Cynthia Magro, MD

The Diagnosis: Cutaneous Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare benign non- Langerhans cell histiocytopathy that can manifest initially with lymph node involvement—classically, massive painless cervical lymphadenopathy.¹ Cutaneous Rosai-Dorfman disease (CRDD) is a variant that can be associated with lymph node and internal involvement, but more than 80% of cases lack extracutaneous involvement.^2,3 In cases with extracutaneous involvement, lymph node disease is most frequent.3 Cutaneous Rosai-Dorfman disease unassociated with extracutaneous disease is a benign self-limiting histiocytopathy that manifests as painless red-brown, yellow, or fleshcolored nodules, plaques, or papules that may become tender or ulcerated.⁴

Cutaneous Rosai-Dorfman disease represents a benign histiocytopathy of resident dendritic cell derivation.³ A characteristic immunohistochemical finding is S-100 positivity, which might suggest a Langerhans cell transdifferentiation phenotype, but other markers corroborative of a Langerhans cell phenotype—namely CD1a and langerin—will be negative. Biopsies typically show a mid to deep dermal histiocytic infiltration in a variably dense polymorphous inflammatory cell background comprised of a mixture of lymphocytes, plasma cells, and neutrophils.³ At times the extent of lymphocytic infiltration can be to a magnitude that resembles a lymphoma on histopathology. In our patient, lymphoma was excluded based on clinical presentation, as this patient lacked the typical symptoms of lymphadenopathy or B symptoms that come with B-cell lymphoma.⁵

The histiocytes in CRDD are characteristically large mononuclear cells exhibiting a low nuclear to cytoplasmic ratio reflective of the voluminous, nonvacuolated, watery cytoplasm. They have ill-defined cytoplasmic membranes resulting in a seemingly syncytial growth pattern. A hallmark of the histiocytes is emperipolesis characterized by intracytoplasmic localization of intact inflammatory cells including neutrophils, lymphocytes, and plasma cells.³

The differential diagnosis of CRDD includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. All of these conditions can be differentiated by their unique histopathologic and phenotypic characteristics.

Langerhans cell histiocytosis is a distinct clonal histiocytopathy that has a varied presentation ranging from cutaneous confined cases manifesting as a solitary lesion to one of disseminated cutaneous disease with the potential for multiorgan involvement. Regardless of the variant of LCH, the hallmark cell is one showing an eccentrically disposed, reniform nucleus with an open chromatin and abundant eosinophilic cytoplasm (Figure 1).⁶ Both LCH and CRDD stain positive for S-100. However, unlike the histiocytes in CRDD, those seen in LCH stain positive for CD1a and langerin and would not express factor XIIIA. Additionally, the neoplastic cells would not exhibit the same extent of CD68 positivity seen in CRDD.⁶ Treatment of LCH depends on the extent of disease, especially for the presence or absence of extracutaneous disease.⁷

A variant of LCH is indeterminate cell histiocytosis, which can be seen in neonates or adults. It represents a neoplastic proliferation of Langerhans cells that are devoid of Birbeck granules, reflective of an immature early phase of differentiation in the skin prior to the cells acquiring the Birbeck granule (as would be seen in neonates) or a later phase of differentiation after the mature Langerhans cell has encountered antigen and is en route to the lymph node (typically seen in adults).⁸ The phenotypic profile is identical to conventional LCH except the cells do not express langerin. Microscopically, the infiltrates are composed of Langerhans cells that are morphologically indistinguishable from classic LCH but without epidermotropism and exhibit a dominant localization in the dermis typically unassociated with other inflammatory cell elements (Figure 2).⁹

Xanthogranuloma is seen in young children (juvenile xanthogranuloma) as a solitary lesion, though a multifocal cutaneous variant and extracutaneous presentations have been described. Similar lesions can be seen in adults.¹⁰ These lesions are evolutionary in their morphology. In the inception of a juvenile xanthogranuloma, the lesions are highly cellular, and the histiocytes typically are poorly lipidized; there may be a dearth of other inflammatory cell elements. As the lesions mature, the histiocytes become lipidized, and characteristic Touton giant cells that exhibit a wreath of nuclei with peripheral lipidization may develop (Figure 3). In the later stages, there is considerable hyalinizing fibrosis, and the cells can acquire a spindled appearance. The absence of emperipolesis and the presence of notable lipidization are useful light microscopy features differentiating xanthogranuloma from CRDD.¹¹ Treatment of xanthogranuloma can range from a conservative monitoring approach to an aggressive approach combining various antineoplastic therapies with immunosuppressive agents.¹²

