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Drug-induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially fatal drug-induced hypersensitivity reaction that is characterized by a cutaneous eruption, multiorgan involvement, viral reactivation, and hematologic abnormalities. As the nomenclature of this disease advances, consensus groups have adopted DIHS/DRESS to underscore that both names refer to the same clinical phenomenon.1 Autoimmune sequelae have been reported after DIHS/DRESS that include vitiligo, thyroid disease, and type 1 diabetes mellitus (T1DM). We present a case of lamotrigine-associated DIHS/DRESS complicated by an unusually prolonged course requiring oral corticosteroids and narrow-band ultraviolet B (UVB) treatment and with development of extensive alopecia areata and autoimmune thyroiditis.
Case Presentation
A 35-year-old female Filipino patient was prescribed lamotrigine 25 mg daily for bipolar II disorder and titrated to 100 mg twice daily after 1 month. One week after the increase, the patient developed a diffuse morbilliform rash covering their entire body along with facial swelling and generalized pruritus. Lamotrigine was discontinued after lamotrigine allergy was diagnosed. The patient improved following a 9-day oral prednisone taper and was placed on oxcarbazepine 300 mg twice daily to manage their bipolar disorder. One day after completing the taper, the patient presented again with worsening rash, swelling, and cervical lymphadenopathy. Oxcarbazepine was discontinued, and oral prednisone 60 mg was reinstituted for an additional 11 days.
Dermatology evaluated the patient 10 days after completion of the second oral steroid taper (1 month after cessation of lamotrigine). The patient had erythroderma along with malaise, fevers, chills, and fatigue and a diffuse burning sensation (Figure 1). The patient was hypotensive and tachycardic with significant eosinophilia (42%; reference range, 0%-8%), transaminitis, and renal insufficiency. The patient was diagnosed with DIHS/DRESS based on their clinical presentation and calculated RegiSCAR score of 7 (score > 5 corresponds with definite DIHS/DRESS and points were given for fever, enlarged lymph nodes, eosinophilia ≥ 20%, skin rash extending > 50% of their body, edema and scaling, and 2 organs involved).2 A punch biopsy was confirmatory (Figure 2A).3 The patient was started on prednisone 80 mg once daily along with topical fluocinonide 0.05% ointment. However, the patient’s clinical status deteriorated, requiring hospital admission for heart failure evaluation. The echocardiogram revealed hyperdynamic circulation but was otherwise unremarkable.
The patient was maintained on prednisone 70 to 80 mg daily for 2 months before improvement of the rash and pruritus. The prednisone was slowly tapered over a 6-week period and then discontinued. Shortly after discontinuation, the patient redeveloped erythroderma. Skin biopsy and complete blood count (17.3% eosinophilia) confirmed the suspected DIHS/DRESS relapse (Figure 2B). In addition, the patient reported upper respiratory tract symptoms and concurrently tested positive for human herpesvirus 6 (HHV-6). The patient was restarted on prednisone and low-dose narrow-band UVB (nbUVB) therapy was added. Over the following 2 months, they responded well to low-dose nbUVB therapy. By the end of nbUVB treatment, about 5 months after initial presentation, the patient’s erythroderma improved, eosinophilia resolved, and they were able to tolerate prednisone taper. Ten months after cessation of lamotrigine, prednisone was finally discontinued. Two weeks later, the patient was screened for adrenal insufficiency (AI) given the prolonged steroid course. Their serum morning cortisol level was within normal limits.
Four months after DIHS/DRESS resolution and cessation of steroids, the patient noted significant patches of smooth alopecia on their posterior scalp and was diagnosed with alopecia areata. Treatment with intralesional triamcinolone over 2 months resulted in regrowth of hair (Figure 3). A month later, the patient reported increasing fatigue and anorexia. The patient was evaluated once more for AI, this time with low morning cortisol and low adrenocorticotrophic hormone (ACTH) levels—consistent with AI secondary to prolonged glucocorticoid therapy. The patient also was concomitantly evaluated for hypothyroidism with significantly elevated thyroperoxidase antibodies—confirming the diagnosis of Hashimoto thyroiditis.
