Mohs layer for comprehensive staging.

Genetic studies have attempted to identify gene expression patterns in cSCCs that predispose to invasion.³ Three of the top 6 genes in this “invasion signature gene set” were matrix metalloproteases; additionally, IL-24 messenger RNA was upregulated in both the cSCC invasion front and in situ cSCCs. IL-24 has been shown to upregulate the expression of matrix metalloprotease 7 in vitro, suggesting that it may influence tumor progression.³ Although gene expression was not included in this series, the identification of genetic variability in the most poorly differentiated cells residing in the deep margins is of great interest and may reveal mutations contributing to irregular cell morphology and cSCC invasiveness.

Prior studies have indicated that a proportion of cSCCs are histopathologically upgraded from the initial biopsy during MMS due to evidence of perineural invasion, bony invasion, or lesser differentiation noted during MMS stages or debulk analysis.^1,4 However, the majority of Mohs surgeons report immediately discarding debulk specimens without further evaluation.⁵ Herein, we highlight 4 cSCC cases in which the deep margins of the debulk specimen contained the most dedifferentiated cells. Our findings emphasize the importance of thoroughly examining deep tumor margins for complete staging yet also highlight that identifying cells at these margins may not change patient management when high-risk criteria are already met.

To the Editor:

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

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

A 75-year-old man (patient 2) presented with a 2-cm erythematous plaque on the left vertex scalp with hemorrhagic crusting, yellow scale, and purulent drainage. He had a history of cSCCs. A biopsy revealed ­well-differentiated invasive cSCC, which was upgraded from a T2a tumor to T2b during MMS due to tumor extension beyond the subcutaneous fat. Examination of the second Mohs stage revealed moderately differentiated cSCC, with the least-differentiated cells at the deep margin, infiltration beyond the subcutaneous fat, and perineural invasion (Figure 1B). Given T2b staging, baseline imaging and radiation therapy were recommended.

An 86-year-old woman (patient 3) presented with a tender 2.4-cm plum-colored nodule on the right lower leg. She had a history of basal cell carcinoma. A biopsy revealed a well-differentiated invasive cSCC staged at T2a. Debulk analysis revealed moderately differentiated cSCC, with the least-differentiated cells at the deep margin, though the staging remained the same (Figure 1C).

An 82-year-old man (patient 4) presented with a ­2.7-cm ulcerated nodule with adjacent scaling on the vertex scalp. He had no history of skin cancer. A biopsy revealed a well-differentiated cSCC (Figure 2) that was upgraded from a T2a tumor to T2b during MMS due to tumor extension beyond the subcutaneous fat. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells with single-cell ­extension at the deep margin in the galea (Figure 1D). Given T2b staging, baseline imaging and radiation therapy were recommended.

Tumor differentiation is a factor included in the Brigham and Women’s Hospital staging system, and intratumor variability can be clinically relevant for tumor staging.¹ Specifically, cSCCs may exhibit intratumor heterogeneity in which predominantly well-differentiated tumors contain focal areas of poorer differentiation.² This intratumor heterogeneity complicates estimation of tumor risk, as a well-differentiated tumor on biopsy may exhibit poor differentiation at a deeper margin. Our cases highlight that the cells at the deeper margin indeed can show poorer differentiation or other higher-risk tumor features. Thus, the most clinically relevant cells for tumor staging and prognostication may not be visible on initial biopsy, underscoring the utility of close examination of the deep layer of the debulk specimen and Mohs layer for comprehensive staging.

Genetic studies have attempted to identify gene expression patterns in cSCCs that predispose to invasion.³ Three of the top 6 genes in this “invasion signature gene set” were matrix metalloproteases; additionally, IL-24 messenger RNA was upregulated in both the cSCC invasion front and in situ cSCCs. IL-24 has been shown to upregulate the expression of matrix metalloprotease 7 in vitro, suggesting that it may influence tumor progression.³ Although gene expression was not included in this series, the identification of genetic variability in the most poorly differentiated cells residing in the deep margins is of great interest and may reveal mutations contributing to irregular cell morphology and cSCC invasiveness.

