Neutrophilic Urticarial Dermatosis Research Articles

Neutrophilic urticarial dermatosis without systemic disease: case report

Neutrophilic urticarial dermatosis (NUD) is an uncommon and not well understood disease. We report a 24-year-old female with persistent present with pruritic and painful urticarial plaques unresponsive to convential treatment. Histopathologically, it demonstrates a perivascular and interstitial neutrophilic infiltrate with leukocytoclasia without evidence of vasculitis or dermal edema consistent with neutrophilic urticarial dermatosis. Further investigations to rule out underlying autoimmune, autoinflammatory and gentic systemic disease were negative. Furthermore, the cutaneous eruption was resistant to multiple therapeutic interventions including colchicine and dapsone treatment, and show significant response to treatment with anakinra, interleukin-1 receptor antagonist. Based on literature review, the case reported here is the second case with clinical and pathologic features of NUD without systemic disease and the first case of NUD that showed resistant to colchicine and dapsone treatment, with adequate response to anakinra.

Annular Neutrophilic Dermatoses.

Neutrophilic dermatoses (NDs) are a group of diseases characterized by sterile neutrophilic infiltrations. Many of the NDs usually present with infiltrated erythematous plaques, nodules, urticarial plaques, or pustules. Lesions may show variability, and atypical presentations may develop among the NDs. Annular lesions have been reported in many NDs and may lead to diagnostic problems. Clinical features and histopathologic findings such as localization of the neutrophilic infiltrate, existence of other cell types, and absence of true vasculitis may be helpful to distinguish NDs. Some of these NDs are associated with infections, inflammatory diseases, and malignancies. In most NDs, systemic steroids and dapsone are very effective and usually first choices. Colchicine, antimicrobials, such as doxycycline, tetracycline, and sulphapyridine, and other immunosuppressants, such a cyclosporine, methotrexate, and mycophenolate mofetil have been used successfully in treating many NDs. TNF-α inhibitors have also been used successfully in many NDs. JAK kinase inhibitors are effective in CANDLE syndrome, anakinra in neutrophilic urticarial dermatosis, and intravenous immunoglobulin in resistant pyoderma gangrenosum. We discuss the diagnosis and management of the NDs that may present with annular lesions.

Systemic autoinflammatory disorders.

Inflammation is a physiologic defense mechanism against an out-side attack. Usually, it resolves after the removal of noxious causes, but systemic autoinflammatory disorders (SAIDs) have recurrent or repeated acute inflammation through uncontrolled gene function, which can present as gain-of-function or loss-of-function of a gene during inflammation. Most SAIDs are hereditary autoinflammatory diseases and develop by dysregulation of innate immunity through various pathways including inflammasomes, endoplasmic reticulum stress, nuclear factor-κB dysregulation, and interferon production. The clinical manifestations include periodic fever with various skin findings such as neutrophilic urticarial dermatosis, or vasculitic lesions. Some SAID cases stem from immunodeficiency or allergic reactions related to monogenic mutation. The diagnosis of SAIDs is based on clinical findings of systemic inflammation and genetic confirmation, and have to exclude infections or malignancies. Moreover, a genetic study is essential for clinical features to be suspect SAID with or without a family history. Treatment is based on understanding the immunopathology of SAID, and targeted therapy to control disease flares, reduce recurrent acute phases and prevent serious complications. Diagnosing and treating SAID requires understanding its comprehensive clinical features and pathogenesis related to genetic mutation.

