Brandon L. Adler, MD

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Photoallergic contact dermatitis (PACD), a subtype of allergic contact dermatitis that occurs because of the specific combination of exposure to an exogenous chemical applied topically to the skin and UV radiation, may be more common than was once thought.¹ Although the incidence in the general population is unknown, current research points to approximately 20% to 40% of patients with suspected photosensitivity having a PACD diagnosis.² Recently, the North American Contact Dermatitis Group (NACDG) reported that 21% of 373 patients undergoing photopatch testing (PPT) were diagnosed with PACD²; however, PPT is not routinely performed, which may contribute to underdiagnosis.

Mechanism of Disease

Similar to allergic contact dermatitis, PACD is a delayed type IV hypersensitivity reaction; however, it only occurs when an exogenous chemical is applied topically to the skin with concomitant exposure to UV radiation, usually in the UVA range (315–400 nm).^3,4 When exposed to UV radiation, it is thought that the exogenous chemical combines with a protein in the skin and transforms into a photoantigen. In the sensitization phase, the photoantigen is taken up by antigen-presenting cells in the epidermis and transported to local lymph nodes where antigen-specific T cells are generated.⁵ In the elicitation phase, the inflammatory reaction of PACD occurs upon subsequent exposure to the same chemical plus UV radiation.⁴ Development of PACD does not necessarily depend on the dose of the chemical or the amount of UV radiation.⁶ Why certain individuals may be more susceptible is unknown, though major histocompatibility complex haplotypes could be influential.^7,8

Clinical Manifestations

Photoallergic contact dermatitis primarily presents in sun-exposed areas of the skin (eg, face, neck, V area of the chest, dorsal upper extremities) with sparing of naturally photoprotected sites, such as the upper eyelids and nasolabial and retroauricular folds. Other than its characteristic photodistribution, PACD often is clinically indistinguishable from routine allergic contact dermatitis. It manifests as a pruritic, poorly demarcated, eczematous or sometimes vesiculobullous eruption that develops in a delayed fashion—24 to 72 hours after sun exposure. The dermatitis may extend to other parts of the body either through spread of the chemical agent by the hands or clothing or due to the systemic nature of the immune response. The severity of the presentation can vary depending on multiple factors, such as concentration and absorption of the agent, length of exposure, intensity and duration of UV radiation exposure, and individual susceptibility.⁴ Chronic PACD may become lichenified. Generally, rashes resolve after discontinuation of the causative agent; however, long-term exposure may lead to development of chronic actinic dermatitis, with persistent photodistributed eczema regardless of contact with the initial inciting agent.⁹

Differential Diagnosis

The differential diagnosis for patients presenting with photodistributed dermatitis is broad; therefore, taking a thorough history is important. Considerations include age of onset, timing and persistence of reactions, use of topical and systemic medications (both prescription and over-the-counter [OTC]), personal care products, occupation, and hobbies, as well as a thorough review of systems.

It is important to distinguish PACD from phototoxic contact dermatitis (PTCD)(also known as photoirritant contact dermatitis)(Table). Asking about the onset and timing of the eruption may be critical for distinction, as PTCD can occur within minutes to hours of the first exposure to a chemical and UV radiation, while there is a sensitization delay in PACD.⁶ Phytophotodermatitis is a well-known type of PTCD caused by exposure to furocoumarin-containing plants, most commonly limes.¹⁰ Other causes of PTCD include tar products and certain medications.¹¹ Importantly, PPT to a known phototoxic chemical should never be performed because it will cause a strong reaction in anyone tested, regardless of exposure history.

Diagnosis

Histologically, PACD presents similarly to allergic contact dermatitis with spongiotic dermatitis; therefore, biopsy cannot be relied upon to make the diagnosis.⁶ Photopatch testing is required for definitive diagnosis. It is reasonable to perform PPT in any patient with chronic dermatitis primarily affecting sun-exposed areas without a clear alternative diagnosis.^14,15 Of note, at present there are no North American consensus guidelines for PPT, but typically duplicate sets of photoallergens are applied to both sides of the patient’s back and one side is exposed to UVA radiation. The reactions are compared after 48 to 96 hours.¹⁵ A positive reaction only at the irradiated site is consistent with photoallergy, while a reaction of equal strength at both the irradiated and nonirradiated sites indicates regular contact allergy. The case of a reaction occurring at both sites with a stronger response at the irradiated site is known as photoaggravated contact allergy, which can be thought of as allergic contact dermatitis that worsens but does not solely occur with exposure to sunlight.

Although PPT is necessary for the accurate diagnosis of PACD, it is infrequently used. Two surveys of 112 and 117 American Contact Dermatitis Society members, respectively, have revealed that only around half performed PPT, most of them testing fewer than 20 times per year.^16,17 Additionally, there was variability in the test methodology and allergens employed. Nevertheless, most respondents tested sunscreens, nonsteroidal anti-inflammatory drugs (NSAIDs), fragrances, and their patients’ own products.^16,17 The most common reasons for not performing PPT were lack of equipment, insufficient skills, rare clinical suspicion, and cost. Dermatologists at academic centers performed more PPT than those in other practice settings, including multispecialty group practices and private offices.¹⁶ These findings highlight multiple factors that may contribute to reduced patient access to PPT and thus potential underdiagnosis of PACD.

Common Photoallergens

The most common photoallergens change over time in response to market trends; for example, fragrance was once a top photoallergen in the United States in the 1970s and 1980s but declined in prominence after musk ambrette—the primary allergen associated with PACD at the time—was removed as an ingredient in fragrances.¹⁸

In the largest and most recent PPT series from North America (1999-2009),² sunscreens comprised 7 of the top 10 most common photoallergens, which is consistent with other studies showing sunscreens to be the most common North American photoallergens.^19-22 The frequency of PACD due to sunscreens likely relates to their increasing use worldwide as awareness of photocarcinogenesis and photoaging grows, as well as the common use of UV filters in nonsunscreen personal care products, ranging from lip balms to perfumes and bodywashes. Chemical (organic) UV filters—in particular oxybenzone (benzophenone-3) and avobenzone (butyl methoxydibenzoylmethane)—are the most common sunscreen photoallergens.^2,23 Para-aminobenzoic acid was once a common photoallergen, but it is no longer used in US sunscreens due to safety concerns.^19,20 The physical (inorganic) UV filters zinc oxide and titanium dioxide are not known photosensitizers.

Methylisothiazolinone (MI) is a highly allergenic preservative commonly used in a wide array of personal care products, including sunscreens.²⁴ In the most recent NACDG patch test data, MI was the second most common contact allergen.²⁵ Allergic contact dermatitis caused by MI in sunscreen can mimic PACD.²⁶ In addition, MI can cause photoaggravated contact dermatitis, with some affected patients experiencing ongoing photosensitivity even after avoiding this allergen.^26-30 The European Union and Canada have introduced restrictions on the use of MI in personal care products, but no such regulatory measures have been taken in the United States to date.^25,31,32

After sunscreens, another common cause of PACD are topical NSAIDs, which are frequently used for musculoskeletal pain relief. These are of particular concern in Europe, where a variety of formulations are widely available OTC.³³ Ketoprofen and etofenamate are responsible for the largest number of PACD reactions in Europe.^2,34,35 Meanwhile, the only OTC topical NSAID available in the United States is diclofenac gel, which was approved in 2020. Cases of PACD due to use of diclofenac gel have been reported in the literature, but testing in larger populations is needed.^36-39

Notably, ketoprofen may co- or cross-react with certain UV filters—oxybenzone and octocrylene—and the lipid-lowering agent fenofibrate due to chemical similarities.^40-43 Despite the relatively high number of photoallergic reactions to ketoprofen in the NACDG photopatch series, only 25% (5/20) were considered clinically relevant (ie, the allergen could not be verified as present in the known skin contactants of the patient, and the patient was not exposed to circumstances in which contact with materials known to contain the allergen would likely occur), which suggests that they likely represented cross-reactions in patients sensitized to sunscreens.²

Other agents that may cause PACD include antimicrobials, plants and plant derivatives, and pesticides.^2,4,18 The antimicrobial fentichlor is a common cause of positive PPT reactions, but it rarely is clinically relevant.⁴⁴

Treatment

The primary management of PACD centers on identification of the causative photoallergen to avoid future exposure. Patients should be educated on the various names by which the causative allergen can be identified on product labels and should be given a list of safe products that are free from relevant allergens and cross-reacting chemicals.⁴⁵ Additionally, sun protection education should be provided. Exposure to UVA radiation can occur through windows, making the use of broad-spectrum sunscreens and protective clothing crucial. In cases of sunscreen-induced PACD, the responsible chemical UV filter(s) should be avoided, or alternatively, patients may use physical sunscreens containing only zinc oxide and/or titanium dioxide as active ingredients, as these are not known to cause PACD.⁴

When avoidance alone is insufficient, topical corticosteroids are the usual first-line treatment for localized PACD. When steroid-sparing treatments are preferred, topical calcineurin inhibitors such as tacrolimus and pimecrolimus may be used. If PACD is more widespread and severe, systemic therapy using steroids or steroid-sparing agents may be necessary to provide symptomatic relief.⁴

Final Interpretation

Photoallergic contact dermatitis is not uncommon, particularly among photosensitive patients. Most cases are due to sunscreens or topical NSAIDs. Consideration of PPT should be given in any patient with a chronic photodistributed dermatitis to evaluate for the possibility of PACD.

Photoallergic contact dermatitis (PACD), a subtype of allergic contact dermatitis that occurs because of the specific combination of exposure to an exogenous chemical applied topically to the skin and UV radiation, may be more common than was once thought.¹ Although the incidence in the general population is unknown, current research points to approximately 20% to 40% of patients with suspected photosensitivity having a PACD diagnosis.² Recently, the North American Contact Dermatitis Group (NACDG) reported that 21% of 373 patients undergoing photopatch testing (PPT) were diagnosed with PACD²; however, PPT is not routinely performed, which may contribute to underdiagnosis.

