Burning urticarial plaques in a middle-aged woman

Abstract

A 52-year-old woman presented to the dermatology department with a 4-day history of hives and a burning sensation, which initially appeared on her abdomen and then spread within several hours to her back, neck, head, and extremities. She showed no improvement with oral antihistamines and prednisone at 40 mg daily. She denied systemic or respiratory symptoms, new medications, and known exposures. Individual lesions persisted longer than 24 hours. Numerous erythematous edematous plaques were seen on the back and extremities, intermixed with bruise-like patches (Fig 1, Fig 2, Fig 3). A punch biopsy was performed, and direct immunofluorescence was negative for immune complex deposition.Fig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3View Large Image Figure ViewerDownload Hi-res image Download (PPT)Question 1: What is the most appropriate next step?A.Check for glucose-6 phosphate dehydrogenase deficiencyB.Start doxycycline and niacinamideC.Order urinalysis and serum chemistriesD.Start high-dose aspirin and refer to the rheumatology departmentE.Start oral danazol and famotidineAnswers:A.Check for glucose-6 phosphate dehydrogenase deficiency – Incorrect. This would be necessary prior to starting systemic dapsone, which has shown partial or complete remission of cutaneous symptoms in a subset of patients with urticarial vasculitis (UV). However, dapsone is not the recommended first-line therapy.1Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Additionally, further workup is needed at this point to rule out end-organ damage and other acute processes.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarB.Start doxycycline and niacinamide – Incorrect. The clinical differential diagnosis includes early bullous pemphigoid, which can be treated with this regimen. However, the patient’s burning sensation is inconsistent with this diagnosis. Further, the biopsy findings are not characteristic of pemphigoid, which is ruled out by the negative direct immunofluorescence result.C.Order urinalysis and serum chemistries – Correct. The differential diagnosis includes chronic urticaria, UV, mast cell disorders, hypereosinophilic syndrome, lupus, neutrophilic urticarial dermatosis (NUD), and autoinflammatory disease. Some of these conditions confer the potential for end-organ damage, which should be checked using urinalysis and serum chemistries.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarD.Start high-dose aspirin and refer to the rheumatology department – Incorrect. Aspirin can be used to treat physical urticaria and urticarial vasculitis, which are included in the differential diagnosis; however, further workup should be done before considering this therapy.E.Start oral danazol and famotidine – Incorrect. A systematic review has shown both these medications to be ineffective for UV.1Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Additionally, further workup is needed to rule out end-organ damage and other acute processes.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarQuestion 2: Laboratory tests revealed an elevated neutrophil count (9.29/mm3; normal range [nr], 1.5-8.0/mm3), erythrocyte sedimentation rate (49 mm/hour; nr 1-20 mm/h), total serum protein level (8.6 g/dL; nr 6.0-8.3 g/dL), and C-reactive protein level (1.3 mg/L; nr 8-10 mg/L) as well as mild leukocytosis (11.2 × 109/L; nr 4.5 × 109/L-11.0 ×109/L). A comprehensive metabolic panel, complete blood count, and urinalysis were otherwise unremarkable. The level of serum C3 was normal and that of C4 was mildly elevated (53 mg/dL; nr 12-42 mg/dL). What is the most likely diagnosis?A.Normocomplementemic UVB.NUDC.Adult-onset Still diseaseD.Schnitzler syndromeE.Hypocomplementemic UV syndromeAnswers:A.Normocomplementemic UV – Correct. UV is a rare subtype of leukocytoclastic vasculitis that predominantly affects the skin. Individual hive-like lesions of UV characteristically persist longer than 24 hours, a trait distinguishing it from ordinary urticaria. A burning sensation often accompanies edematous plaques, which leave bruise-like patches upon resolution. Based on complement consumption, UV is categorized as normocomplementemic (80% of cases), hypocomplementemic, and rare hypocomplementemic UV syndrome. The serum levels of C3 and C4 should be checked to differentiate normocomplementemic UV from these.1Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (32) Google ScholarB.NUD – Incorrect. There can be diagnostic and histologic overlap between NUD and UV, and workup for underlying systemic, autoimmune conditions is necessary in unclear cases. Most patients with NUD have fever, polyarthritis, leukocytosis, and associated systemic disease (Still disease, lupus, or Schnitzler syndrome).3Kieffer C. Cribier B. Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature.Medicine (Baltimore). 2009; 88: 23-31https://doi.org/10.1097/MD.0b013e3181943f5eCrossref PubMed Scopus (173) Google Scholar This patient’s lack of systemic symptoms argues against NUD.C.Adult-onset Still disease – Incorrect. Our patient’s lack of fever and arthritis argues against adult-onset Still disease, which classically presents as evanescent salmon-colored papules.3Kieffer C. Cribier B. Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature.Medicine (Baltimore). 