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A Solitary Axillary Subcutaneous Mass
A Solitary Axillary Subcutaneous Mass
THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease
The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.
Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman1 as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.3,4
Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.5 Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.6 Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.
Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.12 Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.
Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.5 Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.6
The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.15 While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.20,21
Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.24 Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.5 There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.22
- Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. a newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63-70.
- Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7:19-73.
- Stefanato CM, Ellerin PS, Bhawan J. Cutaneous sinus histiocytosis (Rosai-Dorfman disease) presenting clinically as vasculitis. J Am Acad Dermatol. 2002;46:775-778.
- Dalia S, Sagatys E, Sokol L, et al. Rosai-Dorfman Disease: tumor biology, clinical features, pathology, and treatment. Cancer Control. 2014;21:322-327.
- Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020;73:697.
- Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. ed. Elsevier Saunders 2012.
- Salva KA, Stenstrom M, Breadon JY, et al. Possible association of cutaneous rosai-dorfman disease and chronic crohn disease: a case series report. JAMA Dermatol. 2014;150:177-181.
- Brenn T, Calonje E, Granter SR, et al. Cutaneous Rosai-Dorfman disease is a distinct clinical entity. Am J Dermatopathol. 2002; 24:385-391.
- Betini N, Munger AM, Rottmann D, et al. Rare presentation of Rosai- Dorfman disease in soft tissue: diagnostic findings and surgical treatment. Case Rep Surg. 2022;2022:8440836.
- Cravero JC, Ibrahim S. Recurrent soft tissue rosai dorfman disease of right medial thigh lipoma with lymph node involvement. Fed Pract. 2024;41(suppl 2):S20-S23
- Tenny SO, McGinness M, Zhang D, et al. Rosai-Dorfman disease presenting as a breast mass and enlarged axillary lymph node mimicking malignancy: a case report and review of the literature. Breast J. 2011;17:516-520.
- Goyal G, Ravindran A, Young JR, et al. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2020;105:348-357.
- Li H, Li D, Xia J, et al. Radiological features of Rosai-Dorfman disease: case series and review of the literature. Clin Radiol. 2022;77:E799-E805.
- Elbaz Younes I, Sokol L, Zhang L. Rosai-Dorfman disease between proliferation and neoplasia. Cancers. 2022;14:5271.
- Ravindran A, Rech KL. How I diagnose Rosai-Dorfman disease. Am J Clin Pathol. 2023;160:1-10.
- Kutlubay Z, Bairamov O, Sevim A, et al. Rosai-Dorfman disease: a case report with nodal and cutaneous involvement and review of the literature. Am J Dermatopathol. 2014;36:353-357.
- Luppi M, Barozzi P, Garber R, et al. Expression of human herpesvirus 6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol. 1998;153:815-823.
- Wang KH, Chen WY, Liu HN, et al. Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol. 2006;154:277-286.
- Vaiselbuh SR, Bryceson YT, Allen CE, et al. Updates on histiocytic disorders. Pediatr Blood Cancer. 2014;61:1329-1335.
- Ravindran A, Goyal G, Go RS, et al. Rosai-Dorfman disease displays a unique monocyte-macrophage phenotype characterized by expression of OCT2. Am J Surg Pathol. 2021;45:35-44.
- Hoogewerf CJ, van Baar ME, Middelkoop E, et al. Impact of facial burns: relationship between depressive symptoms, self-esteem and scar severity. Gen Hosp Psychiatry. 2014;36:271-276.
- Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018;131:2877-2890.
- Al-Khateeb THH. Cutaneous Rosai-Dorfman disease of the face: a comprehensive literature review and case report. J Oral Maxillofacial Surg. 2016;74:528-540.
- Cheng SP, Jeng KS, Liu CL. Subcutaneous Rosai–Dorfman disease: is surgical excision justified? J Eur Acad Dermatol Venereol. 2005; 19:747-750.
- Garcia RA, DiCarlo EF. Rosai-Dorfman disease of bone and soft tissue. Arch Pathol Lab Med. 2021;146:40-46.
THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease
The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.
Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman1 as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.3,4
Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.5 Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.6 Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.
Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.12 Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.
Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.5 Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.6
The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.15 While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.20,21
Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.24 Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.5 There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.22
THE DIAGNOSIS: Cutaneous Rosai-Dorfman Disease
The clinical differential diagnosis in our patient included a broad array of soft-tissue neoplasms ranging from benign entities to sarcomas. Histology was notable for a dense, dermal-based, lymphohistiocytic infiltrate with alternating hypocellular and hypercellular areas imparting a marbled appearance on low-power view (Figure, A). Further immunohistochemical staining revealed large, S100-positive histiocytes containing intact inflammatory cells (emperipolesis), which confirmed a diagnosis of cutaneous Rosai-Dorfman disease (RDD)(Figure, B). Our patient elected to undergo surgical removal of the mass, and he will be monitored for recurrence.
Rosai-Dorfman disease is a non–Langerhans cell histiocytosis that most commonly affects the lymph nodes but can affect other organs including the skin. Rosai-Dorfman disease initially was documented in the medical literature in 1969 by Rosai and Dorfman1 as benign sinus histiocytosis with massive lymphadenopathy. Classic RDD usually manifests with painless cervical lymphadenopathy in children or young adults along with fever, leukocytosis, anemia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers.2,3 Extranodal involvement has been reported in up to 43% of cases, with common sites including the skin, central nervous system, and gastrointestinal tract.3,4
Cutaneous RDD is a distinct, less common clinical entity that is limited to the skin and shows no nodal involvement or systemic symptoms such as fever, night sweats, or weight loss.5 Cutaneous RDD classically manifests with localized indurated papules and plaques, but it can manifest with tumorlike lesions in the subcutaneous tissues.6 Cutaneous RDD is very rare, with fewer than 200 known case reports in the literature as of 2014; in comparison to classic forms of RDD, cutaneous RDD has a female predominance.7,8 There are few reports of isolated cutaneous disease manifesting as soft-tissue masses, and our case represents a rare case of cutaneous RDD manifesting as a solitary soft-tissue mass in the axilla.9-11 Diagnosis of cutaneous RDD is challenging due to its variable clinical manifestations and nonspecific imaging findings, requiring clinicopathologic correlation.
Imaging of subcutaneous RDD lesions typically shows well-defined, irregularly shaped masses with homogenous enhancement on computed tomography/ magnetic resonance imaging. Additional imaging with positron emission tomography/computed tomography is recommended to examine for organ involvement, as RDD lesions have avid uptake.12,13 Imaging may help differentiate RDD lesions from malignant neoplasms prior to biopsy. Additional workup includes baseline laboratory testing with inflammatory markers and a complete blood count for evaluation of laboratory abnormalities seen in classic RDD, including leukocytosis, anemia, or systemic inflammation.12 Following imaging and laboratory testing, definitive diagnosis of RDD necessitates histopathologic examination.
