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Q:

Reviewed: February 24, 2020
10/7/2014
My patient is a 64 year-old lady with chronic urticaria. When she became my patient 2 years ago she had been maintained on doxepine for many years. However, this year her episodes of hives became much worse and her symptoms were that the lesions were quite painful and left a mark when they subsided. Previous CU labs were normal. She underwent a skin biopsy at a local dermatology office and it came back as neutrophillic perivascular and intravascular dermatitis c/w urticarial vasculitis. No immunohistochemistry was done.

Labs done: G6PD - normal, complement studies normal. cbc with diff normal. She was started on dapsone, after taking this medication for a few days only she developed hypertension, fever and a dry hacking cough. CXR - normal, cbc with diff normal, CMP normal, ESR normal. Dapsone was stopped, cbc with diff wnl. She has had a low grade fever and couch for several weeks which has improved after a z pack.

My question is whether I need to further treat the presumed diagnosis of urticarial vasculitis with immunosuppressants? Or, if I should question the diagnosis all together because of a normal ESR?

A:

The case presentation fulfills both the clinical and histologic features of urticarial vasculitis although hypocomplementic urticarial vasculitis is excluded by the normal complement studies. I would be concerned that the change in urticaria may reflect the development of another condition that is affecting the urticaria. Conditions that I would consider include an autoimmune disease, malignancy, hepatitis, drug reaction, and chronic bacterial infection. This is a broad differential and would be influenced by the clinical and laboratory features. The normal laboratory is reassuring but you may consider a urinalysis for protein, immunofixation for monoclonal protein, rheumatoid factor, ANA, C reactive protein (rarely shows immune activation with normal ESR), and antineutrophil cytoplasmic antibody. Cryoglobulin studies may be helpful but are not generally available in commercial laboratories but the rheumatoid factor would be positive with essential mixed cryoglobulinemia and the immunofixation will exclude cryoglobulinemia associated with monoclonal protein. I would not perform general body CT scans looking for malignancy but may consider CT of chest with the development of cough. Also pay close attention to changes in lymphocyte count on peripheral blood and perform careful exam to exclude lymphadenopathy or spleen enlargement as lymphoma is a possiblity. Be sure to review medication list to be sure no medication added when urticaria changed.

I would recommend treatment. Dapsone is a reasonable choice and I am not convinced that the hypertension and cough are due to the dapsone. I would be very concerned about hypertension due to change in renal function that may reflect vasculitis or the cough suggesting involvement of the chest with vasculitis that may not show on initial chest radiograph. Recheck creatinine and watch urine analysis as you monitor. The normal ESR is reassuring but I would not discount the possibility of other forms of vasculitis at this point. If she cannot tolerate dapsone, I would consider colchicine. Low dose oral corticosteroids (prednisone 10-15 mg/day) may offer symptomatic relief for the short term but would try to avoid for long term strategy. Other immunomodulator treatment including low dose methotrexate, azathioprine if thiopurine methyl transferase is normal, mycophenalate mofitil are considerations. I have occasionally had success with H1 inhibitor combined with NSAID but risk of bleeding and increasing blood pressure would limit this choice.

There is limited evidenced based medicine to help with treatment choices. There are reviews you may find useful, and I have included one I wrote and is available on World Allergy Organization site and two other reviews.

Vasculitis

Autoimmun Rev. 2013 Feb;12(4):467-76. doi: 10.1016/j.autrev.2012.08.005. Epub 2012 Aug 16.
Skin involvement in cutaneous and systemic vasculitis.
Marzano AV1, Vezzoli P, Berti E.
Cutaneous vasculitides are a heterogeneous group of inflammatory disorders affecting skin blood vessels. They may be triggered by several factors, such as infection or drug, or may be related to underlying disease, notably connective tissue or malignancies. However, vasculitis occurs without any demonstrable triggering agents in a relevant number of patients. On the other hand, vasculitic skin lesions may manifest as a component of vasculitis affecting also internal organs; in someone of these patients, skin involvement occurs initially as the sole sign of disease, leading to consider cutaneous vasculitis a diagnosis of exclusion. In this review, we have focused on the most common variants of cutaneous vasculitis, including cutaneous small vessel vasculitis and urticarial vasculitis as well as Henoch-Schönlein purpura, a systemic form in which however skin involvement often predominates. We have also argued on livedoid vasculopathy, a cutaneous entity which, although nonfrankly vasculitic in origin, is frequently associated with connective tissue disease. Finally, we have analyzed the variety of cutaneous manifestations that may develop during the course of the main systemic vasculitides, such as Wegener's granulomatosis, Churg-Strauss syndrome and polyarteritis nodosa.

Medicine (Baltimore). 2009 Jan;88(1):23-31. doi: 10.1097/MD.0b013e3181943f5e.
Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature.
Kieffer C1, Cribier B, Lipsker D.
We conducted the current study to define within the spectrum of the neutrophilic dermatoses a group of patients with an urticarial rash clinically and a neutrophilic dermatosis histopathologically. We reviewed the literature on neutrophilic urticaria and we report here a series of patients with this unique presentation. We reviewed all cutaneous biopsies submitted to our department between 2000 and 2006 in which histopathologic evaluation was compatible with this entity. We then retrieved the patient medical records and obtained information about follow-up and associated diseases. This allowed us to identify 9 patients with an urticarial eruption that was characterized histopathologically by a perivascular and interstitial neutrophilic infiltrate with intense leukocytoclasia but without vasculitis and without dermal edema. Four patients also had small foci of necrobiotic collagen bundles. The eruption consisted of pale, flat or only slightly raised, nonpruritic macules, papules, or plaques. Elementary lesions resolved within 24 hours. Purpura, angioedema, and facial swelling were not seen, but dermographism was present in 1 patient. Six patients had fever, 7 had polyarthritis, and 6 had leukocytosis. Seven patients had associated systemic diseases: adult-onset Still disease (3 patients), systemic lupus erythematosus (3 patients), and Schnitzler syndrome (1 patient).A similar rash has been reported previously in the literature, mostly in patients with systemic inflammatory diseases, but the majority of patients reported under the undefined designation of "neutrophilic urticaria" did have a different clinicopathologic presentation. Thus, we suggest naming this eruption "neutrophilic urticarial dermatosis," to emphasize that this entity expands the broad group of cutaneous manifestations of neutrophilic aseptic disease. This entity bears important medical significance as it is strongly indicative of an associated systemic disease, mainly Schnitzler syndrome, adult-onset Still disease, lupus erythematosus, and the hereditary autoinflammatory fever syndromes.

I trust this information is of some help for you and your patient.

With warm regards,
Dennis K. Ledford, M.D., FAAAAI

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