2009; 88: 23-31https://doi.org/10.1097/MD.0b013e3181943f5eCrossref PubMed Scopus (173) Google ScholarD.Schnitzler syndrome – Incorrect. Although skin biopsy for Schnitzler syndrome most commonly exhibits neutrophilic urticaria (with leukocytoclastic vasculitis seen in 25% of patients), these patients also present with fever, arthralgias, hepatosplenomegaly, and lymphadenopathy, which were absent in this patient.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarE.Hypocomplementemic UV syndrome – Incorrect. This is a severe syndrome defined by specific diagnostic criteria – urticaria for 6 months as well as hypocomplementemia and 2 of the following criteria: (1) vasculitis on biopsy, (2) arthralgia or arthritis, (3) uveitis or episcleritis, (4) glomerulonephritis, (5) recurrent abdominal pain, or (6) positive C1q precipitin test result with a low C1q level.4Lipsker D. Gattorno M. Other rheumatologic disorders and autoinflammatory diseases.in: Bolognia J.L. Schaffer J.V. Cerroni L. Dermatology. 4th ed. Elsevier, 2018: 728-729Google ScholarQuestion 3: Which of the following is most likely to be associated with this diagnosis?A.Cutaneous melanomaB.SporotrichosisC.Sjögren syndrome (SjS)D.Elevated serum immunoglobulin EE.There are no known specific triggers of UVAnswers:A.Cutaneous melanoma – Incorrect. However, UV may be associated with multiple malignancies, including lymphoma, leukemia, myelodysplasia, solid organ tumors, and myeloproliferative diseases.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarB.Sporotrichosis – Incorrect. However, there are infections that can trigger UV, including neurocysticercosis, mononucleosis, Lyme disease, Epstein-Barr virus, and hepatitis B or C.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarC.SjS – Correct. Cutaneous findings in patients with SjS may precede sicca symptoms by months or years and, if present, vasculitis is the most important cutaneous finding in patients with SjS because it portends increased morbidity and mortality.4Lipsker D. Gattorno M. Other rheumatologic disorders and autoinflammatory diseases.in: Bolognia J.L. Schaffer J.V. Cerroni L. Dermatology. 4th ed. Elsevier, 2018: 728-729Google Scholar Long-term follow-up with the rheumatology department may be warranted to monitor for gradual emergence of SjS or other underlying autoimmune conditions.D.Elevated serum immunoglobulin E – Incorrect. UV has been described in association with immunologic immunoglobulin G 4 disease.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarE.There are no known specific triggers of UV – Incorrect. UV may be associated with the same triggers as leukocytoclastic vasculitis in general: infections, medications, autoimmunity, or malignancy; however, it is often idiopathic.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar A 52-year-old woman presented to the dermatology department with a 4-day history of hives and a burning sensation, which initially appeared on her abdomen and then spread within several hours to her back, neck, head, and extremities. She showed no improvement with oral antihistamines and prednisone at 40 mg daily. She denied systemic or respiratory symptoms, new medications, and known exposures. Individual lesions persisted longer than 24 hours. Numerous erythematous edematous plaques were seen on the back and extremities, intermixed with bruise-like patches (Fig 1, Fig 2, Fig 3). A punch biopsy was performed, and direct immunofluorescence was negative for immune complex deposition. Question 1: What is the most appropriate next step?A.Check for glucose-6 phosphate dehydrogenase deficiencyB.Start doxycycline and niacinamideC.Order urinalysis and serum chemistriesD.Start high-dose aspirin and refer to the rheumatology departmentE.Start oral danazol and famotidine Answers:A.Check for glucose-6 phosphate dehydrogenase deficiency – Incorrect. This would be necessary prior to starting systemic dapsone, which has shown partial or complete remission of cutaneous symptoms in a subset of patients with urticarial vasculitis (UV). However, dapsone is not the recommended first-line therapy.1Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Additionally, further workup is needed at this point to rule out end-organ damage and other acute processes.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarB.Start doxycycline and niacinamide – Incorrect. The clinical differential diagnosis includes early bullous pemphigoid, which can be treated with this regimen. However, the patient’s burning sensation is inconsistent with this diagnosis. Further, the biopsy findings are not characteristic of pemphigoid, which is ruled out by the negative direct immunofluorescence result.C.Order urinalysis and serum chemistries – Correct. The differential diagnosis includes chronic urticaria, UV, mast cell disorders, hypereosinophilic syndrome, lupus, neutrophilic urticarial dermatosis (NUD), and autoinflammatory disease. Some of these conditions confer the potential for end-organ damage, which should be checked using urinalysis and serum chemistries.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarD.Start high-dose aspirin and refer to the rheumatology department – Incorrect. Aspirin can be used to treat physical urticaria and urticarial vasculitis, which are included in the differential diagnosis; however, further workup should be done before considering this therapy.E.Start oral danazol and famotidine – Incorrect. A systematic review has shown both these medications to be ineffective for UV.1Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Additionally, further workup is needed to rule out end-organ damage and other acute processes.