Prior studies have indicated that a proportion of cSCCs are histopathologically upgraded from the initial biopsy during MMS due to evidence of perineural invasion, bony invasion, or lesser differentiation noted during MMS stages or debulk analysis.^1,4 However, the majority of Mohs surgeons report immediately discarding debulk specimens without further evaluation.⁵ Herein, we highlight 4 cSCC cases in which the deep margins of the debulk specimen contained the most dedifferentiated cells. Our findings emphasize the importance of thoroughly examining deep tumor margins for complete staging yet also highlight that identifying cells at these margins may not change patient management when high-risk criteria are already met.

To the Editor:

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

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

A 75-year-old man (patient 2) presented with a 2-cm erythematous plaque on the left vertex scalp with hemorrhagic crusting, yellow scale, and purulent drainage. He had a history of cSCCs. A biopsy revealed ­well-differentiated invasive cSCC, which was upgraded from a T2a tumor to T2b during MMS due to tumor extension beyond the subcutaneous fat. Examination of the second Mohs stage revealed moderately differentiated cSCC, with the least-differentiated cells at the deep margin, infiltration beyond the subcutaneous fat, and perineural invasion (Figure 1B). Given T2b staging, baseline imaging and radiation therapy were recommended.

An 86-year-old woman (patient 3) presented with a tender 2.4-cm plum-colored nodule on the right lower leg. She had a history of basal cell carcinoma. A biopsy revealed a well-differentiated invasive cSCC staged at T2a. Debulk analysis revealed moderately differentiated cSCC, with the least-differentiated cells at the deep margin, though the staging remained the same (Figure 1C).

An 82-year-old man (patient 4) presented with a ­2.7-cm ulcerated nodule with adjacent scaling on the vertex scalp. He had no history of skin cancer. A biopsy revealed a well-differentiated cSCC (Figure 2) that was upgraded from a T2a tumor to T2b during MMS due to tumor extension beyond the subcutaneous fat. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells with single-cell ­extension at the deep margin in the galea (Figure 1D). Given T2b staging, baseline imaging and radiation therapy were recommended.

Tumor differentiation is a factor included in the Brigham and Women’s Hospital staging system, and intratumor variability can be clinically relevant for tumor staging.¹ Specifically, cSCCs may exhibit intratumor heterogeneity in which predominantly well-differentiated tumors contain focal areas of poorer differentiation.² This intratumor heterogeneity complicates estimation of tumor risk, as a well-differentiated tumor on biopsy may exhibit poor differentiation at a deeper margin. Our cases highlight that the cells at the deeper margin indeed can show poorer differentiation or other higher-risk tumor features. Thus, the most clinically relevant cells for tumor staging and prognostication may not be visible on initial biopsy, underscoring the utility of close examination of the deep layer of the debulk specimen and Mohs layer for comprehensive staging.

Genetic studies have attempted to identify gene expression patterns in cSCCs that predispose to invasion.³ Three of the top 6 genes in this “invasion signature gene set” were matrix metalloproteases; additionally, IL-24 messenger RNA was upregulated in both the cSCC invasion front and in situ cSCCs. IL-24 has been shown to upregulate the expression of matrix metalloprotease 7 in vitro, suggesting that it may influence tumor progression.³ Although gene expression was not included in this series, the identification of genetic variability in the most poorly differentiated cells residing in the deep margins is of great interest and may reveal mutations contributing to irregular cell morphology and cSCC invasiveness.

Prior studies have indicated that a proportion of cSCCs are histopathologically upgraded from the initial biopsy during MMS due to evidence of perineural invasion, bony invasion, or lesser differentiation noted during MMS stages or debulk analysis.^1,4 However, the majority of Mohs surgeons report immediately discarding debulk specimens without further evaluation.⁵ Herein, we highlight 4 cSCC cases in which the deep margins of the debulk specimen contained the most dedifferentiated cells. Our findings emphasize the importance of thoroughly examining deep tumor margins for complete staging yet also highlight that identifying cells at these margins may not change patient management when high-risk criteria are already met.