Mechanism of Disease

Similar to allergic contact dermatitis, PACD is a delayed type IV hypersensitivity reaction; however, it only occurs when an exogenous chemical is applied topically to the skin with concomitant exposure to UV radiation, usually in the UVA range (315–400 nm).^3,4 When exposed to UV radiation, it is thought that the exogenous chemical combines with a protein in the skin and transforms into a photoantigen. In the sensitization phase, the photoantigen is taken up by antigen-presenting cells in the epidermis and transported to local lymph nodes where antigen-specific T cells are generated.⁵ In the elicitation phase, the inflammatory reaction of PACD occurs upon subsequent exposure to the same chemical plus UV radiation.⁴ Development of PACD does not necessarily depend on the dose of the chemical or the amount of UV radiation.⁶ Why certain individuals may be more susceptible is unknown, though major histocompatibility complex haplotypes could be influential.^7,8

Clinical Manifestations

Photoallergic contact dermatitis primarily presents in sun-exposed areas of the skin (eg, face, neck, V area of the chest, dorsal upper extremities) with sparing of naturally photoprotected sites, such as the upper eyelids and nasolabial and retroauricular folds. Other than its characteristic photodistribution, PACD often is clinically indistinguishable from routine allergic contact dermatitis. It manifests as a pruritic, poorly demarcated, eczematous or sometimes vesiculobullous eruption that develops in a delayed fashion—24 to 72 hours after sun exposure. The dermatitis may extend to other parts of the body either through spread of the chemical agent by the hands or clothing or due to the systemic nature of the immune response. The severity of the presentation can vary depending on multiple factors, such as concentration and absorption of the agent, length of exposure, intensity and duration of UV radiation exposure, and individual susceptibility.⁴ Chronic PACD may become lichenified. Generally, rashes resolve after discontinuation of the causative agent; however, long-term exposure may lead to development of chronic actinic dermatitis, with persistent photodistributed eczema regardless of contact with the initial inciting agent.⁹

Differential Diagnosis

The differential diagnosis for patients presenting with photodistributed dermatitis is broad; therefore, taking a thorough history is important. Considerations include age of onset, timing and persistence of reactions, use of topical and systemic medications (both prescription and over-the-counter [OTC]), personal care products, occupation, and hobbies, as well as a thorough review of systems.

It is important to distinguish PACD from phototoxic contact dermatitis (PTCD)(also known as photoirritant contact dermatitis)(Table). Asking about the onset and timing of the eruption may be critical for distinction, as PTCD can occur within minutes to hours of the first exposure to a chemical and UV radiation, while there is a sensitization delay in PACD.⁶ Phytophotodermatitis is a well-known type of PTCD caused by exposure to furocoumarin-containing plants, most commonly limes.¹⁰ Other causes of PTCD include tar products and certain medications.¹¹ Importantly, PPT to a known phototoxic chemical should never be performed because it will cause a strong reaction in anyone tested, regardless of exposure history.

Diagnosis

Histologically, PACD presents similarly to allergic contact dermatitis with spongiotic dermatitis; therefore, biopsy cannot be relied upon to make the diagnosis.⁶ Photopatch testing is required for definitive diagnosis. It is reasonable to perform PPT in any patient with chronic dermatitis primarily affecting sun-exposed areas without a clear alternative diagnosis.^14,15 Of note, at present there are no North American consensus guidelines for PPT, but typically duplicate sets of photoallergens are applied to both sides of the patient’s back and one side is exposed to UVA radiation. The reactions are compared after 48 to 96 hours.¹⁵ A positive reaction only at the irradiated site is consistent with photoallergy, while a reaction of equal strength at both the irradiated and nonirradiated sites indicates regular contact allergy. The case of a reaction occurring at both sites with a stronger response at the irradiated site is known as photoaggravated contact allergy, which can be thought of as allergic contact dermatitis that worsens but does not solely occur with exposure to sunlight.

Although PPT is necessary for the accurate diagnosis of PACD, it is infrequently used. Two surveys of 112 and 117 American Contact Dermatitis Society members, respectively, have revealed that only around half performed PPT, most of them testing fewer than 20 times per year.^16,17 Additionally, there was variability in the test methodology and allergens employed. Nevertheless, most respondents tested sunscreens, nonsteroidal anti-inflammatory drugs (NSAIDs), fragrances, and their patients’ own products.^16,17 The most common reasons for not performing PPT were lack of equipment, insufficient skills, rare clinical suspicion, and cost. Dermatologists at academic centers performed more PPT than those in other practice settings, including multispecialty group practices and private offices.¹⁶ These findings highlight multiple factors that may contribute to reduced patient access to PPT and thus potential underdiagnosis of PACD.

Common Photoallergens

The most common photoallergens change over time in response to market trends; for example, fragrance was once a top photoallergen in the United States in the 1970s and 1980s but declined in prominence after musk ambrette—the primary allergen associated with PACD at the time—was removed as an ingredient in fragrances.¹⁸

In the largest and most recent PPT series from North America (1999-2009),² sunscreens comprised 7 of the top 10 most common photoallergens, which is consistent with other studies showing sunscreens to be the most common North American photoallergens.^19-22 The frequency of PACD due to sunscreens likely relates to their increasing use worldwide as awareness of photocarcinogenesis and photoaging grows, as well as the common use of UV filters in nonsunscreen personal care products, ranging from lip balms to perfumes and bodywashes. Chemical (organic) UV filters—in particular oxybenzone (benzophenone-3) and avobenzone (butyl methoxydibenzoylmethane)—are the most common sunscreen photoallergens.^2,23 Para-aminobenzoic acid was once a common photoallergen, but it is no longer used in US sunscreens due to safety concerns.^19,20 The physical (inorganic) UV filters zinc oxide and titanium dioxide are not known photosensitizers.

Methylisothiazolinone (MI) is a highly allergenic preservative commonly used in a wide array of personal care products, including sunscreens.²⁴ In the most recent NACDG patch test data, MI was the second most common contact allergen.²⁵ Allergic contact dermatitis caused by MI in sunscreen can mimic PACD.²⁶ In addition, MI can cause photoaggravated contact dermatitis, with some affected patients experiencing ongoing photosensitivity even after avoiding this allergen.^26-30 The European Union and Canada have introduced restrictions on the use of MI in personal care products, but no such regulatory measures have been taken in the United States to date.^25,31,32

After sunscreens, another common cause of PACD are topical NSAIDs, which are frequently used for musculoskeletal pain relief. These are of particular concern in Europe, where a variety of formulations are widely available OTC.³³ Ketoprofen and etofenamate are responsible for the largest number of PACD reactions in Europe.^2,34,35 Meanwhile, the only OTC topical NSAID available in the United States is diclofenac gel, which was approved in 2020. Cases of PACD due to use of diclofenac gel have been reported in the literature, but testing in larger populations is needed.^36-39

Notably, ketoprofen may co- or cross-react with certain UV filters—oxybenzone and octocrylene—and the lipid-lowering agent fenofibrate due to chemical similarities.^40-43 Despite the relatively high number of photoallergic reactions to ketoprofen in the NACDG photopatch series, only 25% (5/20) were considered clinically relevant (ie, the allergen could not be verified as present in the known skin contactants of the patient, and the patient was not exposed to circumstances in which contact with materials known to contain the allergen would likely occur), which suggests that they likely represented cross-reactions in patients sensitized to sunscreens.²

Other agents that may cause PACD include antimicrobials, plants and plant derivatives, and pesticides.^2,4,18 The antimicrobial fentichlor is a common cause of positive PPT reactions, but it rarely is clinically relevant.⁴⁴

Treatment

The primary management of PACD centers on identification of the causative photoallergen to avoid future exposure. Patients should be educated on the various names by which the causative allergen can be identified on product labels and should be given a list of safe products that are free from relevant allergens and cross-reacting chemicals.⁴⁵ Additionally, sun protection education should be provided. Exposure to UVA radiation can occur through windows, making the use of broad-spectrum sunscreens and protective clothing crucial. In cases of sunscreen-induced PACD, the responsible chemical UV filter(s) should be avoided, or alternatively, patients may use physical sunscreens containing only zinc oxide and/or titanium dioxide as active ingredients, as these are not known to cause PACD.⁴

When avoidance alone is insufficient, topical corticosteroids are the usual first-line treatment for localized PACD. When steroid-sparing treatments are preferred, topical calcineurin inhibitors such as tacrolimus and pimecrolimus may be used. If PACD is more widespread and severe, systemic therapy using steroids or steroid-sparing agents may be necessary to provide symptomatic relief.⁴

Final Interpretation

Photoallergic contact dermatitis is not uncommon, particularly among photosensitive patients. Most cases are due to sunscreens or topical NSAIDs. Consideration of PPT should be given in any patient with a chronic photodistributed dermatitis to evaluate for the possibility of PACD.

Photoallergic contact dermatitis (PACD), a subtype of allergic contact dermatitis that occurs because of the specific combination of exposure to an exogenous chemical applied topically to the skin and UV radiation, may be more common than was once thought.¹ Although the incidence in the general population is unknown, current research points to approximately 20% to 40% of patients with suspected photosensitivity having a PACD diagnosis.² Recently, the North American Contact Dermatitis Group (NACDG) reported that 21% of 373 patients undergoing photopatch testing (PPT) were diagnosed with PACD²; however, PPT is not routinely performed, which may contribute to underdiagnosis.