Discussion
DIHS/DRESS syndrome is a rare, but potentially life-threatening hypersensitivity to a medication, often beginning 2 to 6 weeks after exposure to the causative agent. The incidence of DIHS/DRESS in the general population is about 2 per 100,000.3 Our patient presented with DIHS/DRESS 33 days after starting lamotrigine, which corresponds with the published mean onset of anticonvulsant-induced DIHS/DRESS (29.7-33.3 days).4 Recent evidence shows that time from drug exposure to DIHS/DRESS symptoms may vary by drug class, with antibiotics implicated as precipitating DIHS/DRESS in < 15 days.3 The diagnosis of DIHS/DRESS may be complicated for many reasons. The accompanying rash may be morbilliform, erythroderma, or exfoliative dermatitis with multiple anatomic regions affected.5 Systemic involvement with various internal organs occurs in > 90% of cases, with the liver and kidney involved most frequently.5 Overall mortality rate may be as high as 10% most commonly due to acute liver failure.5 Biopsy may be helpful in the diagnosis but is not always specific.5 Diagnostic criteria include RegiSCAR and J-SCAR scores; our patient met criteria for both (Table).5
The pathogenesis of DIHS/DRESS remains unclear. Proposed mechanisms include genetic predisposition with human leukocyte antigen (HLA) haplotypes, autoimmune with a delayed cell-mediated immune response associated with herpesviruses, and abnormal enzymatic pathways that metabolize medications.2 Although no HLA has been identified between lamotrigine and DIHS, HLA-A*02:07 and HLA-B*15:02 have been associated with lamotrigine-induced cutaneous drug reactions in patients of Thai ancestry.6 Immunosuppression also is a risk factor, especially when accompanied by a primary or reactivated HHV-6 infection, as seen in our patient.2 Additionally, HHV-6 infection may be a common link between DIHS/DRESS and autoimmune thyroiditis but is believed to involve elevated levels of interferon-γ-induced protein-10 (IP-10) that may lead to excessive recruitment of cytotoxic T cells into target tissues.7 Elevated levels of IP-10 are seen in many autoimmune conditions, such as autoimmune thyroiditis, Sjögren syndrome, and Graves disease.8
DIHS/DRESS syndrome has been associated with development of autoimmune diseases as long-term sequelae. The most commonly affected organs are the thyroid and pancreas; approximately 4.8% of patients develop autoimmune thyroiditis and 3.5% develop fulminant T1DM.9 The time from onset of DIHS/DRESS to development of autoimmune thyroiditis can range from 2 months to 2 years, whereas the range from DIHS/DRESS onset to fulminant T1DM is about 40 days.9 Alopecia had been reported in 1, occurring 4 months after DIHS/DRESS onset. Our patient’s alopecia areata and Hashimoto thyroiditis occurred 14 and 15 months after DIHS/DRESS presentation, respectively.
Treatment
For management, early recognition and discontinuation of the offending agent is paramount. Systemic corticosteroids are the accepted treatment standard. Symptoms of DIHS/DRESS usually resolve between 3 and 18 weeks, with the mean resolution time at 7 weeks.10 Our patient developed a prolonged course with persistent eosinophilia for 20 weeks and cutaneous symptoms for 32 weeks—requiring 40 weeks of oral prednisone. The most significant clinical improvement occurred during the 8-week period low-dose nbUVB was used (Figure 4). There also are reports outlining the successful use of intravenous immunoglobulin, cyclosporine, cyclophosphamide, rituximab, or plasma exchange in cases refractory to oral corticosteroids.11
A recent retrospective case control study showed that treatment of DIHS/DRESS with cyclosporine in patients who had a contraindication to steroids resulted in faster resolution of symptoms, shorter treatment durations, and shorter hospitalizations than did those treated with corticosteroids.12 However, the data are limited by a significantly smaller number of patients treated with cyclosporine than steroids and the cyclosporine treatment group having milder cases of DIHS/DRESS.12
The risk of AI is increased for patients who have taken > 20 mg of prednisone daily ≥ 3 weeks, an evening dose ≥ 5 mg for a few weeks, or have a Cushingoid appearance.13 Patients may not regain full adrenal function for 12 to 18 months.14 Our patient had a normal basal serum cortisol level 2 weeks after prednisone cessation and then presented 5 months later with AI. While the reason for this period of normality is unclear, it may partly be due to the variable length of hypothalamic-pituitary-adrenal axis recovery time. Thus, ACTH stimulation tests in addition to serum cortisol may be done in patients with suspected AI for higher diagnostic certainty.10
Conclusions
DIHS/DRESS is a severe cutaneous adverse reaction that may require a prolonged treatment course until symptom resolution (40 weeks of oral prednisone in our patient). Oral corticosteroids are the mainstay of treatment, but long-term use is associated with significant adverse effects, such as AI in our patient. Alternative therapies, such as cyclosporine, look promising, but further studies are needed to determine safety profile and efficacy.12 Additionally, patients with DIHS/DRESS should be educated and followed for potential autoimmune sequelae; in our patient alopecia areata and autoimmune thyroiditis were late sequelae, occurring 14 and 15 months, respectively, after onset of DIHS/DRESS.