Although cutaneous RDD is clinically distinct from its classic RDD counterpart, the conditions share the same characteristic histologic features.5 Histology is notable for a dense mixed inflammatory infiltrate comprised of large pale histiocytes exhibiting emperipolesis, lymphocytes, plasma cells, and occasional eosinophils and neutrophils. Histiocytes stain positive for CD68, CD163, and S100 and are negative for Langerhans cell markers CD1a and CD207.6
The etiology of RDD remains poorly understood. Classic RDD has been associated with both sporadic and familial forms, with somatic mutations identified in the mitogen-activated protein kinase/KRAS pathway in up to one-third of cases, and less frequently in the BRAF gene.14,15 Germline mutations in familial cases of RDD have been identified in the SLC29A3 gene; mutations in this gene are associated with a spectrum of syndromes with histiocytosis and lymphadenopathy.14,15 In contrast, molecular drivers have yet to be identified in cutaneous RDD lesions, and the current predominant hypothesis is that cutaneous RDD has a reactive or immunologic pathophysiology. Autoimmune diseases, infections, and lymphomas have been reported to co-occur with both classic and cutaneous RDD.15 While subclinical viral infections such as Epstein-Barr virus and human herpesvirus 6 have been identified in RDD cases, studies have failed to prove their role as pathogenic drivers of the disease.14,16,17 Commonly reported comorbidities include systemic lupus erythematous, diabetes, hemolytic anemia, acute/chronic uveitis (though it is controversial whether these cases represent orbital involvement in systemic RDD), and Crohn disease.7,8,18,19 Immunohistochemical findings have supported that cells within RDD are activated monocytes responding to T-cell cytokine signaling following an infectious or immunologic insult.20,21
Consensus guidelines on treatment for cutaneous RDD recommend either observation for asymptomatic disease or surgical excision for unifocal lesions with consideration of systemic therapy for refractory cutaneous disease.22,23 Most patients with cutaneous RDD have self-limited disease, but long-term follow-up is recommended following surgical excision to monitor for recurrence, especially if there is a residual positive margin.24 Radiation therapy also may have to be utilized for residual or recurrent disease that becomes symptomatic; however, further studies are needed to determine its efficacy in limiting recurrence.4,12,25 Systemic treatment options include immunosuppressive or immunomodulatory agents such as corticosteroids, methotrexate, and rituximab.5 There currently are no guidelines on length of follow-up, but surveillance is recommended initially at 4 months, followed by 6- to 12-month intervals.22
- Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. a newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63-70.
- Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7:19-73.
- Stefanato CM, Ellerin PS, Bhawan J. Cutaneous sinus histiocytosis (Rosai-Dorfman disease) presenting clinically as vasculitis. J Am Acad Dermatol. 2002;46:775-778.
- Dalia S, Sagatys E, Sokol L, et al. Rosai-Dorfman Disease: tumor biology, clinical features, pathology, and treatment. Cancer Control. 2014;21:322-327.
- Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020;73:697.
- Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. ed. Elsevier Saunders 2012.
- Salva KA, Stenstrom M, Breadon JY, et al. Possible association of cutaneous rosai-dorfman disease and chronic crohn disease: a case series report. JAMA Dermatol. 2014;150:177-181.
- Brenn T, Calonje E, Granter SR, et al. Cutaneous Rosai-Dorfman disease is a distinct clinical entity. Am J Dermatopathol. 2002; 24:385-391.
- Betini N, Munger AM, Rottmann D, et al. Rare presentation of Rosai- Dorfman disease in soft tissue: diagnostic findings and surgical treatment. Case Rep Surg. 2022;2022:8440836.
- Cravero JC, Ibrahim S. Recurrent soft tissue rosai dorfman disease of right medial thigh lipoma with lymph node involvement. Fed Pract. 2024;41(suppl 2):S20-S23
- Tenny SO, McGinness M, Zhang D, et al. Rosai-Dorfman disease presenting as a breast mass and enlarged axillary lymph node mimicking malignancy: a case report and review of the literature. Breast J. 2011;17:516-520.
- Goyal G, Ravindran A, Young JR, et al. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2020;105:348-357.
- Li H, Li D, Xia J, et al. Radiological features of Rosai-Dorfman disease: case series and review of the literature. Clin Radiol. 2022;77:E799-E805.
- Elbaz Younes I, Sokol L, Zhang L. Rosai-Dorfman disease between proliferation and neoplasia. Cancers. 2022;14:5271.
- Ravindran A, Rech KL. How I diagnose Rosai-Dorfman disease. Am J Clin Pathol. 2023;160:1-10.
- Kutlubay Z, Bairamov O, Sevim A, et al. Rosai-Dorfman disease: a case report with nodal and cutaneous involvement and review of the literature. Am J Dermatopathol. 2014;36:353-357.
- Luppi M, Barozzi P, Garber R, et al. Expression of human herpesvirus 6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol. 1998;153:815-823.
- Wang KH, Chen WY, Liu HN, et al. Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol. 2006;154:277-286.