Mechanism of Disease

Similar to allergic contact dermatitis, PACD is a delayed type IV hypersensitivity reaction; however, it only occurs when an exogenous chemical is applied topically to the skin with concomitant exposure to UV radiation, usually in the UVA range (315–400 nm).^3,4 When exposed to UV radiation, it is thought that the exogenous chemical combines with a protein in the skin and transforms into a photoantigen. In the sensitization phase, the photoantigen is taken up by antigen-presenting cells in the epidermis and transported to local lymph nodes where antigen-specific T cells are generated.⁵ In the elicitation phase, the inflammatory reaction of PACD occurs upon subsequent exposure to the same chemical plus UV radiation.⁴ Development of PACD does not necessarily depend on the dose of the chemical or the amount of UV radiation.⁶ Why certain individuals may be more susceptible is unknown, though major histocompatibility complex haplotypes could be influential.^7,8

Clinical Manifestations

Photoallergic contact dermatitis primarily presents in sun-exposed areas of the skin (eg, face, neck, V area of the chest, dorsal upper extremities) with sparing of naturally photoprotected sites, such as the upper eyelids and nasolabial and retroauricular folds. Other than its characteristic photodistribution, PACD often is clinically indistinguishable from routine allergic contact dermatitis. It manifests as a pruritic, poorly demarcated, eczematous or sometimes vesiculobullous eruption that develops in a delayed fashion—24 to 72 hours after sun exposure. The dermatitis may extend to other parts of the body either through spread of the chemical agent by the hands or clothing or due to the systemic nature of the immune response. The severity of the presentation can vary depending on multiple factors, such as concentration and absorption of the agent, length of exposure, intensity and duration of UV radiation exposure, and individual susceptibility.⁴ Chronic PACD may become lichenified. Generally, rashes resolve after discontinuation of the causative agent; however, long-term exposure may lead to development of chronic actinic dermatitis, with persistent photodistributed eczema regardless of contact with the initial inciting agent.⁹

Differential Diagnosis

The differential diagnosis for patients presenting with photodistributed dermatitis is broad; therefore, taking a thorough history is important. Considerations include age of onset, timing and persistence of reactions, use of topical and systemic medications (both prescription and over-the-counter [OTC]), personal care products, occupation, and hobbies, as well as a thorough review of systems.

It is important to distinguish PACD from phototoxic contact dermatitis (PTCD)(also known as photoirritant contact dermatitis)(Table). Asking about the onset and timing of the eruption may be critical for distinction, as PTCD can occur within minutes to hours of the first exposure to a chemical and UV radiation, while there is a sensitization delay in PACD.⁶ Phytophotodermatitis is a well-known type of PTCD caused by exposure to furocoumarin-containing plants, most commonly limes.¹⁰ Other causes of PTCD include tar products and certain medications.¹¹ Importantly, PPT to a known phototoxic chemical should never be performed because it will cause a strong reaction in anyone tested, regardless of exposure history.

Diagnosis

Histologically, PACD presents similarly to allergic contact dermatitis with spongiotic dermatitis; therefore, biopsy cannot be relied upon to make the diagnosis.⁶ Photopatch testing is required for definitive diagnosis. It is reasonable to perform PPT in any patient with chronic dermatitis primarily affecting sun-exposed areas without a clear alternative diagnosis.^14,15 Of note, at present there are no North American consensus guidelines for PPT, but typically duplicate sets of photoallergens are applied to both sides of the patient’s back and one side is exposed to UVA radiation. The reactions are compared after 48 to 96 hours.¹⁵ A positive reaction only at the irradiated site is consistent with photoallergy, while a reaction of equal strength at both the irradiated and nonirradiated sites indicates regular contact allergy. The case of a reaction occurring at both sites with a stronger response at the irradiated site is known as photoaggravated contact allergy, which can be thought of as allergic contact dermatitis that worsens but does not solely occur with exposure to sunlight.

Although PPT is necessary for the accurate diagnosis of PACD, it is infrequently used. Two surveys of 112 and 117 American Contact Dermatitis Society members, respectively, have revealed that only around half performed PPT, most of them testing fewer than 20 times per year.^16,17 Additionally, there was variability in the test methodology and allergens employed. Nevertheless, most respondents tested sunscreens, nonsteroidal anti-inflammatory drugs (NSAIDs), fragrances, and their patients’ own products.^16,17 The most common reasons for not performing PPT were lack of equipment, insufficient skills, rare clinical suspicion, and cost. Dermatologists at academic centers performed more PPT than those in other practice settings, including multispecialty group practices and private offices.¹⁶ These findings highlight multiple factors that may contribute to reduced patient access to PPT and thus potential underdiagnosis of PACD.

Common Photoallergens

The most common photoallergens change over time in response to market trends; for example, fragrance was once a top photoallergen in the United States in the 1970s and 1980s but declined in prominence after musk ambrette—the primary allergen associated with PACD at the time—was removed as an ingredient in fragrances.¹⁸

In the largest and most recent PPT series from North America (1999-2009),² sunscreens comprised 7 of the top 10 most common photoallergens, which is consistent with other studies showing sunscreens to be the most common North American photoallergens.^19-22 The frequency of PACD due to sunscreens likely relates to their increasing use worldwide as awareness of photocarcinogenesis and photoaging grows, as well as the common use of UV filters in nonsunscreen personal care products, ranging from lip balms to perfumes and bodywashes. Chemical (organic) UV filters—in particular oxybenzone (benzophenone-3) and avobenzone (butyl methoxydibenzoylmethane)—are the most common sunscreen photoallergens.^2,23 Para-aminobenzoic acid was once a common photoallergen, but it is no longer used in US sunscreens due to safety concerns.^19,20 The physical (inorganic) UV filters zinc oxide and titanium dioxide are not known photosensitizers.

Methylisothiazolinone (MI) is a highly allergenic preservative commonly used in a wide array of personal care products, including sunscreens.²⁴ In the most recent NACDG patch test data, MI was the second most common contact allergen.²⁵ Allergic contact dermatitis caused by MI in sunscreen can mimic PACD.²⁶ In addition, MI can cause photoaggravated contact dermatitis, with some affected patients experiencing ongoing photosensitivity even after avoiding this allergen.^26-30 The European Union and Canada have introduced restrictions on the use of MI in personal care products, but no such regulatory measures have been taken in the United States to date.^25,31,32

After sunscreens, another common cause of PACD are topical NSAIDs, which are frequently used for musculoskeletal pain relief. These are of particular concern in Europe, where a variety of formulations are widely available OTC.³³ Ketoprofen and etofenamate are responsible for the largest number of PACD reactions in Europe.^2,34,35 Meanwhile, the only OTC topical NSAID available in the United States is diclofenac gel, which was approved in 2020. Cases of PACD due to use of diclofenac gel have been reported in the literature, but testing in larger populations is needed.^36-39

Notably, ketoprofen may co- or cross-react with certain UV filters—oxybenzone and octocrylene—and the lipid-lowering agent fenofibrate due to chemical similarities.^40-43 Despite the relatively high number of photoallergic reactions to ketoprofen in the NACDG photopatch series, only 25% (5/20) were considered clinically relevant (ie, the allergen could not be verified as present in the known skin contactants of the patient, and the patient was not exposed to circumstances in which contact with materials known to contain the allergen would likely occur), which suggests that they likely represented cross-reactions in patients sensitized to sunscreens.²

Other agents that may cause PACD include antimicrobials, plants and plant derivatives, and pesticides.^2,4,18 The antimicrobial fentichlor is a common cause of positive PPT reactions, but it rarely is clinically relevant.⁴⁴

Treatment

The primary management of PACD centers on identification of the causative photoallergen to avoid future exposure. Patients should be educated on the various names by which the causative allergen can be identified on product labels and should be given a list of safe products that are free from relevant allergens and cross-reacting chemicals.⁴⁵ Additionally, sun protection education should be provided. Exposure to UVA radiation can occur through windows, making the use of broad-spectrum sunscreens and protective clothing crucial. In cases of sunscreen-induced PACD, the responsible chemical UV filter(s) should be avoided, or alternatively, patients may use physical sunscreens containing only zinc oxide and/or titanium dioxide as active ingredients, as these are not known to cause PACD.⁴

When avoidance alone is insufficient, topical corticosteroids are the usual first-line treatment for localized PACD. When steroid-sparing treatments are preferred, topical calcineurin inhibitors such as tacrolimus and pimecrolimus may be used. If PACD is more widespread and severe, systemic therapy using steroids or steroid-sparing agents may be necessary to provide symptomatic relief.⁴

Final Interpretation

Photoallergic contact dermatitis is not uncommon, particularly among photosensitive patients. Most cases are due to sunscreens or topical NSAIDs. Consideration of PPT should be given in any patient with a chronic photodistributed dermatitis to evaluate for the possibility of PACD.

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are 2 common inflammatory skin conditions that may have similar clinical presentations. Historically, it was thought that these conditions could not be diagnosed simultaneously due to their differing immune mechanisms; however, this belief has been challenged by recent evidence suggesting a more nuanced relationship between the 2 disease processes. In this review, we examine the complex interplay between AD and ACD and explain how shifts in conventional understanding of the 2 conditions shaped our evolving recognition of their ability to coexist.

Epidemiology of AD and ACD

Atopic dermatitis is the most common inflammatory skin disease in children and adolescents, with an estimated prevalence reaching 21%.¹ In 60% of cases, onset of AD will occur within the first year of life, and 90% of cases begin within the first 5 years.² Resolution may occur by adulthood; however, AD may continue to impact up to 8% to 9% of adults, with an increased prevalence in those older than 75 years.¹ This may represent an underestimation of the burden of adult AD; one systematic review of 17 studies found that the pooled proportion of adult-onset AD was greater than 25%.³

In contrast, ACD previously was assumed to be a disease that more commonly impacted adults and only rarely children, primarily due to an early misconception that children were not frequently exposed to contact allergens and their immune systems were too immature to react to them even if exposed.^4,5 However, it is now known that children do have risk factors for development of ACD, including a thinner stratum corneum and potentially a more absorbent skin surface.⁴ In addition, a 2022 study by the North American Contact Dermatitis Group (NACDG) found similar rates of ACD in children (n=1871) and adults (n=41,699) referred for patch testing (55.2% and 57.3%, respectively) as well as similar rates of having at least 1 relevant positive patch test (49.2% and 52.2%).⁶

In opposition to traditional beliefs, these findings highlight that AD and ACD can occur across age groups.