1. RegiSCAR. Accessed June 3, 2022. http://www.regiscar.org
2. Shiohara T, Mizukawa Y. Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019. Allergol Int. 2019;68(3):301-308. doi:10.1016/j.alit.2019.03.006
3. Wolfson AR, Zhou L, Li Y, Phadke NA, Chow OA, Blumenthal KG. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome identified in the electronic health record allergy module. J Allergy Clin Immunol Pract. 2019;7(2):633-640. doi:10.1016/j.jaip.2018.08.013
4. Sasidharanpillai S, Govindan A, Riyaz N, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a histopathology based analysis. Indian J Dermatol Venereol Leprol. 2016;82(1):28. doi:10.4103/0378-6323.168934
5. Kardaun SH, Sekula P, Valeyrie‐Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071-1080. doi:10.1111/bjd.12501
6. Koomdee N, Pratoomwun J, Jantararoungtong T, et al. Association of HLA-A and HLA-B alleles with lamotrigine-induced cutaneous adverse drug reactions in the Thai population. Front Pharmacol. 2017;8. doi:10.3389/fphar.2017.00879
7. Yang C-W, Cho Y-T, Hsieh Y-C, Hsu S-H, Chen K-L, Chu C-Y. The interferon-γ-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms. Br J Dermatol. 2020;183(5):909-919. doi:10.1111/bjd.18942
8. Ruffilli I, Ferrari SM, Colaci M, Ferri C, Fallahi P, Antonelli A. IP-10 in autoimmune thyroiditis. Horm Metab Res. 2014;46(9):597-602. doi:10.1055/s-0034-1382053
9. Kano Y, Tohyama M, Aihara M, et al. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol. 2015;42(3):276-282. doi:10.1111/1346-8138.12770
10. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588-597. doi:10.1016/j.amjmed.2011.01.017
11. Bommersbach TJ, Lapid MI, Leung JG, Cunningham JL, Rummans TA, Kung S. Management of psychotropic drug-induced dress syndrome: a systematic review. Mayo Clin Proc. 2016;91(6):787-801. doi:10.1016/j.mayocp.2016.03.006
12. Nguyen E, Yanes D, Imadojemu S, Kroshinsky D. Evaluation of cyclosporine for the treatment of DRESS syndrome. JAMA Dermatol. 2020;156(6):704-706. doi:10.1001/jamadermatol.2020.0048
13. Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid therapy and adrenal insufficiency in adults: a systematic review. Semin Arthritis Rheum. 2016;46(1):133-141. doi:10.1016/j.semarthrit.2016.03.001
14. Jamilloux Y, Liozon E, Pugnet G, et al. Recovery of adrenal function after long-term glucocorticoid therapy for giant cell arteritis: a cohort study. PLoS ONE. 2013;8(7):e68713. doi:10.1371/journal.pone.0068713
Drug-induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially fatal drug-induced hypersensitivity reaction that is characterized by a cutaneous eruption, multiorgan involvement, viral reactivation, and hematologic abnormalities. As the nomenclature of this disease advances, consensus groups have adopted DIHS/DRESS to underscore that both names refer to the same clinical phenomenon.1 Autoimmune sequelae have been reported after DIHS/DRESS that include vitiligo, thyroid disease, and type 1 diabetes mellitus (T1DM). We present a case of lamotrigine-associated DIHS/DRESS complicated by an unusually prolonged course requiring oral corticosteroids and narrow-band ultraviolet B (UVB) treatment and with development of extensive alopecia areata and autoimmune thyroiditis.
Case Presentation
A 35-year-old female Filipino patient was prescribed lamotrigine 25 mg daily for bipolar II disorder and titrated to 100 mg twice daily after 1 month. One week after the increase, the patient developed a diffuse morbilliform rash covering their entire body along with facial swelling and generalized pruritus. Lamotrigine was discontinued after lamotrigine allergy was diagnosed. The patient improved following a 9-day oral prednisone taper and was placed on oxcarbazepine 300 mg twice daily to manage their bipolar disorder. One day after completing the taper, the patient presented again with worsening rash, swelling, and cervical lymphadenopathy. Oxcarbazepine was discontinued, and oral prednisone 60 mg was reinstituted for an additional 11 days.