Cutaneous involvement in VEXAS syndrome: clinical and histopathologic findings.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disease with frequent cutaneous manifestations. We conducted a retrospective study of all patients with genetically confirmed VEXAS syndrome seen at our institution. Available clinical photographs and skin biopsy slides were reviewed. Cutaneous manifestations developed in 22/25 (88%) patients with VEXAS syndrome. From this group, 10/22 (45%) developed skin involvement before or at the time of other clinical features of VEXAS. Twenty distinct dermatologic presentations of VEXAS from 14 patients were reviewed, and histopathologic patterns were classified as follows: neutrophilic urticarial dermatosis (n=5, 25%), leukocytoclastic/urticarial vasculitis (n=4, 20%), urticarial tissue reaction (n=4, 20%), neutrophilic dermatosis (n=3, 15%), neutrophilic panniculitis (n=2, 10%), and nonspecific chronic septal panniculitis (n=2, 10%). Common systemic findings included macrocytic anemia (96%), fever (88%), thrombocytopenia (76%), weight loss (76%), ocular inflammation (64%), pulmonary infiltrates (56%), deep venous thrombosis or pulmonary embolism (52%), and inflammatory arthritis (52%). Cutaneous involvement is a common feature of VEXAS syndrome, and histopathologic findings exist on a spectrum of neutrophilic inflammatory dermatoses.

A RED HERRING? PAINFUL URTICARIA FOLLOWING AMPICILLIN CONTACT EXPOSURE

<h3>Introduction</h3> Acute painful urticaria is often caused by an underlying systemic illness or exposure to a drug or vaccine. Occasionally, no cause is found which prompts consideration of other etiologies. <h3>Case Description</h3> A 22-year-old male nurse with a history of Amoxicillin allergy (delayed-onset exanthematous rash) presented to the ED with an urticarial rash, 48 hours following an accidental ampicillin exposure to his right hand at work. Initial symptoms started 24 hours later with painful swelling of bilateral hands. Despite treatment with prednisone and diphenhydramine, a painful, pruritic urticarial rash developed on his arms, trunk, gluteal cleft, and knees. New onset arthralgias and angioedema prompted presentation to the ED, where he was treated for anaphylaxis and started on intravenous steroids and antihistamines. Initial labs showed a neutrophilic leukocytosis and a mild elevation in CRP. Workup revealed normal complement with negative infectious and rheumatologic evaluations. A punch biopsy showed "perivascular and interstitial neutrophilic infiltrate with few eosinophils," concerning for neutrophilic urticarial dermatosis (NUD) or a serum sickness like drug reaction (SSLR). Seven days after exposure, symptoms began to improve leading to discharge. <h3>Discussion</h3> NUD often occurs in the setting of an underlying systemic disease such as SLE or adult-onset Still's disease. Recently, SSLRs have also been identified as a cause of NUD. SSLRs are not well understood and have not previously been described as systemic contact reactions. Although, ampicillin exposure was thought to be a red herring in this case, further investigation is needed to better understand a potential relationship when another etiology cannot be identified.

Neutrophilic urticarial dermatosis of the extremities: Report of one case

Sir, Neutrophilic urticarial dermatosis (NUD) is a recently described entity part of the spectrum of neutrophilic dermatoses (ND). It is often associated with inflammatory diseases or neoplasms, such as hemopathies. Herein, we report the case of a 67-year-old patient with a history of pulmonary tuberculosis, treated and declared cured, chronic obstructive pulmonary disease, operated prostatic adenoma, smoking at a rate of 50 pack-years, weaned four months ago, alcoholism, and cannabis use, weaned sixteen years ago. The patient presented with non-itchy, slightly infiltrated, maculopapular, erythematous-to-purplish plaques, which were present only in the extremities of the upper and lower limbs (Figs. 1a – 1c). The rash had persisted for almost ten years in relapses or remissions and progressed against a background of fever, polyarthralgia, and asthenia.

Burning urticarial plaques in a middle-aged woman

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.

Neutrophilic dermatoses

Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND are classified based upon the localization of neutrophils within the skin and clinical features. Recent findings suggest that ND are due to two main mechanisms: i) a polyclonal hereditary activation of the innate immune system (polygenic or monogenic); or ii) a clonal somatic activation of myeloid cells such as encountered in myelodysplastic syndrome or VEXAS syndrome. ND belong to internal medicine as a great number of patients with ND suffer from an underlying condition (such as hematological malignancy, inflammatory bowel disease, auto-immune and auto-inflammatory diseases). ND are diagnoses of exclusion and physicians should always consider differential diagnoses, particularly skin infections. Here, we review the pathophysiology and classification of the main ND (i.e., subcorneal pustular dermatosis (Sneddon–Wilkinson Disease) and Intercellular IgA dermatoses, aseptic pustulosis of the folds, Sweet syndrome, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, erythema elevatum diutinum, neutrophilic urticarial dermatosis and neutrophilic panniculitis), their clinical and histopathological features, and we highlight the investigations that are useful to identify ND-associated diseases and to exclude the differential diagnoses.