Solitary and multicentric reticulohistiocytoma is another form of resident dendritic cell histiocytopathy that can resemble Rosai-Dorfman disease. It is a dermal histiocytic infiltrate accompanied by a polymorphous inflammatory cell infiltrate (Figure 4) and can show variable fibrosis.¹³ One of the hallmarks is the distinct amphophilic cytoplasms, possibly attributable to nuclear DNA released into the cytoplasm from effete nuclei.¹³ The solitary form is unassociated with systemic disease, whereas the multicentric variant can be a paraneoplastic syndrome in the setting of solid and hematologic malignancies.¹⁴ In addition, in the multicentric variant, similar lesions can affect any organ but there can be a proclivity to involve the hand and knee joints, leading to a crippling arthritis.¹⁵ We presented a case of CRDD, a benign resident dendritic cell histiocytopathy that can manifest as a cutaneous confined process in the skin where the clinical course is characteristically benign. It potentially can be confused with LCH, indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. For a solitary lesion, intralesional triamcinolone injection and excision are options. Multifocal cutaneous disease or CRDD with notable extracutaneous disease may require systemic treatment.16 In our patient, one intralesional triamcinolone injection was performed with notable resolution.

The Diagnosis: Cutaneous Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare benign non- Langerhans cell histiocytopathy that can manifest initially with lymph node involvement—classically, massive painless cervical lymphadenopathy.¹ Cutaneous Rosai-Dorfman disease (CRDD) is a variant that can be associated with lymph node and internal involvement, but more than 80% of cases lack extracutaneous involvement.^2,3 In cases with extracutaneous involvement, lymph node disease is most frequent.3 Cutaneous Rosai-Dorfman disease unassociated with extracutaneous disease is a benign self-limiting histiocytopathy that manifests as painless red-brown, yellow, or fleshcolored nodules, plaques, or papules that may become tender or ulcerated.⁴

Cutaneous Rosai-Dorfman disease represents a benign histiocytopathy of resident dendritic cell derivation.³ A characteristic immunohistochemical finding is S-100 positivity, which might suggest a Langerhans cell transdifferentiation phenotype, but other markers corroborative of a Langerhans cell phenotype—namely CD1a and langerin—will be negative. Biopsies typically show a mid to deep dermal histiocytic infiltration in a variably dense polymorphous inflammatory cell background comprised of a mixture of lymphocytes, plasma cells, and neutrophils.³ At times the extent of lymphocytic infiltration can be to a magnitude that resembles a lymphoma on histopathology. In our patient, lymphoma was excluded based on clinical presentation, as this patient lacked the typical symptoms of lymphadenopathy or B symptoms that come with B-cell lymphoma.⁵

The histiocytes in CRDD are characteristically large mononuclear cells exhibiting a low nuclear to cytoplasmic ratio reflective of the voluminous, nonvacuolated, watery cytoplasm. They have ill-defined cytoplasmic membranes resulting in a seemingly syncytial growth pattern. A hallmark of the histiocytes is emperipolesis characterized by intracytoplasmic localization of intact inflammatory cells including neutrophils, lymphocytes, and plasma cells.³

The differential diagnosis of CRDD includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. All of these conditions can be differentiated by their unique histopathologic and phenotypic characteristics.