To the Editor:

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

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

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

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

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

Verrucous keratosis is a known cutaneous AE of BRAF inhibitor treatment with vemurafenib and dabrafenib, with fewer cases attributed to encorafenib.^5,6 Within the oncologic setting, the eruption of verrucous papules as a paraneoplastic phenomenon is heavily debated in the literature and is known as the Leser-Trélat sign. This phenomenon is commonly associated with adenocarcinomas of the gastrointestinal tract, as seen in our patient.¹⁰ Based on Curth’s postulates—the criteria used to evaluate the relationship between an internal malignancy and a cutaneous disorder—this was unlikely in our patient. The criteria, which do not all need to be met to suggest a paraneoplastic phenomenon, include concurrent onset of the malignancy and the dermatosis, parallel course, association of a specific dermatosis with a specific malignancy, statistical significance of the association, and the presence of a genetic basis for the association.¹¹ Several features favored a drug-related cutaneous eruption vs a paraneoplastic phenomenon: (1) the malignancy was identified months before the cutaneous eruptions manifested; (2) the cutaneous lesions appeared once treatment had already been initiated; and (3) the cutaneous lesions persisted long after the malignancy was no longer identifiable on CT. Indeed, eruption of the papules temporally coincided closely with the initiation of BRAF inhibitor therapy, arguing for correlation.

As a suspected BRAF inhibitor–associated cutaneous AE, the eruption of verrucous keratoses in our patient is remarkable for its spontaneous resolution despite ongoing therapy. It is speculated that keratinocytic proliferation while on BRAF inhibitor therapy may be caused by a paradoxical increase in signaling through CRAF, another Raf isoform that plays a role in the induction of terminal differentiation of keratinocytes, with a subsequent increase in MAPK signaling.^12-14 Self-resolution of this cycle despite continuing BRAF inhibitor therapy suggests the possible involvement of balancing and/or alternative mechanistic pathways that may be related to the immune system. Although verrucous keratoses are considered benign proliferations and do not necessarily require any specific treatment or reduction in BRAF inhibitor dosage, they may be treated with cryotherapy, electrocautery, shave removal, or excision,¹⁵ which often is done if the lesions become inflamed and cause pain. Additionally, some patients may feel distress from the appearance of the lesions and desire treatment for this reason. Understanding that verrucous keratoses can be a transient cutaneous AE rather than a persistent one may be useful to clinicians as they manage AEs during BRAF inhibitor therapy.

To the Editor:

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

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

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

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

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

Verrucous keratosis is a known cutaneous AE of BRAF inhibitor treatment with vemurafenib and dabrafenib, with fewer cases attributed to encorafenib.^5,6 Within the oncologic setting, the eruption of verrucous papules as a paraneoplastic phenomenon is heavily debated in the literature and is known as the Leser-Trélat sign. This phenomenon is commonly associated with adenocarcinomas of the gastrointestinal tract, as seen in our patient.¹⁰ Based on Curth’s postulates—the criteria used to evaluate the relationship between an internal malignancy and a cutaneous disorder—this was unlikely in our patient. The criteria, which do not all need to be met to suggest a paraneoplastic phenomenon, include concurrent onset of the malignancy and the dermatosis, parallel course, association of a specific dermatosis with a specific malignancy, statistical significance of the association, and the presence of a genetic basis for the association.¹¹ Several features favored a drug-related cutaneous eruption vs a paraneoplastic phenomenon: (1) the malignancy was identified months before the cutaneous eruptions manifested; (2) the cutaneous lesions appeared once treatment had already been initiated; and (3) the cutaneous lesions persisted long after the malignancy was no longer identifiable on CT. Indeed, eruption of the papules temporally coincided closely with the initiation of BRAF inhibitor therapy, arguing for correlation.

As a suspected BRAF inhibitor–associated cutaneous AE, the eruption of verrucous keratoses in our patient is remarkable for its spontaneous resolution despite ongoing therapy. It is speculated that keratinocytic proliferation while on BRAF inhibitor therapy may be caused by a paradoxical increase in signaling through CRAF, another Raf isoform that plays a role in the induction of terminal differentiation of keratinocytes, with a subsequent increase in MAPK signaling.^12-14 Self-resolution of this cycle despite continuing BRAF inhibitor therapy suggests the possible involvement of balancing and/or alternative mechanistic pathways that may be related to the immune system. Although verrucous keratoses are considered benign proliferations and do not necessarily require any specific treatment or reduction in BRAF inhibitor dosage, they may be treated with cryotherapy, electrocautery, shave removal, or excision,¹⁵ which often is done if the lesions become inflamed and cause pain. Additionally, some patients may feel distress from the appearance of the lesions and desire treatment for this reason. Understanding that verrucous keratoses can be a transient cutaneous AE rather than a persistent one may be useful to clinicians as they manage AEs during BRAF inhibitor therapy.