Dermatology evaluated the patient 10 days after completion of the second oral steroid taper (1 month after cessation of lamotrigine). The patient had erythroderma along with malaise, fevers, chills, and fatigue and a diffuse burning sensation (Figure 1). The patient was hypotensive and tachycardic with significant eosinophilia (42%; reference range, 0%-8%), transaminitis, and renal insufficiency. The patient was diagnosed with DIHS/DRESS based on their clinical presentation and calculated RegiSCAR score of 7 (score > 5 corresponds with definite DIHS/DRESS and points were given for fever, enlarged lymph nodes, eosinophilia ≥ 20%, skin rash extending > 50% of their body, edema and scaling, and 2 organs involved).2 A punch biopsy was confirmatory (Figure 2A).3 The patient was started on prednisone 80 mg once daily along with topical fluocinonide 0.05% ointment. However, the patient’s clinical status deteriorated, requiring hospital admission for heart failure evaluation. The echocardiogram revealed hyperdynamic circulation but was otherwise unremarkable.
The patient was maintained on prednisone 70 to 80 mg daily for 2 months before improvement of the rash and pruritus. The prednisone was slowly tapered over a 6-week period and then discontinued. Shortly after discontinuation, the patient redeveloped erythroderma. Skin biopsy and complete blood count (17.3% eosinophilia) confirmed the suspected DIHS/DRESS relapse (Figure 2B). In addition, the patient reported upper respiratory tract symptoms and concurrently tested positive for human herpesvirus 6 (HHV-6). The patient was restarted on prednisone and low-dose narrow-band UVB (nbUVB) therapy was added. Over the following 2 months, they responded well to low-dose nbUVB therapy. By the end of nbUVB treatment, about 5 months after initial presentation, the patient’s erythroderma improved, eosinophilia resolved, and they were able to tolerate prednisone taper. Ten months after cessation of lamotrigine, prednisone was finally discontinued. Two weeks later, the patient was screened for adrenal insufficiency (AI) given the prolonged steroid course. Their serum morning cortisol level was within normal limits.
Four months after DIHS/DRESS resolution and cessation of steroids, the patient noted significant patches of smooth alopecia on their posterior scalp and was diagnosed with alopecia areata. Treatment with intralesional triamcinolone over 2 months resulted in regrowth of hair (Figure 3). A month later, the patient reported increasing fatigue and anorexia. The patient was evaluated once more for AI, this time with low morning cortisol and low adrenocorticotrophic hormone (ACTH) levels—consistent with AI secondary to prolonged glucocorticoid therapy. The patient also was concomitantly evaluated for hypothyroidism with significantly elevated thyroperoxidase antibodies—confirming the diagnosis of Hashimoto thyroiditis.
Discussion
DIHS/DRESS syndrome is a rare, but potentially life-threatening hypersensitivity to a medication, often beginning 2 to 6 weeks after exposure to the causative agent. The incidence of DIHS/DRESS in the general population is about 2 per 100,000.3 Our patient presented with DIHS/DRESS 33 days after starting lamotrigine, which corresponds with the published mean onset of anticonvulsant-induced DIHS/DRESS (29.7-33.3 days).4 Recent evidence shows that time from drug exposure to DIHS/DRESS symptoms may vary by drug class, with antibiotics implicated as precipitating DIHS/DRESS in < 15 days.3 The diagnosis of DIHS/DRESS may be complicated for many reasons. The accompanying rash may be morbilliform, erythroderma, or exfoliative dermatitis with multiple anatomic regions affected.5 Systemic involvement with various internal organs occurs in > 90% of cases, with the liver and kidney involved most frequently.5 Overall mortality rate may be as high as 10% most commonly due to acute liver failure.5 Biopsy may be helpful in the diagnosis but is not always specific.5 Diagnostic criteria include RegiSCAR and J-SCAR scores; our patient met criteria for both (Table).5
The pathogenesis of DIHS/DRESS remains unclear. Proposed mechanisms include genetic predisposition with human leukocyte antigen (HLA) haplotypes, autoimmune with a delayed cell-mediated immune response associated with herpesviruses, and abnormal enzymatic pathways that metabolize medications.2 Although no HLA has been identified between lamotrigine and DIHS, HLA-A*02:07 and HLA-B*15:02 have been associated with lamotrigine-induced cutaneous drug reactions in patients of Thai ancestry.6 Immunosuppression also is a risk factor, especially when accompanied by a primary or reactivated HHV-6 infection, as seen in our patient.2 Additionally, HHV-6 infection may be a common link between DIHS/DRESS and autoimmune thyroiditis but is believed to involve elevated levels of interferon-γ-induced protein-10 (IP-10) that may lead to excessive recruitment of cytotoxic T cells into target tissues.7 Elevated levels of IP-10 are seen in many autoimmune conditions, such as autoimmune thyroiditis, Sjögren syndrome, and Graves disease.8
DIHS/DRESS syndrome has been associated with development of autoimmune diseases as long-term sequelae. The most commonly affected organs are the thyroid and pancreas; approximately 4.8% of patients develop autoimmune thyroiditis and 3.5% develop fulminant T1DM.9 The time from onset of DIHS/DRESS to development of autoimmune thyroiditis can range from 2 months to 2 years, whereas the range from DIHS/DRESS onset to fulminant T1DM is about 40 days.9 Alopecia had been reported in 1, occurring 4 months after DIHS/DRESS onset. Our patient’s alopecia areata and Hashimoto thyroiditis occurred 14 and 15 months after DIHS/DRESS presentation, respectively.