Immune Mechanism

The pathogenesis of AD represents a multifactorial process involving the immune system, cutaneous flora, genetic predisposition, and surrounding environment. Immunologically, acute AD is driven by a predominantly T_H2 helper T-cell response with high levels of IL-4, IL-5, and IL-13⁷; T_H22, T_H17, and T_H1 also have been implicated.⁸ Notably, T_H17 is found in high levels during the acute eczema phase, while T_H1 and T_H22are associated with the chronic phase.⁷

The pathophysiology of ACD is not completely understood. The classic paradigm involves 2 phases: sensitization and elicitation. Sensitization involves antigen-presenting cells that take up allergens absorbed by the skin to present them in regional lymph nodes where antigen-specific T lymphocytes are generated. Elicitation occurs upon re-exposure to the allergen, at which time the primed T lymphocytes are recruited to the skin, causing inflammation.⁹ Allergic contact dermatitis initially was thought to be driven by T_H1 cytokines and IL-17 but now is understood to be more complex.¹⁰ Studies have revealed immune polarization of contact allergens, demonstrating that nickel primarily induces a T_H1/T_H17 response, whereas fragrance and rubber accelerators skew to T_H2; T_H9 and T_H22 also may be involved depending on the causative allergen.^11,12

Of note, the immunologic differences between AD and ACD led early investigators to believe that patients with AD were relatively protected from ACD.¹³ However, as previously described, there are several overlapping cytokines between AD and ACD. Furthermore, research has revealed that risk of contact sensitization might be increased in the chronic eczema phase due to the shared T_H1 pathway.¹⁴ Barrier-disrupted skin (such as that in AD) also may increase the cytokine response and the density of antigen-presenting cells, leading to a proallergic state.¹⁵ This suggests that the immunologic pathways of AD and ACD are more intertwined than was previously understood.

Underlying Risk Factors

Skin barrier dysfunction is a key step in the pathogenesis of AD. Patients with AD commonly have loss-of-function mutations in the filaggrin gene, a protein that is key to the function of the stratum corneum. Loss of this protein may not only impact the immune response as previously noted but also may lead to increased transepidermal water loss and bacterial colonization.¹⁶ Interestingly, a 2014 review examined how this mutation could lead to an increased risk of sensitization to bivalent metal ions via an impaired chelating ability of the skin.¹⁷ Furthermore, a 2016 study conducted in Dutch construction workers revealed an increased risk for contact dermatitis (irritant and allergic) for those with a loss-of-function filaggrin mutation.¹⁸

Importantly, this same mutation may explain why patients with AD tend to have increased skin colonization by Staphylococcus aureus. The abundance of S aureus and the relative decrease in the diversity of other microorganisms on the skin may be associated with increased AD severity.¹⁹ Likewise, S aureus may play a role in the pathogenesis of ACD via production of its exotoxin directed at the T-cell receptor V beta 17 region. In particular, this receptor has been associated with nickel sensitization.¹⁷

Another risk factor to consider is increased exposure to contact sensitizers when treating AD. For instance, management often includes use of over-the-counter emollients, natural or botanical remedies with purported benefits for AD, cleansers, and detergents. However, these products can contain some of the most prevalent contact allergens seen in those with AD, including methyl-isothiazolinone, formaldehyde releasers, and fragrance.²⁰ Topical corticosteroids also are frequently used, and ACD to steroid molecules can occur, particularly to tixocortol-21-pivalate (a marker for class A corticosteroids) and budesonide (a marker for class B corticosteroids).²¹ Other allergens (eg, benzyl alcohol, propylene glycol) also may be found as inactive ingredients of topical corticosteroids.²² These exposures may place AD patients at risk for ACD.

The Coexistence of AD and ACD

Given the overlapping epidemiology, immunology, and potentially increased risk for the development of ACD in patients with AD, it would be reasonable to assume that the 2 diagnoses could coexist; however, is there clinical data to support this idea? Based on recent database reviews, the answer appears to be yes.^20,23-26 An analysis from the Pediatric Contact Dermatitis Registry revealed that 30% of 1142 pediatric patch test cases analyzed were diagnosed as AD and ACD simultaneously.²⁴ The NACDG found similar results in its 2021 review, as 29.5% of children (n=1648) and 20.7% of adults (n=36,834) had a concurrent diagnosis of AD and ACD.²⁰ Notably, older results from these databases also demonstrated an association between the 2 conditions.^23,25,26

It remains unclear whether the prevalence of ACD is higher in those with or without AD. A comprehensive systematic review conducted in 2017 examined this topic through analysis of 74 studies. The results demonstrated a similar prevalence of contact sensitization in individuals with and without AD.²⁷ Another systematic review of 31 studies conducted in 2017 found a higher prevalence for ACD in children without AD; however, the authors noted that the included studies were too variable (eg, size, design, allergens tested) to draw definitive conclusions.²⁸

Even though there is no clear overall increased risk for ACD in patients with AD, research has suggested that certain allergens may be more prevalent in the setting of AD. An NACDG study found that adults with AD had increased odds of reacting to 10 of the top 25 NACDG screening allergens compared to those without AD.²⁰ Other studies have found that AD patients may be more likely to become sensitized to certain allergens, such as fragrance and lanolin.¹⁴

Considerations for Management

Diagnosis of ACD in patients with AD can be challenging because these conditions may present similarly with chronic, pruritic, inflammatory patches and plaques. Chronic ACD may be misdiagnosed as AD if patch testing is not performed.²⁹ Given the prevalence of ACD in the setting of AD, there should be a low threshold to pursue patch testing, especially when dermatitis is recalcitrant to standard therapies or presents in an atypical distribution (ie, perioral, predominantly head/neck, hand and foot, isolated eyelid involvement, buttocks).^4,30 Various allergen series are available for patch testing adults and children including the NACDG Standard Series, American Contact Dermatitis Society Core Allergen Series, or the Pediatric Baseline Series.^31-33

If potentially relevant allergens are uncovered by patch testing, patients should be counseled on avoidance strategies. However, allergen avoidance may not always lead to complete symptom resolution, especially if AD is present concomitantly with ACD. Therefore, use of topical or systemic therapies still may be required. Topical corticosteroids can be used when dermatitis is acute and localized. Systemic corticosteroids are utilized for both diagnoses when cases are more severe or extensive, but their adverse-effect profile limits long-term use. Other systemic treatments, including conventional agents (ie, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil), biologics, and small molecule inhibitors also may be considered for severe cases.^34,35 Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for use in moderate to severe AD in patients 6 months and older. Recent evidence has suggested that dupilumab also may be an effective off-label treatment choice for ACD when allergen avoidance alone is insufficient.³⁶ Studies have been conducted on secukinumab, a monoclonal antibody against IL-17; however, it has not been shown to be effective in either AD or ACD.^37,38 This indicates that targeted biologics may not always be successful in treating these diagnoses, likely due to their complex immune pathways. Finally, there is an emerging role for JAK inhibitors. Three are approved for AD: topical ruxolitinib, oral abrocitinib, and oral upadacitinib.³⁹ Further investigation is needed to determine the efficacy of JAK inhibitors in ACD.

Final Interpretation

Evolving evidence shows that AD and ACD can occur at the same time despite the historical perspective that their immune pathways were too polarized for this to happen. Atopic dermatitis may be an important risk factor for subsequent development of ACD. Management should include a low threshold to perform patch testing, while pharmacotherapies utilized in the treatment of both conditions should be considered.

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are 2 common inflammatory skin conditions that may have similar clinical presentations. Historically, it was thought that these conditions could not be diagnosed simultaneously due to their differing immune mechanisms; however, this belief has been challenged by recent evidence suggesting a more nuanced relationship between the 2 disease processes. In this review, we examine the complex interplay between AD and ACD and explain how shifts in conventional understanding of the 2 conditions shaped our evolving recognition of their ability to coexist.

Epidemiology of AD and ACD

Atopic dermatitis is the most common inflammatory skin disease in children and adolescents, with an estimated prevalence reaching 21%.¹ In 60% of cases, onset of AD will occur within the first year of life, and 90% of cases begin within the first 5 years.² Resolution may occur by adulthood; however, AD may continue to impact up to 8% to 9% of adults, with an increased prevalence in those older than 75 years.¹ This may represent an underestimation of the burden of adult AD; one systematic review of 17 studies found that the pooled proportion of adult-onset AD was greater than 25%.³

In contrast, ACD previously was assumed to be a disease that more commonly impacted adults and only rarely children, primarily due to an early misconception that children were not frequently exposed to contact allergens and their immune systems were too immature to react to them even if exposed.^4,5 However, it is now known that children do have risk factors for development of ACD, including a thinner stratum corneum and potentially a more absorbent skin surface.⁴ In addition, a 2022 study by the North American Contact Dermatitis Group (NACDG) found similar rates of ACD in children (n=1871) and adults (n=41,699) referred for patch testing (55.2% and 57.3%, respectively) as well as similar rates of having at least 1 relevant positive patch test (49.2% and 52.2%).⁶

In opposition to traditional beliefs, these findings highlight that AD and ACD can occur across age groups.