- Vaiselbuh SR, Bryceson YT, Allen CE, et al. Updates on histiocytic disorders. Pediatr Blood Cancer. 2014;61:1329-1335.
- Ravindran A, Goyal G, Go RS, et al. Rosai-Dorfman disease displays a unique monocyte-macrophage phenotype characterized by expression of OCT2. Am J Surg Pathol. 2021;45:35-44.
- Hoogewerf CJ, van Baar ME, Middelkoop E, et al. Impact of facial burns: relationship between depressive symptoms, self-esteem and scar severity. Gen Hosp Psychiatry. 2014;36:271-276.
- Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018;131:2877-2890.
- Al-Khateeb THH. Cutaneous Rosai-Dorfman disease of the face: a comprehensive literature review and case report. J Oral Maxillofacial Surg. 2016;74:528-540.
- Cheng SP, Jeng KS, Liu CL. Subcutaneous Rosai–Dorfman disease: is surgical excision justified? J Eur Acad Dermatol Venereol. 2005; 19:747-750.
- Garcia RA, DiCarlo EF. Rosai-Dorfman disease of bone and soft tissue. Arch Pathol Lab Med. 2021;146:40-46.
- Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. a newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63-70.
- Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7:19-73.
- Stefanato CM, Ellerin PS, Bhawan J. Cutaneous sinus histiocytosis (Rosai-Dorfman disease) presenting clinically as vasculitis. J Am Acad Dermatol. 2002;46:775-778.
- Dalia S, Sagatys E, Sokol L, et al. Rosai-Dorfman Disease: tumor biology, clinical features, pathology, and treatment. Cancer Control. 2014;21:322-327.
- Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020;73:697.
- Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. ed. Elsevier Saunders 2012.
- Salva KA, Stenstrom M, Breadon JY, et al. Possible association of cutaneous rosai-dorfman disease and chronic crohn disease: a case series report. JAMA Dermatol. 2014;150:177-181.
- Brenn T, Calonje E, Granter SR, et al. Cutaneous Rosai-Dorfman disease is a distinct clinical entity. Am J Dermatopathol. 2002; 24:385-391.
- Betini N, Munger AM, Rottmann D, et al. Rare presentation of Rosai- Dorfman disease in soft tissue: diagnostic findings and surgical treatment. Case Rep Surg. 2022;2022:8440836.
- Cravero JC, Ibrahim S. Recurrent soft tissue rosai dorfman disease of right medial thigh lipoma with lymph node involvement. Fed Pract. 2024;41(suppl 2):S20-S23
- Tenny SO, McGinness M, Zhang D, et al. Rosai-Dorfman disease presenting as a breast mass and enlarged axillary lymph node mimicking malignancy: a case report and review of the literature. Breast J. 2011;17:516-520.
- Goyal G, Ravindran A, Young JR, et al. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2020;105:348-357.
- Li H, Li D, Xia J, et al. Radiological features of Rosai-Dorfman disease: case series and review of the literature. Clin Radiol. 2022;77:E799-E805.
- Elbaz Younes I, Sokol L, Zhang L. Rosai-Dorfman disease between proliferation and neoplasia. Cancers. 2022;14:5271.
- Ravindran A, Rech KL. How I diagnose Rosai-Dorfman disease. Am J Clin Pathol. 2023;160:1-10.
- Kutlubay Z, Bairamov O, Sevim A, et al. Rosai-Dorfman disease: a case report with nodal and cutaneous involvement and review of the literature. Am J Dermatopathol. 2014;36:353-357.
- Luppi M, Barozzi P, Garber R, et al. Expression of human herpesvirus 6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol. 1998;153:815-823.
- Wang KH, Chen WY, Liu HN, et al. Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol. 2006;154:277-286.
- Vaiselbuh SR, Bryceson YT, Allen CE, et al. Updates on histiocytic disorders. Pediatr Blood Cancer. 2014;61:1329-1335.