To the Editor:

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

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

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

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

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

Verrucous keratosis is a known cutaneous AE of BRAF inhibitor treatment with vemurafenib and dabrafenib, with fewer cases attributed to encorafenib.^5,6 Within the oncologic setting, the eruption of verrucous papules as a paraneoplastic phenomenon is heavily debated in the literature and is known as the Leser-Trélat sign. This phenomenon is commonly associated with adenocarcinomas of the gastrointestinal tract, as seen in our patient.¹⁰ Based on Curth’s postulates—the criteria used to evaluate the relationship between an internal malignancy and a cutaneous disorder—this was unlikely in our patient. The criteria, which do not all need to be met to suggest a paraneoplastic phenomenon, include concurrent onset of the malignancy and the dermatosis, parallel course, association of a specific dermatosis with a specific malignancy, statistical significance of the association, and the presence of a genetic basis for the association.¹¹ Several features favored a drug-related cutaneous eruption vs a paraneoplastic phenomenon: (1) the malignancy was identified months before the cutaneous eruptions manifested; (2) the cutaneous lesions appeared once treatment had already been initiated; and (3) the cutaneous lesions persisted long after the malignancy was no longer identifiable on CT. Indeed, eruption of the papules temporally coincided closely with the initiation of BRAF inhibitor therapy, arguing for correlation.

As a suspected BRAF inhibitor–associated cutaneous AE, the eruption of verrucous keratoses in our patient is remarkable for its spontaneous resolution despite ongoing therapy. It is speculated that keratinocytic proliferation while on BRAF inhibitor therapy may be caused by a paradoxical increase in signaling through CRAF, another Raf isoform that plays a role in the induction of terminal differentiation of keratinocytes, with a subsequent increase in MAPK signaling.^12-14 Self-resolution of this cycle despite continuing BRAF inhibitor therapy suggests the possible involvement of balancing and/or alternative mechanistic pathways that may be related to the immune system. Although verrucous keratoses are considered benign proliferations and do not necessarily require any specific treatment or reduction in BRAF inhibitor dosage, they may be treated with cryotherapy, electrocautery, shave removal, or excision,¹⁵ which often is done if the lesions become inflamed and cause pain. Additionally, some patients may feel distress from the appearance of the lesions and desire treatment for this reason. Understanding that verrucous keratoses can be a transient cutaneous AE rather than a persistent one may be useful to clinicians as they manage AEs during BRAF inhibitor therapy.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

When adalimumab was discontinued, the patient sought alternative treatment for the skin symptoms and began self-administering kratom in an attempt to ­alleviate associated physical discomfort. He ingested approximately 3 bottles of liquid kratom per day, with each bottle containing 180 mg of mitragynine and less than 8 mg of 7-hydroxymitragynine. Although not scientifically proven, kratom has been colloquially advertised to improve psoriasis.¹¹ The patient reported no other medication use or allergies.

Shave biopsies of hyperpigmented lesions on the right side of the neck, ear, and forearm were performed. Histopathology revealed a sparse superficial, perivascular, lymphocytic infiltrate accompanied by a prominent number of melanophages in the superficial dermis (Figure 2). Special stains further confirmed that the pigment was melanin; the specimens stained positive with Fontana-Masson stain (Figure 3) and negative with an iron stain (Figure 4).

Adalimumab-induced hyperpigmentation was considered. A prior case of adalimumab-induced hyperpigmentation manifested on the face. Histopathology was consistent with a superficial, perivascular, lymphocytic infiltrate with melanophages in the dermis; however, hyperpigmentation was absent in the periorbital area, and affected areas faded 4 months after discontinuation of adalimumab.¹² Our patient presented with hyperpigmentation 1 year after adalimumab cessation, and the hyperpigmented areas included the periorbital region. Because of the distinct temporal and clinical features, adalimumab-induced hyperpigmentation was eliminated from the differential diagnosis.

Based on the photodistributed pattern of hyperpigmentation, histopathology, and the temporal relationship between hyperpigmentation onset and kratom usage, a diagnosis of kratom-induced photodistributed hyperpigmentation was made. The patient was advised to discontinue kratom use and use sun protection to prevent further photodamage. The patient subsequently was lost to follow-up.