Langerhans cell histiocytosis is a distinct clonal histiocytopathy that has a varied presentation ranging from cutaneous confined cases manifesting as a solitary lesion to one of disseminated cutaneous disease with the potential for multiorgan involvement. Regardless of the variant of LCH, the hallmark cell is one showing an eccentrically disposed, reniform nucleus with an open chromatin and abundant eosinophilic cytoplasm (Figure 1).⁶ Both LCH and CRDD stain positive for S-100. However, unlike the histiocytes in CRDD, those seen in LCH stain positive for CD1a and langerin and would not express factor XIIIA. Additionally, the neoplastic cells would not exhibit the same extent of CD68 positivity seen in CRDD.⁶ Treatment of LCH depends on the extent of disease, especially for the presence or absence of extracutaneous disease.⁷

A variant of LCH is indeterminate cell histiocytosis, which can be seen in neonates or adults. It represents a neoplastic proliferation of Langerhans cells that are devoid of Birbeck granules, reflective of an immature early phase of differentiation in the skin prior to the cells acquiring the Birbeck granule (as would be seen in neonates) or a later phase of differentiation after the mature Langerhans cell has encountered antigen and is en route to the lymph node (typically seen in adults).⁸ The phenotypic profile is identical to conventional LCH except the cells do not express langerin. Microscopically, the infiltrates are composed of Langerhans cells that are morphologically indistinguishable from classic LCH but without epidermotropism and exhibit a dominant localization in the dermis typically unassociated with other inflammatory cell elements (Figure 2).⁹

Xanthogranuloma is seen in young children (juvenile xanthogranuloma) as a solitary lesion, though a multifocal cutaneous variant and extracutaneous presentations have been described. Similar lesions can be seen in adults.¹⁰ These lesions are evolutionary in their morphology. In the inception of a juvenile xanthogranuloma, the lesions are highly cellular, and the histiocytes typically are poorly lipidized; there may be a dearth of other inflammatory cell elements. As the lesions mature, the histiocytes become lipidized, and characteristic Touton giant cells that exhibit a wreath of nuclei with peripheral lipidization may develop (Figure 3). In the later stages, there is considerable hyalinizing fibrosis, and the cells can acquire a spindled appearance. The absence of emperipolesis and the presence of notable lipidization are useful light microscopy features differentiating xanthogranuloma from CRDD.¹¹ Treatment of xanthogranuloma can range from a conservative monitoring approach to an aggressive approach combining various antineoplastic therapies with immunosuppressive agents.¹²

Solitary and multicentric reticulohistiocytoma is another form of resident dendritic cell histiocytopathy that can resemble Rosai-Dorfman disease. It is a dermal histiocytic infiltrate accompanied by a polymorphous inflammatory cell infiltrate (Figure 4) and can show variable fibrosis.¹³ One of the hallmarks is the distinct amphophilic cytoplasms, possibly attributable to nuclear DNA released into the cytoplasm from effete nuclei.¹³ The solitary form is unassociated with systemic disease, whereas the multicentric variant can be a paraneoplastic syndrome in the setting of solid and hematologic malignancies.¹⁴ In addition, in the multicentric variant, similar lesions can affect any organ but there can be a proclivity to involve the hand and knee joints, leading to a crippling arthritis.¹⁵ We presented a case of CRDD, a benign resident dendritic cell histiocytopathy that can manifest as a cutaneous confined process in the skin where the clinical course is characteristically benign. It potentially can be confused with LCH, indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. For a solitary lesion, intralesional triamcinolone injection and excision are options. Multifocal cutaneous disease or CRDD with notable extracutaneous disease may require systemic treatment.16 In our patient, one intralesional triamcinolone injection was performed with notable resolution.

The Diagnosis: Cutaneous Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare benign non- Langerhans cell histiocytopathy that can manifest initially with lymph node involvement—classically, massive painless cervical lymphadenopathy.¹ Cutaneous Rosai-Dorfman disease (CRDD) is a variant that can be associated with lymph node and internal involvement, but more than 80% of cases lack extracutaneous involvement.^2,3 In cases with extracutaneous involvement, lymph node disease is most frequent.3 Cutaneous Rosai-Dorfman disease unassociated with extracutaneous disease is a benign self-limiting histiocytopathy that manifests as painless red-brown, yellow, or fleshcolored nodules, plaques, or papules that may become tender or ulcerated.⁴