- Ravindran A, Goyal G, Go RS, et al. Rosai-Dorfman disease displays a unique monocyte-macrophage phenotype characterized by expression of OCT2. Am J Surg Pathol. 2021;45:35-44.
- Hoogewerf CJ, van Baar ME, Middelkoop E, et al. Impact of facial burns: relationship between depressive symptoms, self-esteem and scar severity. Gen Hosp Psychiatry. 2014;36:271-276.
- Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018;131:2877-2890.
- Al-Khateeb THH. Cutaneous Rosai-Dorfman disease of the face: a comprehensive literature review and case report. J Oral Maxillofacial Surg. 2016;74:528-540.
- Cheng SP, Jeng KS, Liu CL. Subcutaneous Rosai–Dorfman disease: is surgical excision justified? J Eur Acad Dermatol Venereol. 2005; 19:747-750.
- Garcia RA, DiCarlo EF. Rosai-Dorfman disease of bone and soft tissue. Arch Pathol Lab Med. 2021;146:40-46.
A Solitary Axillary Subcutaneous Mass
A Solitary Axillary Subcutaneous Mass
A 34-year-old man presented to our dermatology clinic for evaluation of a lesion in the right axilla of 1 year’s duration that had recently increased in size. The lesion was nontender and intermittently pruritic and was associated with focal hypohidrosis. The patient denied any fevers, chills, or recent weight change. His medical history was otherwise unremarkable. His only medications were daily ashwagandha and vitamin B and C supplements. On physical examination, a firm, 6-cm, subcutaneous nodule was noted in the right axilla with central alopecia and without a clear punctum. He had no palpable cervical, postauricular, or inguinal lymphadenopathy. The left axilla was clear, and there were no other relevant skin findings. Laboratory testing including a complete blood count, comprehensive metabolic panel, and sexually transmitted infections panel was unremarkable. Ultrasonography and subsequent magnetic resonance imaging of the right axilla showed a 4.9-cm nodule located in the subcutaneous fat with minimal deep infiltration and relatively smooth margins. An incisional biopsy of the lesion was performed.
Prurigo Nodularis: Moving Forward
Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.1 In the United States, Black patients are 3.4-times more likely than White patients to have PN.2 The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.
Treatment Guidelines
In 2020, an expert panel published consensus treatment guidelines for PN.1 The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.1
FDA-Approved Therapy
In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.3 Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.3
The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.6
Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.7 In a recent review of 701 patients with PN, the mean age was 64.8 years,5 highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.
Investigation of Janus Kinase Inhibitors
Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.10 Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.11 The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.
Other New Therapies
Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.12,13 Sustained remission was noted even after discontinuation of the medication.12 Alitretinoin, which has been demonstrated to be effective in treating dermatitis,14 was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.
Topical cannabinoids have shown benefit in the treatment of pruritus15 and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.
Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.16 Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.17 Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.18
Final Thoughts
Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.
- Elmariah S, Kim B, Berger T, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus [published online July 15, 2020]. J Am Acad Dermatol. 2021;84:747-760. doi:10.1016/j.jaad.2020.07.025
- Boozalis E, Tang O, Patel S, et al. Ethnic differences and comorbidities of 909 prurigo nodularis patients. J Am Acad Dermatol. 2018;79:714.
- Yosipovitch G, Mollanazar N, Ständer S, et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023;29:1180-1190. doi:10.1038/s41591-023-02320-9
- Huang AH, Williams KA, Kwatra SG. Prurigo nodularis: epidemiology and clinical features. J Am Acad Dermatol. 2020;83:1559-1565. doi:10.1016/j.jaad.2020.04.183
- Joel MZ, Hydol-Smith J, Kambala A, et al. Prevalence and comorbidity burden of prurigo nodularis in United States adults enrolled in the All of Us research program. J Am Acad Dermatol. 2023;89:1056-1058. doi:10.1016/j.jaad.2023.06.045
- Dupixent. Package insert. Regeneron Pharmaceuticals, Inc; 2017.