Successful Treatment of Schnitzler Syndrome with Tocilizumab

Introduction: Schnitzler syndrome (SchS) is an uncommon, autoinflammatory disorder, which is hard to be controlled by conventional therapy. Recently, anti-interleukin (IL)-1 agents has been reported as the most effective therapeutic regimen. Here, we reported that a patient with SchS has achieved a rapid remission after using tocilizumab, an anti-IL-6 receptor antagonist. Case presentation: A 56-year-old man presented with recurrent generalized urticarial rash and knee soreness, and had irregular febrile episode during these two years, accompanying with or without the skin eruptions. Main laboratory evaluations were notable for inflammatory indicators. Skin biopsy revealed that numerous neutrophils in the superficial dermis and around the vascular vessels. Myeloid inverse conversion of his knee joints was discovered. As soon as the diagnosis of SchS was made, tocilizumab intravenously 400 mg was given, and the patient showed no relapse in 30 weeks follow-up. Discussion: Cytokine activation and elevated inflammasome is involved in the disorder of Schs, in which IL-1 and IL-6 have been considered as important factors. To diagnose Schs, it needs to be distinguished from some autoimmune diseases associated with neutrophilic urticarial dermatosis such as cryopyrin-associated periodic syndromes and adult-onset still disease. Although IL-1 blockers are widely used and get curative effect recent years, patients failed to response to IL-1 blockers may benefit from anti–IL-6 treatment. Conclusion: Anti-IL-6 therapy may be a reliable candidate for Schs from our experience.

A patient with urticarial lesions, recurrent fever, and IgM-type monoclonal gammopathy

Schnitzler syndrome is a rare acquired autoinflammatory syndrome. It presents with an urticarial rash and a monoclonal gammopathy, usually of the IgM kappa type. In addition, patients can present with bone and/or joint pain, recurrent fever, asthenia, weight loss, myalgia, headache, lymphadenopathy, hepatomegaly, or splenomegaly. An elevation of blood inflammation markers is commonly found. Skin biopsy of the urticarial rash reveals neutrophilic infiltrate, known as neutrophilic urticarial dermatosis. To confirm the diagnosis, two sets of diagnostic criteria have been established. The syndrome shares many features with other autoinflammatory disorders, such as adult-onset Still's disease and NLRP3-auto-inflammatory disorders (NLRP3-AID, formerly known as cryopyrin-associated periodic syndromes, or CAPS). The pathogenesis of the disease is not yet fully understood; however, it is believed that interleukin (IL)-1β plays a crucial role and explains the excellent effectiveness of IL-1 blocking agents. It is a chronic disease, and some patients develop lymphoproliferative disease, and seldom AA amyloidosis.

Neutrophilic urticarial dermatosis following BNT162b2 (Pfizer–BioNTech) COVID‐19 vaccination