Cutaneous Rosai-Dorfman disease represents a benign histiocytopathy of resident dendritic cell derivation.³ A characteristic immunohistochemical finding is S-100 positivity, which might suggest a Langerhans cell transdifferentiation phenotype, but other markers corroborative of a Langerhans cell phenotype—namely CD1a and langerin—will be negative. Biopsies typically show a mid to deep dermal histiocytic infiltration in a variably dense polymorphous inflammatory cell background comprised of a mixture of lymphocytes, plasma cells, and neutrophils.³ At times the extent of lymphocytic infiltration can be to a magnitude that resembles a lymphoma on histopathology. In our patient, lymphoma was excluded based on clinical presentation, as this patient lacked the typical symptoms of lymphadenopathy or B symptoms that come with B-cell lymphoma.⁵

The histiocytes in CRDD are characteristically large mononuclear cells exhibiting a low nuclear to cytoplasmic ratio reflective of the voluminous, nonvacuolated, watery cytoplasm. They have ill-defined cytoplasmic membranes resulting in a seemingly syncytial growth pattern. A hallmark of the histiocytes is emperipolesis characterized by intracytoplasmic localization of intact inflammatory cells including neutrophils, lymphocytes, and plasma cells.³

The differential diagnosis of CRDD includes Langerhans cell histiocytosis (LCH), indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. All of these conditions can be differentiated by their unique histopathologic and phenotypic characteristics.

Langerhans cell histiocytosis is a distinct clonal histiocytopathy that has a varied presentation ranging from cutaneous confined cases manifesting as a solitary lesion to one of disseminated cutaneous disease with the potential for multiorgan involvement. Regardless of the variant of LCH, the hallmark cell is one showing an eccentrically disposed, reniform nucleus with an open chromatin and abundant eosinophilic cytoplasm (Figure 1).⁶ Both LCH and CRDD stain positive for S-100. However, unlike the histiocytes in CRDD, those seen in LCH stain positive for CD1a and langerin and would not express factor XIIIA. Additionally, the neoplastic cells would not exhibit the same extent of CD68 positivity seen in CRDD.⁶ Treatment of LCH depends on the extent of disease, especially for the presence or absence of extracutaneous disease.⁷

A variant of LCH is indeterminate cell histiocytosis, which can be seen in neonates or adults. It represents a neoplastic proliferation of Langerhans cells that are devoid of Birbeck granules, reflective of an immature early phase of differentiation in the skin prior to the cells acquiring the Birbeck granule (as would be seen in neonates) or a later phase of differentiation after the mature Langerhans cell has encountered antigen and is en route to the lymph node (typically seen in adults).⁸ The phenotypic profile is identical to conventional LCH except the cells do not express langerin. Microscopically, the infiltrates are composed of Langerhans cells that are morphologically indistinguishable from classic LCH but without epidermotropism and exhibit a dominant localization in the dermis typically unassociated with other inflammatory cell elements (Figure 2).⁹

Xanthogranuloma is seen in young children (juvenile xanthogranuloma) as a solitary lesion, though a multifocal cutaneous variant and extracutaneous presentations have been described. Similar lesions can be seen in adults.¹⁰ These lesions are evolutionary in their morphology. In the inception of a juvenile xanthogranuloma, the lesions are highly cellular, and the histiocytes typically are poorly lipidized; there may be a dearth of other inflammatory cell elements. As the lesions mature, the histiocytes become lipidized, and characteristic Touton giant cells that exhibit a wreath of nuclei with peripheral lipidization may develop (Figure 3). In the later stages, there is considerable hyalinizing fibrosis, and the cells can acquire a spindled appearance. The absence of emperipolesis and the presence of notable lipidization are useful light microscopy features differentiating xanthogranuloma from CRDD.¹¹ Treatment of xanthogranuloma can range from a conservative monitoring approach to an aggressive approach combining various antineoplastic therapies with immunosuppressive agents.¹²