- Khosravi H, Zhang S, Anderson AM, et al. Dupilumab drug survival, treatment failures, and insurance approval at a tertiary care center in the United States. J Am Acad Dermatol. 2020;82:1023-1024. doi:10.1016/j.jaad.2019.12.034
- Liu T, Chu Y, Wang Y, et al. Successful treatment of prurigo nodularis with tofacitinib: the experience from a single center. Int J Dermatol. 2023;62:E293-E295. doi:10.1111/ijd.16568
- Molloy OE, Kearney N, Byrne N, et al. Successful treatment of recalcitrant nodular prurigo with tofacitinib. Clin Exp Dermatol. 2020;45:918-920. doi:10.1111/ced.14320
- Yin M, Wu R, Chen J, et al. Successful treatment of refractory prurigo nodularis with baricitinib. Dermatol Ther. 2022;35:E15642. doi:10.1111/dth.15642
- Klein B, Treudler R, Simon JC. JAK-inhibitors in dermatology—small molecules, big impact? overview of the mechanism of action, previous study results and potential adverse effects. J Dtsch Dermatol Ges. 2022;20:19-24. doi:10.1111/ddg.14668
- Chung BY, Um JY, Kang SY, et al. Oral alitretinoin for patients with refractory prurigo. Medicina (Kaunas). 2020;56:599. doi:10.3390/medicina56110599
- Maqbool T, Kraft JN. Alitretinoin for prurigo nodularis. Clin Exp Dermatol. 2021;46:362-363. doi:10.1111/ced.14385
- Grahovac M, Molin S, Prinz JC, et al. Treatment of atopic eczema with oral alitretinoin. Br J Dermatol. 2010;162:217-218. doi:10.1111/j.1365-2133.2009.09522.x
- Avila C, Massick S, Kaffenberger BH, et al. Cannabinoids for the treatment of chronic pruritus: a review. J Am Acad Dermatol. 2020;82:1205-1212. doi:10.1016/j.jaad.2020.01.036
- Deng J, Liao V, Parthasarathy V, et al. Modulation of neuroimmune and epithelial dysregulation in patients with moderate to severe prurigo nodularis treated with nemolizumab. JAMA Dermatol. 2023;159:977-985. doi:10.1001/jamadermatol.2023.2609
- Park B. Nemolizumab gets breakthrough therapy status for prurigo nodularis. Medical Professionals Reference website. Published December 9, 2019. Accessed November 13, 2023. https://www.empr.com/home/news/nemolizumab-gets-breakthrough-therapy-status-for-prurigo-nodularis/
- Labib A, Vander Does A, Yosipovitch G. Nemolizumab for atopic dermatitis. Drugs Today (Barc). 2022;58:159-173. doi:10.1358/dot.2022.58.4.3378056
Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.1 In the United States, Black patients are 3.4-times more likely than White patients to have PN.2 The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.
Treatment Guidelines
In 2020, an expert panel published consensus treatment guidelines for PN.1 The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.1
FDA-Approved Therapy
In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.3 Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.3
The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.6
Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.7 In a recent review of 701 patients with PN, the mean age was 64.8 years,5 highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.
Investigation of Janus Kinase Inhibitors
Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.10 Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.11 The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.
Other New Therapies
Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.12,13 Sustained remission was noted even after discontinuation of the medication.12 Alitretinoin, which has been demonstrated to be effective in treating dermatitis,14 was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.
Topical cannabinoids have shown benefit in the treatment of pruritus15 and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.
Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.16 Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.17 Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.18
Final Thoughts
Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.
Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.1 In the United States, Black patients are 3.4-times more likely than White patients to have PN.2 The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.
Treatment Guidelines
In 2020, an expert panel published consensus treatment guidelines for PN.1 The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.1
FDA-Approved Therapy
In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.3 Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.3
The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.6
Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.7 In a recent review of 701 patients with PN, the mean age was 64.8 years,5 highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.
Investigation of Janus Kinase Inhibitors
Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.10 Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.11 The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.