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Question 2: Laboratory tests revealed an elevated neutrophil count (9.29/mm3; normal range [nr], 1.5-8.0/mm3), erythrocyte sedimentation rate (49 mm/hour; nr 1-20 mm/h), total serum protein level (8.6 g/dL; nr 6.0-8.3 g/dL), and C-reactive protein level (1.3 mg/L; nr 8-10 mg/L) as well as mild leukocytosis (11.2 × 109/L; nr 4.5 × 109/L-11.0 ×109/L). A comprehensive metabolic panel, complete blood count, and urinalysis were otherwise unremarkable. The level of serum C3 was normal and that of C4 was mildly elevated (53 mg/dL; nr 12-42 mg/dL). What is the most likely diagnosis?A.Normocomplementemic UVB.NUDC.Adult-onset Still diseaseD.Schnitzler syndromeE.Hypocomplementemic UV syndrome Answers:A.Normocomplementemic UV – Correct. UV is a rare subtype of leukocytoclastic vasculitis that predominantly affects the skin. Individual hive-like lesions of UV characteristically persist longer than 24 hours, a trait distinguishing it from ordinary urticaria. A burning sensation often accompanies edematous plaques, which leave bruise-like patches upon resolution. Based on complement consumption, UV is categorized as normocomplementemic (80% of cases), hypocomplementemic, and rare hypocomplementemic UV syndrome. The serum levels of C3 and C4 should be checked to differentiate normocomplementemic UV from these.1Kolkhir P. Grakhova M. Bonnekoh H. Krause K. Maurer M. Treatment of urticarial vasculitis: a systematic review.J Allergy Clin Immunol. 2019; 143: 458-466https://doi.org/10.1016/j.jaci.2018.09.007Abstract Full Text Full Text PDF PubMed Scopus (32) Google ScholarB.NUD – Incorrect. There can be diagnostic and histologic overlap between NUD and UV, and workup for underlying systemic, autoimmune conditions is necessary in unclear cases. Most patients with NUD have fever, polyarthritis, leukocytosis, and associated systemic disease (Still disease, lupus, or Schnitzler syndrome).3Kieffer C. Cribier B. Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature.Medicine (Baltimore). 2009; 88: 23-31https://doi.org/10.1097/MD.0b013e3181943f5eCrossref PubMed Scopus (173) Google Scholar This patient’s lack of systemic symptoms argues against NUD.C.Adult-onset Still disease – Incorrect. Our patient’s lack of fever and arthritis argues against adult-onset Still disease, which classically presents as evanescent salmon-colored papules.3Kieffer C. Cribier B. Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature.Medicine (Baltimore). 2009; 88: 23-31https://doi.org/10.1097/MD.0b013e3181943f5eCrossref PubMed Scopus (173) Google ScholarD.Schnitzler syndrome – Incorrect. Although skin biopsy for Schnitzler syndrome most commonly exhibits neutrophilic urticaria (with leukocytoclastic vasculitis seen in 25% of patients), these patients also present with fever, arthralgias, hepatosplenomegaly, and lymphadenopathy, which were absent in this patient.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarE.Hypocomplementemic UV syndrome – Incorrect. This is a severe syndrome defined by specific diagnostic criteria – urticaria for 6 months as well as hypocomplementemia and 2 of the following criteria: (1) vasculitis on biopsy, (2) arthralgia or arthritis, (3) uveitis or episcleritis, (4) glomerulonephritis, (5) recurrent abdominal pain, or (6) positive C1q precipitin test result with a low C1q level.4Lipsker D. Gattorno M. Other rheumatologic disorders and autoinflammatory diseases.in: Bolognia J.L. Schaffer J.V. Cerroni L. Dermatology. 4th ed. Elsevier, 2018: 728-729Google Scholar Question 3: Which of the following is most likely to be associated with this diagnosis?A.Cutaneous melanomaB.SporotrichosisC.Sjögren syndrome (SjS)D.Elevated serum immunoglobulin EE.There are no known specific triggers of UV Answers:A.Cutaneous melanoma – Incorrect. However, UV may be associated with multiple malignancies, including lymphoma, leukemia, myelodysplasia, solid organ tumors, and myeloproliferative diseases.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarB.Sporotrichosis – Incorrect. However, there are infections that can trigger UV, including neurocysticercosis, mononucleosis, Lyme disease, Epstein-Barr virus, and hepatitis B or C.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarC.SjS – Correct. Cutaneous findings in patients with SjS may precede sicca symptoms by months or years and, if present, vasculitis is the most important cutaneous finding in patients with SjS because it portends increased morbidity and mortality.4Lipsker D. Gattorno M. Other rheumatologic disorders and autoinflammatory diseases.in: Bolognia J.L. Schaffer J.V. Cerroni L. Dermatology. 4th ed. Elsevier, 2018: 728-729Google Scholar Long-term follow-up with the rheumatology department may be warranted to monitor for gradual emergence of SjS or other underlying autoimmune conditions.D.Elevated serum immunoglobulin E – Incorrect. UV has been described in association with immunologic immunoglobulin G 4 disease.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarE.There are no known specific triggers of UV – Incorrect. UV may be associated with the same triggers as leukocytoclastic vasculitis in general: infections, medications, autoimmunity, or malignancy; however, it is often idiopathic.2Davis M.D. van der Hilst J.C. Mimickers of urticaria: urticarial vasculitis and autoinflammatory diseases.J Allergy Clin Immunol Pract. 2018; 6: 1162-1170https://doi.org/10.1016/j.jaip.2018.05.006Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar None disclosed.