Solitary and multicentric reticulohistiocytoma is another form of resident dendritic cell histiocytopathy that can resemble Rosai-Dorfman disease. It is a dermal histiocytic infiltrate accompanied by a polymorphous inflammatory cell infiltrate (Figure 4) and can show variable fibrosis.¹³ One of the hallmarks is the distinct amphophilic cytoplasms, possibly attributable to nuclear DNA released into the cytoplasm from effete nuclei.¹³ The solitary form is unassociated with systemic disease, whereas the multicentric variant can be a paraneoplastic syndrome in the setting of solid and hematologic malignancies.¹⁴ In addition, in the multicentric variant, similar lesions can affect any organ but there can be a proclivity to involve the hand and knee joints, leading to a crippling arthritis.¹⁵ We presented a case of CRDD, a benign resident dendritic cell histiocytopathy that can manifest as a cutaneous confined process in the skin where the clinical course is characteristically benign. It potentially can be confused with LCH, indeterminate cell histiocytosis, xanthogranuloma, and reticulohistiocytoma. For a solitary lesion, intralesional triamcinolone injection and excision are options. Multifocal cutaneous disease or CRDD with notable extracutaneous disease may require systemic treatment.16 In our patient, one intralesional triamcinolone injection was performed with notable resolution.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.

Hydralazine-induced antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is a complex entity characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement. Although it is an established entity, a PubMed search of articles indexed for MEDLINE using the terms hydralazine vasculitis, ANCA positive vasculitis, and hydralazine associated vasculitis revealed a limited number of cases reported in the dermatologic literature (Table 1).^1-6 We report a rare case of hydralazine-induced vasculitis associated with airway compromise and severe gastrointestinal tract bleeding.

RELATED ARTICLE: Sweet Syndrome Associated With Hydralazine-Induced Lupus Erythematosus

Case Report

A 71-year-old woman with a history of end-stage renal disease treated with hemodialysis, as well as hypertension, diabetes mellitus, and ischemic cardiomyopathy, presented to our emergency department with odynophagia, muscle weakness, shortness of breath, and a distinctive mucocutaneous eruption on the left eyelid, lips, and tongue of 2 days’ duration. Physical examination revealed an ill-appearing, afebrile, dyspneic woman with swelling of the left upper eyelid, conjunctival injection, ulcerations on the lips and tongue, and tense hemorrhagic vesicles, as well as vesiculopustules on the elbows, palms, fingers, lower legs, and toes (Figure 1). Given her dyspnea, flexible laryngoscopy was performed and revealed ulceration and edema involving the epiglottis, aryepiglottic folds, and arytenoids. The patient was intubated for airway protection and started on intravenous dexamethasone.

An extensive diagnostic workup commenced. Bacterial, viral, and fungal cultures of blood, skin tissue, and respiratory secretions, as well as human immunodeficiency virus screening, were all negative. Specifically, a tissue culture was performed on skin from the left thigh, viral culture and direct fluorescent antibody were performed on a vesicle on the right knee for herpes simplex virus and herpes zoster, and a superficial wound culture was taken from the left arm, all showing no growth. The patient’s home medications were reviewed and revealed she was currently taking hydralazine (100 mg 3 times daily), which was started approximately 2 years prior. Laboratory results revealed a positive antinuclear antibody titer of 1:320 (diffuse pattern), positive antihistone antibody, and positive ANCA with cytoplasmic and perinuclear accentuation (Table 2). Enzyme-linked immunosorbent assays showed IgG antibodies to myeloperoxidase (MPO) and proteinase 3 (Table 2). Skin biopsies from the right lower leg and right upper arm were compatible with necrotizing leukocytoclastic vasculitis characterized by mural and luminal fibrin deposition involving capillaries and venules of the superficial and deep dermis (Figure 2). The vessel walls were infiltrated by neutrophils with concomitant leukocytoclasia. Vessels in the mid dermis were occluded by cellular fibrin thrombi. Foci of neutrophilic interface dermatitis with subepidermal bulla formation were observed. Infectious stains were negative. On direct immunofluorescence, striking homogeneous mantles of staining of IgG were present within the cutaneous vasculature.