Kratom alkaloids bind all 3 opioid receptors—μOP, δOP, and κOPs—in a G-protein–biased manner with 7-hydroxymitragynine, the most pharmacologically active alkaloid, exhibiting a higher affinity for μ-opioid receptors.^13,14 In human epidermal melanocytes, binding between μ-opioid receptors and β-endorphin, an endogenous opioid, is associated with increased melanin production. This melanogenesis has been linked to hyperpigmentation.¹⁵ Given the similarity between kratom alkaloids and β-endorphin in opioid-receptor binding, it is possible that kratom-induced hyperpigmentation may occur through a similar mechanism involving μ-opioid receptors and melanogenesis in epidermal melanocytes. Moreover, some researchers have theorized that sun exposure may result in free radical formation of certain drugs or their metabolites. These free radicals then can interact with cellular DNA, triggering the release of pigmentary mediators and resulting in hyperpigmentation.¹⁶ This theory may explain the photodistributed pattern of kratom-induced hyperpigmentation. Further studies are needed to understand the mechanism behind this adverse reaction and its implications for patient treatment.

Literature on kratom-induced hyperpigmentation is limited. Powell et al¹⁷ reported a similar case of ­kratom-induced photodistributed hyperpigmentation—a White man had taken kratom to reduce opioid use and subsequently developed hyperpigmented patches on the arms and face. Moreover, anonymous Reddit users have shared anecdotal reports of hyperpigmentation following kratom use.¹⁸

Physicians should be aware of hyperpigmentation as a potential adverse reaction of kratom use as its prevalence increases globally. Further research is warranted to elucidate the mechanism behind this adverse reaction and identify risk factors.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

When adalimumab was discontinued, the patient sought alternative treatment for the skin symptoms and began self-administering kratom in an attempt to ­alleviate associated physical discomfort. He ingested approximately 3 bottles of liquid kratom per day, with each bottle containing 180 mg of mitragynine and less than 8 mg of 7-hydroxymitragynine. Although not scientifically proven, kratom has been colloquially advertised to improve psoriasis.¹¹ The patient reported no other medication use or allergies.

Shave biopsies of hyperpigmented lesions on the right side of the neck, ear, and forearm were performed. Histopathology revealed a sparse superficial, perivascular, lymphocytic infiltrate accompanied by a prominent number of melanophages in the superficial dermis (Figure 2). Special stains further confirmed that the pigment was melanin; the specimens stained positive with Fontana-Masson stain (Figure 3) and negative with an iron stain (Figure 4).

Adalimumab-induced hyperpigmentation was considered. A prior case of adalimumab-induced hyperpigmentation manifested on the face. Histopathology was consistent with a superficial, perivascular, lymphocytic infiltrate with melanophages in the dermis; however, hyperpigmentation was absent in the periorbital area, and affected areas faded 4 months after discontinuation of adalimumab.¹² Our patient presented with hyperpigmentation 1 year after adalimumab cessation, and the hyperpigmented areas included the periorbital region. Because of the distinct temporal and clinical features, adalimumab-induced hyperpigmentation was eliminated from the differential diagnosis.

Based on the photodistributed pattern of hyperpigmentation, histopathology, and the temporal relationship between hyperpigmentation onset and kratom usage, a diagnosis of kratom-induced photodistributed hyperpigmentation was made. The patient was advised to discontinue kratom use and use sun protection to prevent further photodamage. The patient subsequently was lost to follow-up.

Kratom alkaloids bind all 3 opioid receptors—μOP, δOP, and κOPs—in a G-protein–biased manner with 7-hydroxymitragynine, the most pharmacologically active alkaloid, exhibiting a higher affinity for μ-opioid receptors.^13,14 In human epidermal melanocytes, binding between μ-opioid receptors and β-endorphin, an endogenous opioid, is associated with increased melanin production. This melanogenesis has been linked to hyperpigmentation.¹⁵ Given the similarity between kratom alkaloids and β-endorphin in opioid-receptor binding, it is possible that kratom-induced hyperpigmentation may occur through a similar mechanism involving μ-opioid receptors and melanogenesis in epidermal melanocytes. Moreover, some researchers have theorized that sun exposure may result in free radical formation of certain drugs or their metabolites. These free radicals then can interact with cellular DNA, triggering the release of pigmentary mediators and resulting in hyperpigmentation.¹⁶ This theory may explain the photodistributed pattern of kratom-induced hyperpigmentation. Further studies are needed to understand the mechanism behind this adverse reaction and its implications for patient treatment.