Treatment
For management, early recognition and discontinuation of the offending agent is paramount. Systemic corticosteroids are the accepted treatment standard. Symptoms of DIHS/DRESS usually resolve between 3 and 18 weeks, with the mean resolution time at 7 weeks.10 Our patient developed a prolonged course with persistent eosinophilia for 20 weeks and cutaneous symptoms for 32 weeks—requiring 40 weeks of oral prednisone. The most significant clinical improvement occurred during the 8-week period low-dose nbUVB was used (Figure 4). There also are reports outlining the successful use of intravenous immunoglobulin, cyclosporine, cyclophosphamide, rituximab, or plasma exchange in cases refractory to oral corticosteroids.11
A recent retrospective case control study showed that treatment of DIHS/DRESS with cyclosporine in patients who had a contraindication to steroids resulted in faster resolution of symptoms, shorter treatment durations, and shorter hospitalizations than did those treated with corticosteroids.12 However, the data are limited by a significantly smaller number of patients treated with cyclosporine than steroids and the cyclosporine treatment group having milder cases of DIHS/DRESS.12
The risk of AI is increased for patients who have taken > 20 mg of prednisone daily ≥ 3 weeks, an evening dose ≥ 5 mg for a few weeks, or have a Cushingoid appearance.13 Patients may not regain full adrenal function for 12 to 18 months.14 Our patient had a normal basal serum cortisol level 2 weeks after prednisone cessation and then presented 5 months later with AI. While the reason for this period of normality is unclear, it may partly be due to the variable length of hypothalamic-pituitary-adrenal axis recovery time. Thus, ACTH stimulation tests in addition to serum cortisol may be done in patients with suspected AI for higher diagnostic certainty.10
Conclusions
DIHS/DRESS is a severe cutaneous adverse reaction that may require a prolonged treatment course until symptom resolution (40 weeks of oral prednisone in our patient). Oral corticosteroids are the mainstay of treatment, but long-term use is associated with significant adverse effects, such as AI in our patient. Alternative therapies, such as cyclosporine, look promising, but further studies are needed to determine safety profile and efficacy.12 Additionally, patients with DIHS/DRESS should be educated and followed for potential autoimmune sequelae; in our patient alopecia areata and autoimmune thyroiditis were late sequelae, occurring 14 and 15 months, respectively, after onset of DIHS/DRESS.
Drug-induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially fatal drug-induced hypersensitivity reaction that is characterized by a cutaneous eruption, multiorgan involvement, viral reactivation, and hematologic abnormalities. As the nomenclature of this disease advances, consensus groups have adopted DIHS/DRESS to underscore that both names refer to the same clinical phenomenon.1 Autoimmune sequelae have been reported after DIHS/DRESS that include vitiligo, thyroid disease, and type 1 diabetes mellitus (T1DM). We present a case of lamotrigine-associated DIHS/DRESS complicated by an unusually prolonged course requiring oral corticosteroids and narrow-band ultraviolet B (UVB) treatment and with development of extensive alopecia areata and autoimmune thyroiditis.
Case Presentation
A 35-year-old female Filipino patient was prescribed lamotrigine 25 mg daily for bipolar II disorder and titrated to 100 mg twice daily after 1 month. One week after the increase, the patient developed a diffuse morbilliform rash covering their entire body along with facial swelling and generalized pruritus. Lamotrigine was discontinued after lamotrigine allergy was diagnosed. The patient improved following a 9-day oral prednisone taper and was placed on oxcarbazepine 300 mg twice daily to manage their bipolar disorder. One day after completing the taper, the patient presented again with worsening rash, swelling, and cervical lymphadenopathy. Oxcarbazepine was discontinued, and oral prednisone 60 mg was reinstituted for an additional 11 days.