We reported a patient with neutrophilic urticaria following COVID-19 vaccination who required high-dose steroid treatment. Dear Editor, Many people around the world have received the COVID-19 vaccination and cutaneous reactions, for example, delayed significant local reaction, local injection site reaction, urticarial eruption, and morbilliform eruption, are widely reported. While cutaneous reactions to the vaccine are generally minor and self-limited, we report a patient with neutrophilic urticarial dermatosis following COVID-19 vaccination who required high-dose steroid treatment. An 86-year-old woman was brought to our hospital by emergency transport due to difficulty moving, fever, and nonpruritic urticarial patches and plaques on her whole body (Figure 1A Day 0). Within 5 h of receiving the first dose of the COVID-19 vaccine (BNT162b2), she noticed erythema on her neck and lower limbs (Day-4). Several days later, the eruption became widespread, involving her face, arms, chest, and back. Individual lesions did not resolve after several hours. She fell and was unable to get up, prompting her son to call an ambulance. Her vital signs were normal, and she had no breathing difficulties. Blood tests revealed a high C-reactive protein level (6.9 mg/dl) and a high white blood cell count (22,300/μl) with neutrophilia (86.8%). Methylprednisolone (125 mg) was administered by intravenous drip. On Day 1, the erythema on her face, ears, and trunk improved, but erythematous plaque persisted on her thighs (Figure 1A Day 1). The skin lesions were clinically diagnosed as erythema multiforme. Oral prednisolone (25 mg/day, 0.5 mg/kg/day) was started. On Day 2, the plaque on her thighs disappeared within 24 h of onset, but new erythematous lesions appeared on her trunk and knees (Figure 1A Day 2) accompanied by a high fever (38.7°C). The dose of prednisolone was increased to 50 mg/day (1 mg/kg/day). Pathologic analysis of a skin biopsy sample obtained from an erythematous lesion on her thigh (Figure 1A Day 1) revealed infiltration of inflammatory cells (Figure 1B,C) and diffuse neutrophil infiltration with nuclear dust (Figure 1D) in the dermis. Neither vasculitis nor liquefaction was observed. She was diagnosed with neutrophilic urticarial dermatosis. On Day 3, the erythema and fever disappeared. On Day 19, the prednisolone was tapered off. Neutrophilic urticarial dermatosis is a rare disease. Edematous erythema, clinically similar to urticaria, recurs in 24-48 h, with fever and arthritis. It may be associated with systemic lupus erythematosus and adult-onset Still's disease.1 Neutrophilic urticarial dermatosis after COVID-19 vaccination has not yet been reported. Shimabukuro2 reported that the frequency of anaphylaxis with BNT162b2 is 11.1 cases per million. Urticaria was observed in 18 of 74 patients presenting with cutaneous reactions due to BNT162b2.3 Of 18 people presenting with urticaria after the first vaccination, only four developed urticaria after the second vaccination.3 In this case, she developed erythema within 5 h of receiving the COVID-19 vaccine (BNT162b2). This might be a late phase reaction by recruiting neutrophils. It is important to keep in mind that cutaneous reactions associated with the COVID-19 vaccination, although usually mild, may be severe. Further accumulation of similar cases will help to elucidate the underlying mechanisms of neutrophilic urticarial dermatosis. Approval of the research protocol: N/A. Informed Consent: Obtained from the patient. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. The authors declare no conflict of interest.

Schnitzler Syndrome: the paradigm of an acquired adult-onset auto-inflammatory disease.

Schnitzler Syndrome is a rare acquired auto-inflammatory syndrome defined by an urticarial eruption and a monoclonal gammopathy, mainly of the IgM kappa isotype. It shares many clinical and biological features with other autoinflammatory disorders such as NLRP3-auto-inflammatory disorders (NLRP3-AID, formerly cryopyrin associated periodic syndromes or CAPS) or adult-onset Still disease (AOSD). Hence, recurrent fever, urticarial rash with a neutrophilic infiltrate on skin biopsy (i.e. neutrophilic urticarial dermatosis or NUD) and a significant elevation of blood inflammation markers are commonly found in Schnitzler Syndrome as well as in NLRP3-AID or AOSD. IL-1ß plays a crucial role in the pathogenesis and explains the clinical symptoms of Schnitzler Syndrome. This is emphasized by the spectacular effectiveness of IL-1 blocking therapies, especially anakinra. IL-1 blocking therapies are efficient on the inflammation-linked symptoms but not on the monoclonal component. The evolution is chronic and about 15-20% of patients may develop lymphoproliferative disease, in particular Waldenström disease, a proportion similar to patients with IgM monoclonal gammopathy of undetermined significance, and more rarely AA-amyloidosis.