Because the infectious workup was negative and there was no other known instigating factor of vasculitis, concern for a drug-induced process prompted thorough review of the patient’s home medications and discontinuation of hydralazine. A diagnosis of hydralazine-associated cutaneous vasculitis was made when laboratory workup confirmed no underlying infectious process or rheumatologic condition and the medication known to cause her symptoms was on her medication list. The dexamethasone dose was increased, leading to rapid improvement of her mucocutaneous findings; however, on initiation of a steroid taper, she developed substantial gastrointestinal tract bleeding. An esophageal biopsy revealed a neutrophil-rich necrotizing process that essentially mirrored the cutaneous biopsy consistent with vasculitic involvement of the gastrointestinal tract. Steroids were again increased with resolution in gastrointestinal tract bleeding.

Comment

Our case highlights a distinct clinical presentation of hydralazine-induced ANCA-positive cutaneous vasculitis associated with severe involvement of the aerodigestive tract with gastrointestinal tract bleeding and airway compromise requiring intubation. Although discontinuation of hydralazine and in certain cases the addition of immunosuppressive agents may be adequate for resolution of symptoms, some cases progress despite treatment, leading to skin grafting, amputation, and death.^3,4 Therefore, early recognition of hydralazine-induced cutaneous vasculitis and discontinuation of hydralazine are of paramount importance.

Reporting hydralazine-induced vasculitis is valuable because of its unique cutaneous, extracutaneous, and serologic findings. In our case, the cutaneous vasculitis presented clinically with acral hemorrhagic vesiculopustules and necrotic ulcerations resembling septic emboli, as opposed to classic lesions of palpable purpura typical of drug-induced leukocytoclastic vasculitis. Similar cutaneous findings have been described in other cases of hydralazine-induced vasculitis, indicating that this pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration is characteristic of this entity.^1,3,6 In addition, involvement of the oral cavity, larynx, and gastrointestinal tract have been reported in cases of hydralazine-induced vasculitis, indicating mucosal involvement is an important feature of this disease.^3,6 Although involvement of the oral mucosa, larynx, and acral sites appears to be characteristic, the exact basis for this site localization remains elusive. A precedent has been established for a similar pattern of intraoral and laryngeal involvement in other ANCA-positive vasculitic syndromes, most notably Wegener granulomatosis.⁷ Similarly, there are certain occlusive vasculitic syndromes that show acral localization including chronic septic vasculitis and vasculitis of collagen vascular disease.

Serologic trends can aid in diagnosing hydralazine-induced vasculitis. In theory, the nonspecific cutaneous findings, often in association with joint pain and positive antinuclear antibodies, may lead clinicians to the misdiagnosis of a connective tissue disease, such as systemic lupus erythematosus (SLE). However, unlike SLE, hydralazine-induced vasculitis is associated with positive ANCAs, while antibodies against double-stranded DNA, a highly specific antibody for SLE, are uncommon.^8,9 Our patient had both positive perinuclear ANCA with cytoplasmic ANCA as well as a positive antihistone antibodies, a combination highly suggestive of a drug-induced process.

Despite the often acute presentation of hydralazine-induced ANCA-positive vasculitis, afflicted patients have characteristically been on the drug for a long period of time. Our patient is exemplary of most reported cases, as the time from initiation of hydralazine to onset of vasculitis was 2 years.⁴

The mechanism by which hydralazine causes this reaction is still a matter of debate. It seems clear that there are certain at-risk populations, such as slow acetylators and patients with an underlying hypercoagulable state. There are several theories by which hydralazine induces autoantibody formation. The first involves hydralazine metabolization by MPO released from activated neutrophils to form reactive intermediate metabolites. Such metabolites can be cytotoxic and may cause abnormal degradation of chromatin in susceptible individuals, leading to an autoimmune response against histone-DNA complexes. Alternatively, hydralazine may act as a hapten and bind to MPO, inducing an immune response against the hydralazine-MPO complex, with resultant formation of anti-MPO antibodies in susceptible individuals.¹⁰

Conclusion

Hydralazine-induced ANCA-positive vasculitis is a syndromic complex characterized by a distinctive clinical presentation comprising acral hemorrhagic vesiculopustules and necrotic ulcerations, at times with severe mucosal involvement along with a characteristic ANCA-positive serologic profile. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. Older age of onset, female gender, and underlying autoimmune diatheses likely define important risk factors. With more recognition and reporting of this disease, further trends in both clinical and serological presentation will emerge.