Dermatology evaluated the patient 10 days after completion of the second oral steroid taper (1 month after cessation of lamotrigine). The patient had erythroderma along with malaise, fevers, chills, and fatigue and a diffuse burning sensation (Figure 1). The patient was hypotensive and tachycardic with significant eosinophilia (42%; reference range, 0%-8%), transaminitis, and renal insufficiency. The patient was diagnosed with DIHS/DRESS based on their clinical presentation and calculated RegiSCAR score of 7 (score > 5 corresponds with definite DIHS/DRESS and points were given for fever, enlarged lymph nodes, eosinophilia ≥ 20%, skin rash extending > 50% of their body, edema and scaling, and 2 organs involved).2 A punch biopsy was confirmatory (Figure 2A).3 The patient was started on prednisone 80 mg once daily along with topical fluocinonide 0.05% ointment. However, the patient’s clinical status deteriorated, requiring hospital admission for heart failure evaluation. The echocardiogram revealed hyperdynamic circulation but was otherwise unremarkable.
The patient was maintained on prednisone 70 to 80 mg daily for 2 months before improvement of the rash and pruritus. The prednisone was slowly tapered over a 6-week period and then discontinued. Shortly after discontinuation, the patient redeveloped erythroderma. Skin biopsy and complete blood count (17.3% eosinophilia) confirmed the suspected DIHS/DRESS relapse (Figure 2B). In addition, the patient reported upper respiratory tract symptoms and concurrently tested positive for human herpesvirus 6 (HHV-6). The patient was restarted on prednisone and low-dose narrow-band UVB (nbUVB) therapy was added. Over the following 2 months, they responded well to low-dose nbUVB therapy. By the end of nbUVB treatment, about 5 months after initial presentation, the patient’s erythroderma improved, eosinophilia resolved, and they were able to tolerate prednisone taper. Ten months after cessation of lamotrigine, prednisone was finally discontinued. Two weeks later, the patient was screened for adrenal insufficiency (AI) given the prolonged steroid course. Their serum morning cortisol level was within normal limits.
Four months after DIHS/DRESS resolution and cessation of steroids, the patient noted significant patches of smooth alopecia on their posterior scalp and was diagnosed with alopecia areata. Treatment with intralesional triamcinolone over 2 months resulted in regrowth of hair (Figure 3). A month later, the patient reported increasing fatigue and anorexia. The patient was evaluated once more for AI, this time with low morning cortisol and low adrenocorticotrophic hormone (ACTH) levels—consistent with AI secondary to prolonged glucocorticoid therapy. The patient also was concomitantly evaluated for hypothyroidism with significantly elevated thyroperoxidase antibodies—confirming the diagnosis of Hashimoto thyroiditis.
Discussion
DIHS/DRESS syndrome is a rare, but potentially life-threatening hypersensitivity to a medication, often beginning 2 to 6 weeks after exposure to the causative agent. The incidence of DIHS/DRESS in the general population is about 2 per 100,000.3 Our patient presented with DIHS/DRESS 33 days after starting lamotrigine, which corresponds with the published mean onset of anticonvulsant-induced DIHS/DRESS (29.7-33.3 days).4 Recent evidence shows that time from drug exposure to DIHS/DRESS symptoms may vary by drug class, with antibiotics implicated as precipitating DIHS/DRESS in < 15 days.3 The diagnosis of DIHS/DRESS may be complicated for many reasons. The accompanying rash may be morbilliform, erythroderma, or exfoliative dermatitis with multiple anatomic regions affected.5 Systemic involvement with various internal organs occurs in > 90% of cases, with the liver and kidney involved most frequently.5 Overall mortality rate may be as high as 10% most commonly due to acute liver failure.5 Biopsy may be helpful in the diagnosis but is not always specific.5 Diagnostic criteria include RegiSCAR and J-SCAR scores; our patient met criteria for both (Table).5
The pathogenesis of DIHS/DRESS remains unclear. Proposed mechanisms include genetic predisposition with human leukocyte antigen (HLA) haplotypes, autoimmune with a delayed cell-mediated immune response associated with herpesviruses, and abnormal enzymatic pathways that metabolize medications.2 Although no HLA has been identified between lamotrigine and DIHS, HLA-A*02:07 and HLA-B*15:02 have been associated with lamotrigine-induced cutaneous drug reactions in patients of Thai ancestry.6 Immunosuppression also is a risk factor, especially when accompanied by a primary or reactivated HHV-6 infection, as seen in our patient.2 Additionally, HHV-6 infection may be a common link between DIHS/DRESS and autoimmune thyroiditis but is believed to involve elevated levels of interferon-γ-induced protein-10 (IP-10) that may lead to excessive recruitment of cytotoxic T cells into target tissues.7 Elevated levels of IP-10 are seen in many autoimmune conditions, such as autoimmune thyroiditis, Sjögren syndrome, and Graves disease.8
DIHS/DRESS syndrome has been associated with development of autoimmune diseases as long-term sequelae. The most commonly affected organs are the thyroid and pancreas; approximately 4.8% of patients develop autoimmune thyroiditis and 3.5% develop fulminant T1DM.9 The time from onset of DIHS/DRESS to development of autoimmune thyroiditis can range from 2 months to 2 years, whereas the range from DIHS/DRESS onset to fulminant T1DM is about 40 days.9 Alopecia had been reported in 1, occurring 4 months after DIHS/DRESS onset. Our patient’s alopecia areata and Hashimoto thyroiditis occurred 14 and 15 months after DIHS/DRESS presentation, respectively.