13026 Urticaria and a rare mutation: A case of neutrophilic urticarial dermatosis

Neutrophilic urticarial dermatosis (NUD) is a rare condition characterized by a transient urticarial eruption which is typically accompanied by systemic symptoms including fevers, arthralgias, night sweats and fatigue. About 50 cases have been described to date. The histology is specific revealing a neutrophilic interstitial and perivascular infiltrate with leukocytoclasia but lacking leukocytoclastic vasculitis. In this case we discuss a 59-year-old Caucasian woman with history of CML treated with dasatinib who presented with a 10-month history of painful urticaria, arthralgias, fevers and fatigue.

Neutrophilic dermatoses with unusual and atypical presentations

Neutrophilic dermatoses (NDs) are a group of reactive, noninfectious autoinflammatory diseases characterized by (1) infiltration of the epidermis, dermis, and or/hypodermis by neutrophils; (2) their association with distinct diseases (eg, hematologic malignancy and chronic inflammatory diseases); (3) potential extracutaneous involvement; and (4) response to anti-inflammatory drugs, such as corticosteroids, dapsone, colchicine, and novel biologic therapies, such as the anti–interleukin-1 blockade. Although distinct NDs have been described, transitional forms with overlapping features are often identified. These justify a simplified classification of NDs with three major forms: superficial (epidermal or pustular) NDs, dermal (en plaques) NDs, and deep NDs.We review selected or novel variants of NDs, including subcorneal pustular dermatosis, the group of immunoglobulin A neutrophilic dermatoses, amicrobial pustular dermatosis of the folds, and neutrophilic urticarial dermatosis, as well as atypical forms of Sweet syndrome and pyoderma gangrenosum closely mimicking severe infectious diseases. Knowledge of these variants is essential for proper diagnosis, adequate management, and avoidance of a dangerous escalation of therapy, such as unnecessary immunosuppression or extensive surgery.

Neutrophilic urticarial dermatosis: an entity bridging monogenic and polygenic autoinflammatory disorders, and beyond.

Neutrophilic urticarial dermatosis (NUD) has been described in 2009. Clinically, it is an eruption of rose or red macules or slightly elevated plaques, vanishing within 24h. It occurs mostly on the trunk and the limbs. Extracutaneous signs such as fever or joint pain can be associated. The histopathological findings are a dense perivascular and interstitial infiltrate of neutrophils with leucocytoclasia but without vasculitis. It is often associated with other systemic diseases such as Schnitzler syndrome, adult-onset Still disease (AOSD), cryopyrin-associated periodic syndrome (CAPS) and Lupus erythematosus (LE). The pathogenesis of NUD is not well established but its association with CAPS and AOSD suggests that NUD is linked to autoinflammation. The management of NUD depends on the clinical findings and the potential associated systemic condition. Neutrophil migration inhibitors, such as dapsone or colchicine, and IL-1 antagonists, in particular, anakinra, are the main therapeutic options for the treatment of NUD. The prognostic value of NUD, especially when occurring in the setting of LE is not known and needs to be further investigated.

Neutrophilic urticarial dermatosis: A review.

Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis. In clinical terms, it consists of a chronic or recurrent eruption comprising slightly elevated, pink to reddish plaques or macules. The elementary lesion lasts 24 to 48hours and resolves without leaving any residual pigmentation. Extra-cutaneous signs are common, particularly fever or arthralgia. At histopathology, the dermis contains dense neutrophilic interstitial infiltrate with leukocytoclasis, but without fibrinoid necrosis of vessel walls. NUD often occurs in a setting of underlying systemic disease. The most commonly associated diseases are adult-onset Still's disease, Schnitzler syndrome, lupus erythematosus and cryopyrin-associated periodic syndromes. Treatment of NUD depends on the clinical context. Dapsone and colchicine are often effective.

Lymphocytes in Sweet syndrome: A potential diagnostic pitfall.