Immune Mechanism

The pathogenesis of AD represents a multifactorial process involving the immune system, cutaneous flora, genetic predisposition, and surrounding environment. Immunologically, acute AD is driven by a predominantly T_H2 helper T-cell response with high levels of IL-4, IL-5, and IL-13⁷; T_H22, T_H17, and T_H1 also have been implicated.⁸ Notably, T_H17 is found in high levels during the acute eczema phase, while T_H1 and T_H22are associated with the chronic phase.⁷

The pathophysiology of ACD is not completely understood. The classic paradigm involves 2 phases: sensitization and elicitation. Sensitization involves antigen-presenting cells that take up allergens absorbed by the skin to present them in regional lymph nodes where antigen-specific T lymphocytes are generated. Elicitation occurs upon re-exposure to the allergen, at which time the primed T lymphocytes are recruited to the skin, causing inflammation.⁹ Allergic contact dermatitis initially was thought to be driven by T_H1 cytokines and IL-17 but now is understood to be more complex.¹⁰ Studies have revealed immune polarization of contact allergens, demonstrating that nickel primarily induces a T_H1/T_H17 response, whereas fragrance and rubber accelerators skew to T_H2; T_H9 and T_H22 also may be involved depending on the causative allergen.^11,12

Of note, the immunologic differences between AD and ACD led early investigators to believe that patients with AD were relatively protected from ACD.¹³ However, as previously described, there are several overlapping cytokines between AD and ACD. Furthermore, research has revealed that risk of contact sensitization might be increased in the chronic eczema phase due to the shared T_H1 pathway.¹⁴ Barrier-disrupted skin (such as that in AD) also may increase the cytokine response and the density of antigen-presenting cells, leading to a proallergic state.¹⁵ This suggests that the immunologic pathways of AD and ACD are more intertwined than was previously understood.

Underlying Risk Factors

Skin barrier dysfunction is a key step in the pathogenesis of AD. Patients with AD commonly have loss-of-function mutations in the filaggrin gene, a protein that is key to the function of the stratum corneum. Loss of this protein may not only impact the immune response as previously noted but also may lead to increased transepidermal water loss and bacterial colonization.¹⁶ Interestingly, a 2014 review examined how this mutation could lead to an increased risk of sensitization to bivalent metal ions via an impaired chelating ability of the skin.¹⁷ Furthermore, a 2016 study conducted in Dutch construction workers revealed an increased risk for contact dermatitis (irritant and allergic) for those with a loss-of-function filaggrin mutation.¹⁸

Importantly, this same mutation may explain why patients with AD tend to have increased skin colonization by Staphylococcus aureus. The abundance of S aureus and the relative decrease in the diversity of other microorganisms on the skin may be associated with increased AD severity.¹⁹ Likewise, S aureus may play a role in the pathogenesis of ACD via production of its exotoxin directed at the T-cell receptor V beta 17 region. In particular, this receptor has been associated with nickel sensitization.¹⁷

Another risk factor to consider is increased exposure to contact sensitizers when treating AD. For instance, management often includes use of over-the-counter emollients, natural or botanical remedies with purported benefits for AD, cleansers, and detergents. However, these products can contain some of the most prevalent contact allergens seen in those with AD, including methyl-isothiazolinone, formaldehyde releasers, and fragrance.²⁰ Topical corticosteroids also are frequently used, and ACD to steroid molecules can occur, particularly to tixocortol-21-pivalate (a marker for class A corticosteroids) and budesonide (a marker for class B corticosteroids).²¹ Other allergens (eg, benzyl alcohol, propylene glycol) also may be found as inactive ingredients of topical corticosteroids.²² These exposures may place AD patients at risk for ACD.

The Coexistence of AD and ACD

Given the overlapping epidemiology, immunology, and potentially increased risk for the development of ACD in patients with AD, it would be reasonable to assume that the 2 diagnoses could coexist; however, is there clinical data to support this idea? Based on recent database reviews, the answer appears to be yes.^20,23-26 An analysis from the Pediatric Contact Dermatitis Registry revealed that 30% of 1142 pediatric patch test cases analyzed were diagnosed as AD and ACD simultaneously.²⁴ The NACDG found similar results in its 2021 review, as 29.5% of children (n=1648) and 20.7% of adults (n=36,834) had a concurrent diagnosis of AD and ACD.²⁰ Notably, older results from these databases also demonstrated an association between the 2 conditions.^23,25,26

It remains unclear whether the prevalence of ACD is higher in those with or without AD. A comprehensive systematic review conducted in 2017 examined this topic through analysis of 74 studies. The results demonstrated a similar prevalence of contact sensitization in individuals with and without AD.²⁷ Another systematic review of 31 studies conducted in 2017 found a higher prevalence for ACD in children without AD; however, the authors noted that the included studies were too variable (eg, size, design, allergens tested) to draw definitive conclusions.²⁸

Even though there is no clear overall increased risk for ACD in patients with AD, research has suggested that certain allergens may be more prevalent in the setting of AD. An NACDG study found that adults with AD had increased odds of reacting to 10 of the top 25 NACDG screening allergens compared to those without AD.²⁰ Other studies have found that AD patients may be more likely to become sensitized to certain allergens, such as fragrance and lanolin.¹⁴

Considerations for Management

Diagnosis of ACD in patients with AD can be challenging because these conditions may present similarly with chronic, pruritic, inflammatory patches and plaques. Chronic ACD may be misdiagnosed as AD if patch testing is not performed.²⁹ Given the prevalence of ACD in the setting of AD, there should be a low threshold to pursue patch testing, especially when dermatitis is recalcitrant to standard therapies or presents in an atypical distribution (ie, perioral, predominantly head/neck, hand and foot, isolated eyelid involvement, buttocks).^4,30 Various allergen series are available for patch testing adults and children including the NACDG Standard Series, American Contact Dermatitis Society Core Allergen Series, or the Pediatric Baseline Series.^31-33

If potentially relevant allergens are uncovered by patch testing, patients should be counseled on avoidance strategies. However, allergen avoidance may not always lead to complete symptom resolution, especially if AD is present concomitantly with ACD. Therefore, use of topical or systemic therapies still may be required. Topical corticosteroids can be used when dermatitis is acute and localized. Systemic corticosteroids are utilized for both diagnoses when cases are more severe or extensive, but their adverse-effect profile limits long-term use. Other systemic treatments, including conventional agents (ie, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil), biologics, and small molecule inhibitors also may be considered for severe cases.^34,35 Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for use in moderate to severe AD in patients 6 months and older. Recent evidence has suggested that dupilumab also may be an effective off-label treatment choice for ACD when allergen avoidance alone is insufficient.³⁶ Studies have been conducted on secukinumab, a monoclonal antibody against IL-17; however, it has not been shown to be effective in either AD or ACD.^37,38 This indicates that targeted biologics may not always be successful in treating these diagnoses, likely due to their complex immune pathways. Finally, there is an emerging role for JAK inhibitors. Three are approved for AD: topical ruxolitinib, oral abrocitinib, and oral upadacitinib.³⁹ Further investigation is needed to determine the efficacy of JAK inhibitors in ACD.

Final Interpretation

Evolving evidence shows that AD and ACD can occur at the same time despite the historical perspective that their immune pathways were too polarized for this to happen. Atopic dermatitis may be an important risk factor for subsequent development of ACD. Management should include a low threshold to perform patch testing, while pharmacotherapies utilized in the treatment of both conditions should be considered.

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are 2 common inflammatory skin conditions that may have similar clinical presentations. Historically, it was thought that these conditions could not be diagnosed simultaneously due to their differing immune mechanisms; however, this belief has been challenged by recent evidence suggesting a more nuanced relationship between the 2 disease processes. In this review, we examine the complex interplay between AD and ACD and explain how shifts in conventional understanding of the 2 conditions shaped our evolving recognition of their ability to coexist.

Epidemiology of AD and ACD

Atopic dermatitis is the most common inflammatory skin disease in children and adolescents, with an estimated prevalence reaching 21%.¹ In 60% of cases, onset of AD will occur within the first year of life, and 90% of cases begin within the first 5 years.² Resolution may occur by adulthood; however, AD may continue to impact up to 8% to 9% of adults, with an increased prevalence in those older than 75 years.¹ This may represent an underestimation of the burden of adult AD; one systematic review of 17 studies found that the pooled proportion of adult-onset AD was greater than 25%.³

In contrast, ACD previously was assumed to be a disease that more commonly impacted adults and only rarely children, primarily due to an early misconception that children were not frequently exposed to contact allergens and their immune systems were too immature to react to them even if exposed.^4,5 However, it is now known that children do have risk factors for development of ACD, including a thinner stratum corneum and potentially a more absorbent skin surface.⁴ In addition, a 2022 study by the North American Contact Dermatitis Group (NACDG) found similar rates of ACD in children (n=1871) and adults (n=41,699) referred for patch testing (55.2% and 57.3%, respectively) as well as similar rates of having at least 1 relevant positive patch test (49.2% and 52.2%).⁶

In opposition to traditional beliefs, these findings highlight that AD and ACD can occur across age groups.

Immune Mechanism

The pathogenesis of AD represents a multifactorial process involving the immune system, cutaneous flora, genetic predisposition, and surrounding environment. Immunologically, acute AD is driven by a predominantly T_H2 helper T-cell response with high levels of IL-4, IL-5, and IL-13⁷; T_H22, T_H17, and T_H1 also have been implicated.⁸ Notably, T_H17 is found in high levels during the acute eczema phase, while T_H1 and T_H22are associated with the chronic phase.⁷

The pathophysiology of ACD is not completely understood. The classic paradigm involves 2 phases: sensitization and elicitation. Sensitization involves antigen-presenting cells that take up allergens absorbed by the skin to present them in regional lymph nodes where antigen-specific T lymphocytes are generated. Elicitation occurs upon re-exposure to the allergen, at which time the primed T lymphocytes are recruited to the skin, causing inflammation.⁹ Allergic contact dermatitis initially was thought to be driven by T_H1 cytokines and IL-17 but now is understood to be more complex.¹⁰ Studies have revealed immune polarization of contact allergens, demonstrating that nickel primarily induces a T_H1/T_H17 response, whereas fragrance and rubber accelerators skew to T_H2; T_H9 and T_H22 also may be involved depending on the causative allergen.^11,12

Of note, the immunologic differences between AD and ACD led early investigators to believe that patients with AD were relatively protected from ACD.¹³ However, as previously described, there are several overlapping cytokines between AD and ACD. Furthermore, research has revealed that risk of contact sensitization might be increased in the chronic eczema phase due to the shared T_H1 pathway.¹⁴ Barrier-disrupted skin (such as that in AD) also may increase the cytokine response and the density of antigen-presenting cells, leading to a proallergic state.¹⁵ This suggests that the immunologic pathways of AD and ACD are more intertwined than was previously understood.