Treatment
For management, early recognition and discontinuation of the offending agent is paramount. Systemic corticosteroids are the accepted treatment standard. Symptoms of DIHS/DRESS usually resolve between 3 and 18 weeks, with the mean resolution time at 7 weeks.10 Our patient developed a prolonged course with persistent eosinophilia for 20 weeks and cutaneous symptoms for 32 weeks—requiring 40 weeks of oral prednisone. The most significant clinical improvement occurred during the 8-week period low-dose nbUVB was used (Figure 4). There also are reports outlining the successful use of intravenous immunoglobulin, cyclosporine, cyclophosphamide, rituximab, or plasma exchange in cases refractory to oral corticosteroids.11
A recent retrospective case control study showed that treatment of DIHS/DRESS with cyclosporine in patients who had a contraindication to steroids resulted in faster resolution of symptoms, shorter treatment durations, and shorter hospitalizations than did those treated with corticosteroids.12 However, the data are limited by a significantly smaller number of patients treated with cyclosporine than steroids and the cyclosporine treatment group having milder cases of DIHS/DRESS.12
The risk of AI is increased for patients who have taken > 20 mg of prednisone daily ≥ 3 weeks, an evening dose ≥ 5 mg for a few weeks, or have a Cushingoid appearance.13 Patients may not regain full adrenal function for 12 to 18 months.14 Our patient had a normal basal serum cortisol level 2 weeks after prednisone cessation and then presented 5 months later with AI. While the reason for this period of normality is unclear, it may partly be due to the variable length of hypothalamic-pituitary-adrenal axis recovery time. Thus, ACTH stimulation tests in addition to serum cortisol may be done in patients with suspected AI for higher diagnostic certainty.10
Conclusions
DIHS/DRESS is a severe cutaneous adverse reaction that may require a prolonged treatment course until symptom resolution (40 weeks of oral prednisone in our patient). Oral corticosteroids are the mainstay of treatment, but long-term use is associated with significant adverse effects, such as AI in our patient. Alternative therapies, such as cyclosporine, look promising, but further studies are needed to determine safety profile and efficacy.12 Additionally, patients with DIHS/DRESS should be educated and followed for potential autoimmune sequelae; in our patient alopecia areata and autoimmune thyroiditis were late sequelae, occurring 14 and 15 months, respectively, after onset of DIHS/DRESS.