Patients with Sweet syndrome (SS) have acute onset of cutaneous lesions with characteristic histopathology (dense and diffuse neutrophilic infiltrate, dermal edema, leukocytoclasis and no vasculitis) accompanied by systemic symptoms. Sometimes, only skin lesions with classic histopathologic features are seen. Although SS is considered to be a "neutrophilic dermatosis," lymphocytes are also seen on histological examination. We evaluated the cellular infiltrate in 9 biopsies from SS lesions with routine staining and immunohistochemistry. Lymphocytes were present in all biopsies in variable amounts, often exceeding the number of intact neutrophils. Prominent fragmentation of neutrophils rendered some biopsies "lymphocyte-rich" on routine histologic evaluation. Myeloperoxidase was helpful in highlighting the inconspicuous neutrophilic fragments in these cases. Lymphocytes were highlighted with immunohistochemistry, and had a CD3+, CD4+, CD20(-) immunophenotype, with rare CD8+ lymphocytes. Awareness of the lymphocytic component of SS is important to avoid diagnostic errors, especially in subcutaneous lesions of SS, in which the lymphocytic infiltrate predominates in the upper parts of the dermis, while the typical neutrophilic infiltrate may be seen only in the deeper dermis and subcutis. The lymphocytic component may potentially help to differentiate lesions of SS from neutrophilic urticarial dermatosis, which has not been reported to contain a significant lymphocytic population.

Neutrophilic urticarial dermatosis and Sweet-like neutrophilic dermatosis: under-recognized neutrophilic dermatoses in lupus erythematosus.

Background/Objectives Neutrophilic dermatoses can be associated with autoimmune connective tissue diseases such as systemic lupus erythematosus (SLE). We analyzed clinical and histological features of neutrophilic urticarial dermatosis (NUD) and Sweet-like neutrophilic dermatosis (SLND)-the most recently delineated entities of the neutrophilic dermatoses. Methods We retrieved database medical records of patients with SLE whose skin biopsy demonstrated a neutrophilic-predominant infiltrate of the skin, and included those whose biopsies revealed findings of SLND or NUD. Results SLND skin lesions lasted longer than those of NUD and were localized to sun-exposed areas. All NUD cases resolved within one week either spontaneously or with treatment such as antihistamines, but SLND skin lesions lasted longer than one week; prednisone was used in four of these five patients. All NUD cases were found in existing SLE patients and were not associated with systemic signs of flare-up of SLE. However, 80% of SLND cases experienced flare-up of SLE; and in 60%, SLND developed concomitantly with SLE as a presenting sign. Conclusion Different clinical courses and relationships with SLE suggest that NUD and SLND have different pathogeneses for neutrophilic inflammatory reactions.

The Histopathology of Urticaria Revisited-Clinical Pathological Study.

The classic histopathological findings of urticaria include dermal edema and a sparse perivascular infiltrate of neutrophils, eosinophils, macrophages, and lymphocytes. However, this pattern is inconsistently described. To describe the histological and immunofluorescence characteristics of urticaria and to identify distinctive patterns. A retrospective study was performed in which the medical files and biopsy specimens of 58 patients with acute and chronic classical urticaria were reviewed. Pathological parameters were quantified. We recognized 2 distinctive patterns of urticaria: lymphocyte and neutrophil predominant; the former was characterized by a perivascular location, whereas the latter was associated with an interstitial location and a denser infiltrate. Mast cells were relatively sparse, better demonstrated with special stains. Tryptase stain demonstrated more mast cells than Giemsa stain. Extravasated erythrocytes were present in 50% of the cases, but vasculitis was not observed. Histological findings in classical urticaria show a spectrum of findings from a sparse superficial perivascular to a deep perivascular and interstitial infiltrate. Distinctive groups based on the dominant cell type can be identified, accounting for the similarity to neutrophilic urticarial dermatosis. Lesions may have a purpuric appearance, but leukocytoclastic vasculitis is never present.

抗ARS抗体陽性の皮膚筋炎に合併したneutrophilic urticarial dermatosisの1例

抗ARS抗体陽性の皮膚筋炎に合併したneutrophilic urticarial dermatosisの1例