Underlying Risk Factors

Skin barrier dysfunction is a key step in the pathogenesis of AD. Patients with AD commonly have loss-of-function mutations in the filaggrin gene, a protein that is key to the function of the stratum corneum. Loss of this protein may not only impact the immune response as previously noted but also may lead to increased transepidermal water loss and bacterial colonization.¹⁶ Interestingly, a 2014 review examined how this mutation could lead to an increased risk of sensitization to bivalent metal ions via an impaired chelating ability of the skin.¹⁷ Furthermore, a 2016 study conducted in Dutch construction workers revealed an increased risk for contact dermatitis (irritant and allergic) for those with a loss-of-function filaggrin mutation.¹⁸

Importantly, this same mutation may explain why patients with AD tend to have increased skin colonization by Staphylococcus aureus. The abundance of S aureus and the relative decrease in the diversity of other microorganisms on the skin may be associated with increased AD severity.¹⁹ Likewise, S aureus may play a role in the pathogenesis of ACD via production of its exotoxin directed at the T-cell receptor V beta 17 region. In particular, this receptor has been associated with nickel sensitization.¹⁷

Another risk factor to consider is increased exposure to contact sensitizers when treating AD. For instance, management often includes use of over-the-counter emollients, natural or botanical remedies with purported benefits for AD, cleansers, and detergents. However, these products can contain some of the most prevalent contact allergens seen in those with AD, including methyl-isothiazolinone, formaldehyde releasers, and fragrance.²⁰ Topical corticosteroids also are frequently used, and ACD to steroid molecules can occur, particularly to tixocortol-21-pivalate (a marker for class A corticosteroids) and budesonide (a marker for class B corticosteroids).²¹ Other allergens (eg, benzyl alcohol, propylene glycol) also may be found as inactive ingredients of topical corticosteroids.²² These exposures may place AD patients at risk for ACD.

The Coexistence of AD and ACD

Given the overlapping epidemiology, immunology, and potentially increased risk for the development of ACD in patients with AD, it would be reasonable to assume that the 2 diagnoses could coexist; however, is there clinical data to support this idea? Based on recent database reviews, the answer appears to be yes.^20,23-26 An analysis from the Pediatric Contact Dermatitis Registry revealed that 30% of 1142 pediatric patch test cases analyzed were diagnosed as AD and ACD simultaneously.²⁴ The NACDG found similar results in its 2021 review, as 29.5% of children (n=1648) and 20.7% of adults (n=36,834) had a concurrent diagnosis of AD and ACD.²⁰ Notably, older results from these databases also demonstrated an association between the 2 conditions.^23,25,26

It remains unclear whether the prevalence of ACD is higher in those with or without AD. A comprehensive systematic review conducted in 2017 examined this topic through analysis of 74 studies. The results demonstrated a similar prevalence of contact sensitization in individuals with and without AD.²⁷ Another systematic review of 31 studies conducted in 2017 found a higher prevalence for ACD in children without AD; however, the authors noted that the included studies were too variable (eg, size, design, allergens tested) to draw definitive conclusions.²⁸

Even though there is no clear overall increased risk for ACD in patients with AD, research has suggested that certain allergens may be more prevalent in the setting of AD. An NACDG study found that adults with AD had increased odds of reacting to 10 of the top 25 NACDG screening allergens compared to those without AD.²⁰ Other studies have found that AD patients may be more likely to become sensitized to certain allergens, such as fragrance and lanolin.¹⁴

Considerations for Management

Diagnosis of ACD in patients with AD can be challenging because these conditions may present similarly with chronic, pruritic, inflammatory patches and plaques. Chronic ACD may be misdiagnosed as AD if patch testing is not performed.²⁹ Given the prevalence of ACD in the setting of AD, there should be a low threshold to pursue patch testing, especially when dermatitis is recalcitrant to standard therapies or presents in an atypical distribution (ie, perioral, predominantly head/neck, hand and foot, isolated eyelid involvement, buttocks).^4,30 Various allergen series are available for patch testing adults and children including the NACDG Standard Series, American Contact Dermatitis Society Core Allergen Series, or the Pediatric Baseline Series.^31-33

If potentially relevant allergens are uncovered by patch testing, patients should be counseled on avoidance strategies. However, allergen avoidance may not always lead to complete symptom resolution, especially if AD is present concomitantly with ACD. Therefore, use of topical or systemic therapies still may be required. Topical corticosteroids can be used when dermatitis is acute and localized. Systemic corticosteroids are utilized for both diagnoses when cases are more severe or extensive, but their adverse-effect profile limits long-term use. Other systemic treatments, including conventional agents (ie, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil), biologics, and small molecule inhibitors also may be considered for severe cases.^34,35 Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for use in moderate to severe AD in patients 6 months and older. Recent evidence has suggested that dupilumab also may be an effective off-label treatment choice for ACD when allergen avoidance alone is insufficient.³⁶ Studies have been conducted on secukinumab, a monoclonal antibody against IL-17; however, it has not been shown to be effective in either AD or ACD.^37,38 This indicates that targeted biologics may not always be successful in treating these diagnoses, likely due to their complex immune pathways. Finally, there is an emerging role for JAK inhibitors. Three are approved for AD: topical ruxolitinib, oral abrocitinib, and oral upadacitinib.³⁹ Further investigation is needed to determine the efficacy of JAK inhibitors in ACD.

Final Interpretation

Evolving evidence shows that AD and ACD can occur at the same time despite the historical perspective that their immune pathways were too polarized for this to happen. Atopic dermatitis may be an important risk factor for subsequent development of ACD. Management should include a low threshold to perform patch testing, while pharmacotherapies utilized in the treatment of both conditions should be considered.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

Dupilumab is a humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis. Through inhibition of the IL-4R α subunit, it prevents activation of the IL-4/IL-13 signaling cascade. This dampens the T _H 2 inflammatory response, thereby improving the symptoms associated with atopic dermatitis. ^1,2 Recent literature suggests that dupilumab may be useful in the treatment of other chronic dermatologic conditions, including allergic contact dermatitis (ACD) refractory to allergen avoidance and other treatments. Herein, we provide an overview of ACD, the role that dupilumab may play in its management, and its impact on patch testing results.

Pathogenesis of ACD

Allergic contact dermatitis is a cell-mediated type IV hypersensitivity reaction that develops through 2 distinct stages. In the sensitization phase, an allergen penetrates the skin and subsequently is engulfed by a cutaneous antigen-presenting cell. The allergen is then combined with a peptide to form a complex that is presented to naïve T lymphocytes in regional lymph nodes. The result is clonal expansion of a T-cell population that recognizes the allergen. In the elicitation phase, repeat exposure to the allergen leads to the recruitment of primed T cells to the skin, followed by cytokine release, inflammation, and resultant dermatitis.³

Historically, ACD was thought to be primarily driven by the T_H1 inflammatory response; however, it is now known that T_H2, T_H9, T_H17, and T_H22 also may play a role in its pathogenesis.^4,5 Another key finding is that the immune response in ACD appears to be at least partially allergen specific. Molecular profiling has revealed that nickel primarily induces a T_H1/T_H17 response, while allergens such as fragrance and rubber primarily induce a T_H2 response.⁴

Management of ACD

Allergen avoidance is the mainstay of ACD treatment; however, in some patients, this approach does not always improve symptoms. In addition, eliminating the source of the allergen may not be possible in those with certain occupational, environmental, or medical exposures.

There are no FDA-approved treatments for ACD. When allergen avoidance alone is insufficient, first-line pharmacologic therapy typically includes topical or oral corticosteroids, the choice of which depends on the extent and severity of the dermatitis; however, a steroid-sparing agent often is preferred to avoid the unfavorable effects of long-term steroid use. Other systemic treatments for ACD include methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.⁶ These agents are used for severe ACD and typically are chosen as a last resort due to their immunosuppressive activity.

Phototherapy is another option, often as an adjunct to other therapies. Narrowband UVB and psoralen plus UVA have both been used. Psoralen plus UVA tends to have more side effects; therefore, narrowband UVB often is preferred.^7,8

Use of Dupilumab in ACD

Biologics are unique, as they can target a single step in the immune response to improve a wide variety of symptoms. Research investigating their role as a treatment modality for ACD is still evolving alongside our increasing knowledge of its pathophysiology.⁹ Of note, studies examining the anti–IL-17 biologic secukinumab revealed it to be ineffective against ACD,^10,11 which suggests that targeting specific immune components may not always result in improvement of ACD symptoms, likely because its pathophysiology involves several pathways.

There have been multiple reports demonstrating the effectiveness of dupilumab in the treatment of ACD (eTable).^12-20 The findings from these studies show that dupilumab can improve recalcitrant dermatitis caused by a broad range of contact allergens, including nickel. This highlights its ability to improve ACD caused by allergens with a T_H1 bias, despite its primarily T_H2-dampening effects. Notably, several studies have reported successful use of dupilumab for systemic ACD.^12,18 In addition, dupilumab may be able to improve symptoms of ACD in as little as 1 to 4 weeks. Unlike some systemic therapies for ACD, dupilumab also benefits from its lack of notable immunosuppressive effects.⁹ A phase 4 clinical trial at Brigham and Women’s Hospital (Boston, Massachusetts) is recruiting participants, with a primary goal of investigating dupilumab’s impact on ACD in patients who have not improved despite allergen avoidance (ClinicalTrials.gov identifier NCT03935971).