1. RegiSCAR. Accessed June 3, 2022. http://www.regiscar.org
2. Shiohara T, Mizukawa Y. Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019. Allergol Int. 2019;68(3):301-308. doi:10.1016/j.alit.2019.03.006
3. Wolfson AR, Zhou L, Li Y, Phadke NA, Chow OA, Blumenthal KG. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome identified in the electronic health record allergy module. J Allergy Clin Immunol Pract. 2019;7(2):633-640. doi:10.1016/j.jaip.2018.08.013
4. Sasidharanpillai S, Govindan A, Riyaz N, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a histopathology based analysis. Indian J Dermatol Venereol Leprol. 2016;82(1):28. doi:10.4103/0378-6323.168934
5. Kardaun SH, Sekula P, Valeyrie‐Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071-1080. doi:10.1111/bjd.12501
6. Koomdee N, Pratoomwun J, Jantararoungtong T, et al. Association of HLA-A and HLA-B alleles with lamotrigine-induced cutaneous adverse drug reactions in the Thai population. Front Pharmacol. 2017;8. doi:10.3389/fphar.2017.00879
7. Yang C-W, Cho Y-T, Hsieh Y-C, Hsu S-H, Chen K-L, Chu C-Y. The interferon-γ-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms. Br J Dermatol. 2020;183(5):909-919. doi:10.1111/bjd.18942
8. Ruffilli I, Ferrari SM, Colaci M, Ferri C, Fallahi P, Antonelli A. IP-10 in autoimmune thyroiditis. Horm Metab Res. 2014;46(9):597-602. doi:10.1055/s-0034-1382053
9. Kano Y, Tohyama M, Aihara M, et al. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol. 2015;42(3):276-282. doi:10.1111/1346-8138.12770
10. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588-597. doi:10.1016/j.amjmed.2011.01.017
11. Bommersbach TJ, Lapid MI, Leung JG, Cunningham JL, Rummans TA, Kung S. Management of psychotropic drug-induced dress syndrome: a systematic review. Mayo Clin Proc. 2016;91(6):787-801. doi:10.1016/j.mayocp.2016.03.006
12. Nguyen E, Yanes D, Imadojemu S, Kroshinsky D. Evaluation of cyclosporine for the treatment of DRESS syndrome. JAMA Dermatol. 2020;156(6):704-706. doi:10.1001/jamadermatol.2020.0048
13. Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid therapy and adrenal insufficiency in adults: a systematic review. Semin Arthritis Rheum. 2016;46(1):133-141. doi:10.1016/j.semarthrit.2016.03.001
14. Jamilloux Y, Liozon E, Pugnet G, et al. Recovery of adrenal function after long-term glucocorticoid therapy for giant cell arteritis: a cohort study. PLoS ONE. 2013;8(7):e68713. doi:10.1371/journal.pone.0068713
1. RegiSCAR. Accessed June 3, 2022. http://www.regiscar.org
2. Shiohara T, Mizukawa Y. Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019. Allergol Int. 2019;68(3):301-308. doi:10.1016/j.alit.2019.03.006
3. Wolfson AR, Zhou L, Li Y, Phadke NA, Chow OA, Blumenthal KG. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome identified in the electronic health record allergy module. J Allergy Clin Immunol Pract. 2019;7(2):633-640. doi:10.1016/j.jaip.2018.08.013
4. Sasidharanpillai S, Govindan A, Riyaz N, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a histopathology based analysis. Indian J Dermatol Venereol Leprol. 2016;82(1):28. doi:10.4103/0378-6323.168934
5. Kardaun SH, Sekula P, Valeyrie‐Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169(5):1071-1080. doi:10.1111/bjd.12501
6. Koomdee N, Pratoomwun J, Jantararoungtong T, et al. Association of HLA-A and HLA-B alleles with lamotrigine-induced cutaneous adverse drug reactions in the Thai population. Front Pharmacol. 2017;8. doi:10.3389/fphar.2017.00879
7. Yang C-W, Cho Y-T, Hsieh Y-C, Hsu S-H, Chen K-L, Chu C-Y. The interferon-γ-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms. Br J Dermatol. 2020;183(5):909-919. doi:10.1111/bjd.18942
8. Ruffilli I, Ferrari SM, Colaci M, Ferri C, Fallahi P, Antonelli A. IP-10 in autoimmune thyroiditis. Horm Metab Res. 2014;46(9):597-602. doi:10.1055/s-0034-1382053
9. Kano Y, Tohyama M, Aihara M, et al. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol. 2015;42(3):276-282. doi:10.1111/1346-8138.12770
10. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588-597. doi:10.1016/j.amjmed.2011.01.017
11. Bommersbach TJ, Lapid MI, Leung JG, Cunningham JL, Rummans TA, Kung S. Management of psychotropic drug-induced dress syndrome: a systematic review. Mayo Clin Proc. 2016;91(6):787-801. doi:10.1016/j.mayocp.2016.03.006
12. Nguyen E, Yanes D, Imadojemu S, Kroshinsky D. Evaluation of cyclosporine for the treatment of DRESS syndrome. JAMA Dermatol. 2020;156(6):704-706. doi:10.1001/jamadermatol.2020.0048
13. Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid therapy and adrenal insufficiency in adults: a systematic review. Semin Arthritis Rheum. 2016;46(1):133-141. doi:10.1016/j.semarthrit.2016.03.001
14. Jamilloux Y, Liozon E, Pugnet G, et al. Recovery of adrenal function after long-term glucocorticoid therapy for giant cell arteritis: a cohort study. PLoS ONE. 2013;8(7):e68713. doi:10.1371/journal.pone.0068713