Other New Therapies
Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.12,13 Sustained remission was noted even after discontinuation of the medication.12 Alitretinoin, which has been demonstrated to be effective in treating dermatitis,14 was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.
Topical cannabinoids have shown benefit in the treatment of pruritus15 and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.
Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.16 Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.17 Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.18
Final Thoughts
Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.
- Elmariah S, Kim B, Berger T, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus [published online July 15, 2020]. J Am Acad Dermatol. 2021;84:747-760. doi:10.1016/j.jaad.2020.07.025
- Boozalis E, Tang O, Patel S, et al. Ethnic differences and comorbidities of 909 prurigo nodularis patients. J Am Acad Dermatol. 2018;79:714.
- Yosipovitch G, Mollanazar N, Ständer S, et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023;29:1180-1190. doi:10.1038/s41591-023-02320-9
- Huang AH, Williams KA, Kwatra SG. Prurigo nodularis: epidemiology and clinical features. J Am Acad Dermatol. 2020;83:1559-1565. doi:10.1016/j.jaad.2020.04.183
- Joel MZ, Hydol-Smith J, Kambala A, et al. Prevalence and comorbidity burden of prurigo nodularis in United States adults enrolled in the All of Us research program. J Am Acad Dermatol. 2023;89:1056-1058. doi:10.1016/j.jaad.2023.06.045
- Dupixent. Package insert. Regeneron Pharmaceuticals, Inc; 2017.
- Khosravi H, Zhang S, Anderson AM, et al. Dupilumab drug survival, treatment failures, and insurance approval at a tertiary care center in the United States. J Am Acad Dermatol. 2020;82:1023-1024. doi:10.1016/j.jaad.2019.12.034
- Liu T, Chu Y, Wang Y, et al. Successful treatment of prurigo nodularis with tofacitinib: the experience from a single center. Int J Dermatol. 2023;62:E293-E295. doi:10.1111/ijd.16568
- Molloy OE, Kearney N, Byrne N, et al. Successful treatment of recalcitrant nodular prurigo with tofacitinib. Clin Exp Dermatol. 2020;45:918-920. doi:10.1111/ced.14320
- Yin M, Wu R, Chen J, et al. Successful treatment of refractory prurigo nodularis with baricitinib. Dermatol Ther. 2022;35:E15642. doi:10.1111/dth.15642
- Klein B, Treudler R, Simon JC. JAK-inhibitors in dermatology—small molecules, big impact? overview of the mechanism of action, previous study results and potential adverse effects. J Dtsch Dermatol Ges. 2022;20:19-24. doi:10.1111/ddg.14668
- Chung BY, Um JY, Kang SY, et al. Oral alitretinoin for patients with refractory prurigo. Medicina (Kaunas). 2020;56:599. doi:10.3390/medicina56110599
- Maqbool T, Kraft JN. Alitretinoin for prurigo nodularis. Clin Exp Dermatol. 2021;46:362-363. doi:10.1111/ced.14385
- Grahovac M, Molin S, Prinz JC, et al. Treatment of atopic eczema with oral alitretinoin. Br J Dermatol. 2010;162:217-218. doi:10.1111/j.1365-2133.2009.09522.x
- Avila C, Massick S, Kaffenberger BH, et al. Cannabinoids for the treatment of chronic pruritus: a review. J Am Acad Dermatol. 2020;82:1205-1212. doi:10.1016/j.jaad.2020.01.036
- Deng J, Liao V, Parthasarathy V, et al. Modulation of neuroimmune and epithelial dysregulation in patients with moderate to severe prurigo nodularis treated with nemolizumab. JAMA Dermatol. 2023;159:977-985. doi:10.1001/jamadermatol.2023.2609
- Park B. Nemolizumab gets breakthrough therapy status for prurigo nodularis. Medical Professionals Reference website. Published December 9, 2019. Accessed November 13, 2023. https://www.empr.com/home/news/nemolizumab-gets-breakthrough-therapy-status-for-prurigo-nodularis/
- Labib A, Vander Does A, Yosipovitch G. Nemolizumab for atopic dermatitis. Drugs Today (Barc). 2022;58:159-173. doi:10.1358/dot.2022.58.4.3378056
- Elmariah S, Kim B, Berger T, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus [published online July 15, 2020]. J Am Acad Dermatol. 2021;84:747-760. doi:10.1016/j.jaad.2020.07.025
- Boozalis E, Tang O, Patel S, et al. Ethnic differences and comorbidities of 909 prurigo nodularis patients. J Am Acad Dermatol. 2018;79:714.