There are a few potential disadvantages to dupilumab. Because it is not yet FDA approved for the treatment of ACD, insurance companies may deny coverage, making it likely to be unaffordable for most patients. Furthermore, the side-effect profile has not been fully characterized. In addition to ocular adverse effects, a growing number of studies have reported face and neck erythema after starting dupilumab. Although the cause is unclear, one theory is that the inhibition of IL-4/IL-13 leads to T_H1/T_H17 polarization, thereby worsening ACD caused by allergens that activate a T_H1-predominant response.²¹ Finally, not all cases of ACD respond to dupilumab.²²

Patch Testing While on Dupilumab

Diagnosing ACD is a challenging process. An accurate history and physical examination are critical, and patch testing remains the gold standard when it comes to identifying the source of the contact allergen(s).

There is ongoing debate among contact dermatitis experts regarding the diagnostic accuracy of patch testing for those on immunomodulators or immunosuppressants, as these medications can dampen positive results and increase the risk for false-negative readings.²³ Consequently, some have questioned whether patch testing on dupilumab is accurate or feasible.²⁴ Contact dermatitis experts have examined patch testing results before and after initiation of dupilumab to further investigate. Puza and Atwater²⁵ established that patients are able to mount a positive patch test reaction while on dupilumab. Moreover, a retrospective review by Raffi et al²⁶ found that out of 125 before therapy/on therapy patch test pairs, only 13 were lost after administration of dupilumab. Although this would suggest that dupilumab has little impact on patch testing, Jo et al²⁷ found in a systematic review that patch test reactions may remain positive, change to negative, or become newly positive after dupilumab initiation.

This inconsistency in results may relate to the allergen-specific pathogenesis of ACD—one allergen may have a different response to the mechanism of dupilumab than another.^28,29 More recently, de Wijs et al³⁰ reported a series of 20 patients in whom more than two-thirds of prior positive patch test reactions were lost after retesting on dupilumab; there were no clear trends according to the immune polarity of the allergens. This finding suggests that patient-specific factors also should be considered, as this too could have an impact on the reliability of patch test findings after starting dupilumab.²⁹

Final Interpretation

Given its overall excellent safety profile, dupilumab may be a feasible off-label option for patients with ACD that does not respond to allergen avoidance or for those who experience adverse effects from traditional therapies; however, it remains difficult to obtain through insurance because it is not yet FDA approved for ACD. Likewise, its impact on the accuracy of patch testing is not yet well defined. Further investigations are needed to elucidate the pathophysiology of ACD and to guide further use of dupilumab in its treatment.

Dupilumab is a humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis. Through inhibition of the IL-4R α subunit, it prevents activation of the IL-4/IL-13 signaling cascade. This dampens the T _H 2 inflammatory response, thereby improving the symptoms associated with atopic dermatitis. ^1,2 Recent literature suggests that dupilumab may be useful in the treatment of other chronic dermatologic conditions, including allergic contact dermatitis (ACD) refractory to allergen avoidance and other treatments. Herein, we provide an overview of ACD, the role that dupilumab may play in its management, and its impact on patch testing results.

Pathogenesis of ACD

Allergic contact dermatitis is a cell-mediated type IV hypersensitivity reaction that develops through 2 distinct stages. In the sensitization phase, an allergen penetrates the skin and subsequently is engulfed by a cutaneous antigen-presenting cell. The allergen is then combined with a peptide to form a complex that is presented to naïve T lymphocytes in regional lymph nodes. The result is clonal expansion of a T-cell population that recognizes the allergen. In the elicitation phase, repeat exposure to the allergen leads to the recruitment of primed T cells to the skin, followed by cytokine release, inflammation, and resultant dermatitis.³

Historically, ACD was thought to be primarily driven by the T_H1 inflammatory response; however, it is now known that T_H2, T_H9, T_H17, and T_H22 also may play a role in its pathogenesis.^4,5 Another key finding is that the immune response in ACD appears to be at least partially allergen specific. Molecular profiling has revealed that nickel primarily induces a T_H1/T_H17 response, while allergens such as fragrance and rubber primarily induce a T_H2 response.⁴

Management of ACD

Allergen avoidance is the mainstay of ACD treatment; however, in some patients, this approach does not always improve symptoms. In addition, eliminating the source of the allergen may not be possible in those with certain occupational, environmental, or medical exposures.

There are no FDA-approved treatments for ACD. When allergen avoidance alone is insufficient, first-line pharmacologic therapy typically includes topical or oral corticosteroids, the choice of which depends on the extent and severity of the dermatitis; however, a steroid-sparing agent often is preferred to avoid the unfavorable effects of long-term steroid use. Other systemic treatments for ACD include methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.⁶ These agents are used for severe ACD and typically are chosen as a last resort due to their immunosuppressive activity.

Phototherapy is another option, often as an adjunct to other therapies. Narrowband UVB and psoralen plus UVA have both been used. Psoralen plus UVA tends to have more side effects; therefore, narrowband UVB often is preferred.^7,8

Use of Dupilumab in ACD

Biologics are unique, as they can target a single step in the immune response to improve a wide variety of symptoms. Research investigating their role as a treatment modality for ACD is still evolving alongside our increasing knowledge of its pathophysiology.⁹ Of note, studies examining the anti–IL-17 biologic secukinumab revealed it to be ineffective against ACD,^10,11 which suggests that targeting specific immune components may not always result in improvement of ACD symptoms, likely because its pathophysiology involves several pathways.

There have been multiple reports demonstrating the effectiveness of dupilumab in the treatment of ACD (eTable).^12-20 The findings from these studies show that dupilumab can improve recalcitrant dermatitis caused by a broad range of contact allergens, including nickel. This highlights its ability to improve ACD caused by allergens with a T_H1 bias, despite its primarily T_H2-dampening effects. Notably, several studies have reported successful use of dupilumab for systemic ACD.^12,18 In addition, dupilumab may be able to improve symptoms of ACD in as little as 1 to 4 weeks. Unlike some systemic therapies for ACD, dupilumab also benefits from its lack of notable immunosuppressive effects.⁹ A phase 4 clinical trial at Brigham and Women’s Hospital (Boston, Massachusetts) is recruiting participants, with a primary goal of investigating dupilumab’s impact on ACD in patients who have not improved despite allergen avoidance (ClinicalTrials.gov identifier NCT03935971).

There are a few potential disadvantages to dupilumab. Because it is not yet FDA approved for the treatment of ACD, insurance companies may deny coverage, making it likely to be unaffordable for most patients. Furthermore, the side-effect profile has not been fully characterized. In addition to ocular adverse effects, a growing number of studies have reported face and neck erythema after starting dupilumab. Although the cause is unclear, one theory is that the inhibition of IL-4/IL-13 leads to T_H1/T_H17 polarization, thereby worsening ACD caused by allergens that activate a T_H1-predominant response.²¹ Finally, not all cases of ACD respond to dupilumab.²²

Patch Testing While on Dupilumab

Diagnosing ACD is a challenging process. An accurate history and physical examination are critical, and patch testing remains the gold standard when it comes to identifying the source of the contact allergen(s).

There is ongoing debate among contact dermatitis experts regarding the diagnostic accuracy of patch testing for those on immunomodulators or immunosuppressants, as these medications can dampen positive results and increase the risk for false-negative readings.²³ Consequently, some have questioned whether patch testing on dupilumab is accurate or feasible.²⁴ Contact dermatitis experts have examined patch testing results before and after initiation of dupilumab to further investigate. Puza and Atwater²⁵ established that patients are able to mount a positive patch test reaction while on dupilumab. Moreover, a retrospective review by Raffi et al²⁶ found that out of 125 before therapy/on therapy patch test pairs, only 13 were lost after administration of dupilumab. Although this would suggest that dupilumab has little impact on patch testing, Jo et al²⁷ found in a systematic review that patch test reactions may remain positive, change to negative, or become newly positive after dupilumab initiation.

This inconsistency in results may relate to the allergen-specific pathogenesis of ACD—one allergen may have a different response to the mechanism of dupilumab than another.^28,29 More recently, de Wijs et al³⁰ reported a series of 20 patients in whom more than two-thirds of prior positive patch test reactions were lost after retesting on dupilumab; there were no clear trends according to the immune polarity of the allergens. This finding suggests that patient-specific factors also should be considered, as this too could have an impact on the reliability of patch test findings after starting dupilumab.²⁹

Final Interpretation

Given its overall excellent safety profile, dupilumab may be a feasible off-label option for patients with ACD that does not respond to allergen avoidance or for those who experience adverse effects from traditional therapies; however, it remains difficult to obtain through insurance because it is not yet FDA approved for ACD. Likewise, its impact on the accuracy of patch testing is not yet well defined. Further investigations are needed to elucidate the pathophysiology of ACD and to guide further use of dupilumab in its treatment.

Dupilumab is a humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis. Through inhibition of the IL-4R α subunit, it prevents activation of the IL-4/IL-13 signaling cascade. This dampens the T _H 2 inflammatory response, thereby improving the symptoms associated with atopic dermatitis. ^1,2 Recent literature suggests that dupilumab may be useful in the treatment of other chronic dermatologic conditions, including allergic contact dermatitis (ACD) refractory to allergen avoidance and other treatments. Herein, we provide an overview of ACD, the role that dupilumab may play in its management, and its impact on patch testing results.

Pathogenesis of ACD

Allergic contact dermatitis is a cell-mediated type IV hypersensitivity reaction that develops through 2 distinct stages. In the sensitization phase, an allergen penetrates the skin and subsequently is engulfed by a cutaneous antigen-presenting cell. The allergen is then combined with a peptide to form a complex that is presented to naïve T lymphocytes in regional lymph nodes. The result is clonal expansion of a T-cell population that recognizes the allergen. In the elicitation phase, repeat exposure to the allergen leads to the recruitment of primed T cells to the skin, followed by cytokine release, inflammation, and resultant dermatitis.³

Historically, ACD was thought to be primarily driven by the T_H1 inflammatory response; however, it is now known that T_H2, T_H9, T_H17, and T_H22 also may play a role in its pathogenesis.^4,5 Another key finding is that the immune response in ACD appears to be at least partially allergen specific. Molecular profiling has revealed that nickel primarily induces a T_H1/T_H17 response, while allergens such as fragrance and rubber primarily induce a T_H2 response.⁴

Management of ACD

Allergen avoidance is the mainstay of ACD treatment; however, in some patients, this approach does not always improve symptoms. In addition, eliminating the source of the allergen may not be possible in those with certain occupational, environmental, or medical exposures.