Literature on kratom-induced hyperpigmentation is limited. Powell et al¹⁷ reported a similar case of ­kratom-induced photodistributed hyperpigmentation—a White man had taken kratom to reduce opioid use and subsequently developed hyperpigmented patches on the arms and face. Moreover, anonymous Reddit users have shared anecdotal reports of hyperpigmentation following kratom use.¹⁸

Physicians should be aware of hyperpigmentation as a potential adverse reaction of kratom use as its prevalence increases globally. Further research is warranted to elucidate the mechanism behind this adverse reaction and identify risk factors.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

When adalimumab was discontinued, the patient sought alternative treatment for the skin symptoms and began self-administering kratom in an attempt to ­alleviate associated physical discomfort. He ingested approximately 3 bottles of liquid kratom per day, with each bottle containing 180 mg of mitragynine and less than 8 mg of 7-hydroxymitragynine. Although not scientifically proven, kratom has been colloquially advertised to improve psoriasis.¹¹ The patient reported no other medication use or allergies.

Shave biopsies of hyperpigmented lesions on the right side of the neck, ear, and forearm were performed. Histopathology revealed a sparse superficial, perivascular, lymphocytic infiltrate accompanied by a prominent number of melanophages in the superficial dermis (Figure 2). Special stains further confirmed that the pigment was melanin; the specimens stained positive with Fontana-Masson stain (Figure 3) and negative with an iron stain (Figure 4).

Adalimumab-induced hyperpigmentation was considered. A prior case of adalimumab-induced hyperpigmentation manifested on the face. Histopathology was consistent with a superficial, perivascular, lymphocytic infiltrate with melanophages in the dermis; however, hyperpigmentation was absent in the periorbital area, and affected areas faded 4 months after discontinuation of adalimumab.¹² Our patient presented with hyperpigmentation 1 year after adalimumab cessation, and the hyperpigmented areas included the periorbital region. Because of the distinct temporal and clinical features, adalimumab-induced hyperpigmentation was eliminated from the differential diagnosis.

Based on the photodistributed pattern of hyperpigmentation, histopathology, and the temporal relationship between hyperpigmentation onset and kratom usage, a diagnosis of kratom-induced photodistributed hyperpigmentation was made. The patient was advised to discontinue kratom use and use sun protection to prevent further photodamage. The patient subsequently was lost to follow-up.

Kratom alkaloids bind all 3 opioid receptors—μOP, δOP, and κOPs—in a G-protein–biased manner with 7-hydroxymitragynine, the most pharmacologically active alkaloid, exhibiting a higher affinity for μ-opioid receptors.^13,14 In human epidermal melanocytes, binding between μ-opioid receptors and β-endorphin, an endogenous opioid, is associated with increased melanin production. This melanogenesis has been linked to hyperpigmentation.¹⁵ Given the similarity between kratom alkaloids and β-endorphin in opioid-receptor binding, it is possible that kratom-induced hyperpigmentation may occur through a similar mechanism involving μ-opioid receptors and melanogenesis in epidermal melanocytes. Moreover, some researchers have theorized that sun exposure may result in free radical formation of certain drugs or their metabolites. These free radicals then can interact with cellular DNA, triggering the release of pigmentary mediators and resulting in hyperpigmentation.¹⁶ This theory may explain the photodistributed pattern of kratom-induced hyperpigmentation. Further studies are needed to understand the mechanism behind this adverse reaction and its implications for patient treatment.

Literature on kratom-induced hyperpigmentation is limited. Powell et al¹⁷ reported a similar case of ­kratom-induced photodistributed hyperpigmentation—a White man had taken kratom to reduce opioid use and subsequently developed hyperpigmented patches on the arms and face. Moreover, anonymous Reddit users have shared anecdotal reports of hyperpigmentation following kratom use.¹⁸

Physicians should be aware of hyperpigmentation as a potential adverse reaction of kratom use as its prevalence increases globally. Further research is warranted to elucidate the mechanism behind this adverse reaction and identify risk factors.