- Yosipovitch G, Mollanazar N, Ständer S, et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023;29:1180-1190. doi:10.1038/s41591-023-02320-9
- Huang AH, Williams KA, Kwatra SG. Prurigo nodularis: epidemiology and clinical features. J Am Acad Dermatol. 2020;83:1559-1565. doi:10.1016/j.jaad.2020.04.183
- Joel MZ, Hydol-Smith J, Kambala A, et al. Prevalence and comorbidity burden of prurigo nodularis in United States adults enrolled in the All of Us research program. J Am Acad Dermatol. 2023;89:1056-1058. doi:10.1016/j.jaad.2023.06.045
- Dupixent. Package insert. Regeneron Pharmaceuticals, Inc; 2017.
- Khosravi H, Zhang S, Anderson AM, et al. Dupilumab drug survival, treatment failures, and insurance approval at a tertiary care center in the United States. J Am Acad Dermatol. 2020;82:1023-1024. doi:10.1016/j.jaad.2019.12.034
- Liu T, Chu Y, Wang Y, et al. Successful treatment of prurigo nodularis with tofacitinib: the experience from a single center. Int J Dermatol. 2023;62:E293-E295. doi:10.1111/ijd.16568
- Molloy OE, Kearney N, Byrne N, et al. Successful treatment of recalcitrant nodular prurigo with tofacitinib. Clin Exp Dermatol. 2020;45:918-920. doi:10.1111/ced.14320
- Yin M, Wu R, Chen J, et al. Successful treatment of refractory prurigo nodularis with baricitinib. Dermatol Ther. 2022;35:E15642. doi:10.1111/dth.15642
- Klein B, Treudler R, Simon JC. JAK-inhibitors in dermatology—small molecules, big impact? overview of the mechanism of action, previous study results and potential adverse effects. J Dtsch Dermatol Ges. 2022;20:19-24. doi:10.1111/ddg.14668
- Chung BY, Um JY, Kang SY, et al. Oral alitretinoin for patients with refractory prurigo. Medicina (Kaunas). 2020;56:599. doi:10.3390/medicina56110599
- Maqbool T, Kraft JN. Alitretinoin for prurigo nodularis. Clin Exp Dermatol. 2021;46:362-363. doi:10.1111/ced.14385
- Grahovac M, Molin S, Prinz JC, et al. Treatment of atopic eczema with oral alitretinoin. Br J Dermatol. 2010;162:217-218. doi:10.1111/j.1365-2133.2009.09522.x
- Avila C, Massick S, Kaffenberger BH, et al. Cannabinoids for the treatment of chronic pruritus: a review. J Am Acad Dermatol. 2020;82:1205-1212. doi:10.1016/j.jaad.2020.01.036
- Deng J, Liao V, Parthasarathy V, et al. Modulation of neuroimmune and epithelial dysregulation in patients with moderate to severe prurigo nodularis treated with nemolizumab. JAMA Dermatol. 2023;159:977-985. doi:10.1001/jamadermatol.2023.2609
- Park B. Nemolizumab gets breakthrough therapy status for prurigo nodularis. Medical Professionals Reference website. Published December 9, 2019. Accessed November 13, 2023. https://www.empr.com/home/news/nemolizumab-gets-breakthrough-therapy-status-for-prurigo-nodularis/
- Labib A, Vander Does A, Yosipovitch G. Nemolizumab for atopic dermatitis. Drugs Today (Barc). 2022;58:159-173. doi:10.1358/dot.2022.58.4.3378056