There are no FDA-approved treatments for ACD. When allergen avoidance alone is insufficient, first-line pharmacologic therapy typically includes topical or oral corticosteroids, the choice of which depends on the extent and severity of the dermatitis; however, a steroid-sparing agent often is preferred to avoid the unfavorable effects of long-term steroid use. Other systemic treatments for ACD include methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.⁶ These agents are used for severe ACD and typically are chosen as a last resort due to their immunosuppressive activity.

Phototherapy is another option, often as an adjunct to other therapies. Narrowband UVB and psoralen plus UVA have both been used. Psoralen plus UVA tends to have more side effects; therefore, narrowband UVB often is preferred.^7,8

Use of Dupilumab in ACD

Biologics are unique, as they can target a single step in the immune response to improve a wide variety of symptoms. Research investigating their role as a treatment modality for ACD is still evolving alongside our increasing knowledge of its pathophysiology.⁹ Of note, studies examining the anti–IL-17 biologic secukinumab revealed it to be ineffective against ACD,^10,11 which suggests that targeting specific immune components may not always result in improvement of ACD symptoms, likely because its pathophysiology involves several pathways.

There have been multiple reports demonstrating the effectiveness of dupilumab in the treatment of ACD (eTable).^12-20 The findings from these studies show that dupilumab can improve recalcitrant dermatitis caused by a broad range of contact allergens, including nickel. This highlights its ability to improve ACD caused by allergens with a T_H1 bias, despite its primarily T_H2-dampening effects. Notably, several studies have reported successful use of dupilumab for systemic ACD.^12,18 In addition, dupilumab may be able to improve symptoms of ACD in as little as 1 to 4 weeks. Unlike some systemic therapies for ACD, dupilumab also benefits from its lack of notable immunosuppressive effects.⁹ A phase 4 clinical trial at Brigham and Women’s Hospital (Boston, Massachusetts) is recruiting participants, with a primary goal of investigating dupilumab’s impact on ACD in patients who have not improved despite allergen avoidance (ClinicalTrials.gov identifier NCT03935971).

There are a few potential disadvantages to dupilumab. Because it is not yet FDA approved for the treatment of ACD, insurance companies may deny coverage, making it likely to be unaffordable for most patients. Furthermore, the side-effect profile has not been fully characterized. In addition to ocular adverse effects, a growing number of studies have reported face and neck erythema after starting dupilumab. Although the cause is unclear, one theory is that the inhibition of IL-4/IL-13 leads to T_H1/T_H17 polarization, thereby worsening ACD caused by allergens that activate a T_H1-predominant response.²¹ Finally, not all cases of ACD respond to dupilumab.²²

Patch Testing While on Dupilumab

Diagnosing ACD is a challenging process. An accurate history and physical examination are critical, and patch testing remains the gold standard when it comes to identifying the source of the contact allergen(s).

There is ongoing debate among contact dermatitis experts regarding the diagnostic accuracy of patch testing for those on immunomodulators or immunosuppressants, as these medications can dampen positive results and increase the risk for false-negative readings.²³ Consequently, some have questioned whether patch testing on dupilumab is accurate or feasible.²⁴ Contact dermatitis experts have examined patch testing results before and after initiation of dupilumab to further investigate. Puza and Atwater²⁵ established that patients are able to mount a positive patch test reaction while on dupilumab. Moreover, a retrospective review by Raffi et al²⁶ found that out of 125 before therapy/on therapy patch test pairs, only 13 were lost after administration of dupilumab. Although this would suggest that dupilumab has little impact on patch testing, Jo et al²⁷ found in a systematic review that patch test reactions may remain positive, change to negative, or become newly positive after dupilumab initiation.

This inconsistency in results may relate to the allergen-specific pathogenesis of ACD—one allergen may have a different response to the mechanism of dupilumab than another.^28,29 More recently, de Wijs et al³⁰ reported a series of 20 patients in whom more than two-thirds of prior positive patch test reactions were lost after retesting on dupilumab; there were no clear trends according to the immune polarity of the allergens. This finding suggests that patient-specific factors also should be considered, as this too could have an impact on the reliability of patch test findings after starting dupilumab.²⁹

Final Interpretation

Given its overall excellent safety profile, dupilumab may be a feasible off-label option for patients with ACD that does not respond to allergen avoidance or for those who experience adverse effects from traditional therapies; however, it remains difficult to obtain through insurance because it is not yet FDA approved for ACD. Likewise, its impact on the accuracy of patch testing is not yet well defined. Further investigations are needed to elucidate the pathophysiology of ACD and to guide further use of dupilumab in its treatment.

To the Editor:

A 71-year-old Hispanic man with a history of vitiligo presented with an acute-onset blistering rash on the face, arms, and hands. Physical examination demonstrated photodistributed erythematous plaques with overlying vesicles and erosions with hemorrhagic crust on the face, neck, dorsal aspects of the hands, and wrists (Figure). Further history revealed that the patient applied a new cream that was recommended to treat vitiligo the night before the rash onset; he obtained the cream from a Central American market without a prescription. He had gone running in the park without any form of sun protection and then developed the rash within several hours. He denied taking any other medications or supplements. The involvement of sun-protected areas (ie, upper eyelids, nasolabial folds, submental area) was explained when the patient further elaborated that he had performed supine exercises during his outdoor recreation. He brought his new cream into the clinic, which was found to contain prescription-strength methoxsalen (8-methoxypsoralen), confirming the diagnosis of acute phototoxic contact dermatitis. The acute reaction had subsided, and the patient already had discontinued the causative agent. He was counseled on further avoidance of the cream and sun-protective measures.

The photosensitizing properties of certain compounds have been harnessed for therapeutic purposes. For example, psoralen plus UVA therapy has been used for psoriasis and vitiligo and photodynamic therapy for actinic keratoses and superficial nonmelanoma skin cancers.¹ However, these agents can induce severe phototoxicity if UV light exposure is not carefully monitored, as seen in our patient. This case is a classic example of phototoxic contact dermatitis and highlights the importance of obtaining a detailed patient history to allow for proper diagnosis and identification of the causative agent. Importantly, because prescription-strength topical medications are readily available over-the-counter, particularly in stores specializing in international goods, patients should be questioned about the use of all topical and systemic medications, both prescription and nonprescription.²

To the Editor:

A 71-year-old Hispanic man with a history of vitiligo presented with an acute-onset blistering rash on the face, arms, and hands. Physical examination demonstrated photodistributed erythematous plaques with overlying vesicles and erosions with hemorrhagic crust on the face, neck, dorsal aspects of the hands, and wrists (Figure). Further history revealed that the patient applied a new cream that was recommended to treat vitiligo the night before the rash onset; he obtained the cream from a Central American market without a prescription. He had gone running in the park without any form of sun protection and then developed the rash within several hours. He denied taking any other medications or supplements. The involvement of sun-protected areas (ie, upper eyelids, nasolabial folds, submental area) was explained when the patient further elaborated that he had performed supine exercises during his outdoor recreation. He brought his new cream into the clinic, which was found to contain prescription-strength methoxsalen (8-methoxypsoralen), confirming the diagnosis of acute phototoxic contact dermatitis. The acute reaction had subsided, and the patient already had discontinued the causative agent. He was counseled on further avoidance of the cream and sun-protective measures.

The photosensitizing properties of certain compounds have been harnessed for therapeutic purposes. For example, psoralen plus UVA therapy has been used for psoriasis and vitiligo and photodynamic therapy for actinic keratoses and superficial nonmelanoma skin cancers.¹ However, these agents can induce severe phototoxicity if UV light exposure is not carefully monitored, as seen in our patient. This case is a classic example of phototoxic contact dermatitis and highlights the importance of obtaining a detailed patient history to allow for proper diagnosis and identification of the causative agent. Importantly, because prescription-strength topical medications are readily available over-the-counter, particularly in stores specializing in international goods, patients should be questioned about the use of all topical and systemic medications, both prescription and nonprescription.²

To the Editor:

A 71-year-old Hispanic man with a history of vitiligo presented with an acute-onset blistering rash on the face, arms, and hands. Physical examination demonstrated photodistributed erythematous plaques with overlying vesicles and erosions with hemorrhagic crust on the face, neck, dorsal aspects of the hands, and wrists (Figure). Further history revealed that the patient applied a new cream that was recommended to treat vitiligo the night before the rash onset; he obtained the cream from a Central American market without a prescription. He had gone running in the park without any form of sun protection and then developed the rash within several hours. He denied taking any other medications or supplements. The involvement of sun-protected areas (ie, upper eyelids, nasolabial folds, submental area) was explained when the patient further elaborated that he had performed supine exercises during his outdoor recreation. He brought his new cream into the clinic, which was found to contain prescription-strength methoxsalen (8-methoxypsoralen), confirming the diagnosis of acute phototoxic contact dermatitis. The acute reaction had subsided, and the patient already had discontinued the causative agent. He was counseled on further avoidance of the cream and sun-protective measures.

The photosensitizing properties of certain compounds have been harnessed for therapeutic purposes. For example, psoralen plus UVA therapy has been used for psoriasis and vitiligo and photodynamic therapy for actinic keratoses and superficial nonmelanoma skin cancers.¹ However, these agents can induce severe phototoxicity if UV light exposure is not carefully monitored, as seen in our patient. This case is a classic example of phototoxic contact dermatitis and highlights the importance of obtaining a detailed patient history to allow for proper diagnosis and identification of the causative agent. Importantly, because prescription-strength topical medications are readily available over-the-counter, particularly in stores specializing in international goods, patients should be questioned about the use of all topical and systemic medications, both prescription and nonprescription.²