Varsha Pramil, MD; Lianna Valdes, MD , 2025-04-16 18:30:00
April 16, 2025
4 min read
A 43-year-old woman presented with 6 months of recurrent bilateral eye pain and redness alongside spontaneous urticaria.
She noted episodes of quarter-sized itchy lesions appearing on her abdomen, legs and arms one to two times a month that spontaneously resolved within 24 hours. Bilateral eye pain, redness and itching occurred after onset of rash and subsided with resolution of rash.
Figure 1. Injection of left eye at time of flare.
Source: Varsha Pramil, MD, and Lianna Valdes, MD
The patient’s medical history included gastroesophageal reflux disease, diverticulitis and remote history of chickenpox as a child. She had two deviated septum surgeries in the past. She was a smoker, had many tattoos, and lived with two cats and a dog. She had no significant ocular history.
Examination
Initial eye examination showed visual acuity of 20/20-2 in the right eye and 20/25+2 in the left eye. IOP was 15 mm Hg in both eyes. Pupils were equal and reactive to light with no relative afferent pupillary defect. Visual fields by confrontation were full in both eyes. Extraocular movements were full in both eyes. Slit lamp examination showed trace meibomian gland insufficiency along with 1+ conjunctival injection that blanched with phenylephrine and prominent episcleral vessels in both eyes. Anterior exam showed scattered keratic precipitates and deep, rare cell with trace nuclear sclerosis cataracts in both eyes. Dilated fundus examination showed pink optic nerves with superior and nasal elevation and blurring of margins in both eyes. B-scan in both eyes showed no signs of posterior scleritis or mass. OCT scan of the macula was normal with no macular edema. OCT of the retinal nerve fiber layer in both eyes was normal with no optic nerve thinning or swelling. Fundus autofluorescence in both eyes showed no abnormalities. Of note, prior examination at an outside ophthalmologist’s office revealed pigmented keratic precipitates and 1+ anterior chamber cell.
The patient did not have an active flare at the time of the abovementioned examination. Pictures of the eyes at the time of flare were obtained and showed significant injection with possible violet-bluish hue (Figure 1).
She was evaluated by allergy/immunology for chronic, recurrent urticaria and found to have low C3 (74 mg/dL), C4 (8 mg/dL) and CH50 (35 U/mL) with high C1q-binding antibodies (>100).
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Eye pain and skin rash
The patient was started on cetirizine, fexofenadine, famotidine, montelukast and olopatadine eye drops in addition to omalizumab by an allergist. This regimen helped decrease the number of urticaria flares. However, her sclerouveitis flares persisted.
Julia Ernst
William W. Binotti
She was trialed on oral prednisone, which resolved symptoms initially, but once tapered off oral prednisone, she had a recurrence. Further autoimmune and infectious testing was done and was negative for tuberculosis and syphilis. ACE/lysozyme was elevated to 98/8.6 and alkaline phosphatase to 158. Erythrocyte sedimentation rate was elevated, and C-reactive protein was normal. ANCA screen was negative. Rheumatoid factor was high at 134.3 in the setting of elevated CCP IgG/IgA antibodies of more than 250. Based on this testing, it appeared that the patient’s recurrent uveitis and urticaria were linked to an underlying autoimmune etiology. She underwent further workup with rheumatology for presumed sclerouveitis in the setting of urticarial vasculitis. This workup confirmed positive serology for rheumatoid arthritis. She was started on methotrexate and will follow up in 1 month for repeat labs and monitoring of clinical symptoms.
Discussion
Urticarial vasculitis is characterized by inflammation of small blood vessels that can lead to pruritic skin lesions. Biopsy with histological examination of the lesions typically shows leukocytoclastic vasculitis. This disease process tends to affect women in their 40s to 60s, and symptoms typically recur for about 3 years. It can often include systemic manifestations affecting the musculoskeletal, pulmonary, renal, gastrointestinal and ocular systems. Additionally, this syndrome can be triggered by other autoimmune etiologies such as systemic lupus erythematosus, Sjögren’s syndrome and rheumatoid arthritis, such as in this case.
Urticarial vasculitis can be further classified as normocomplementemic urticarial vasculitis (NUV)/non-anti-C1q vasculitis or hypocomplementemic urticarial vasculitis (HUV)/anti-C1q vasculitis. NUV and HUV are differentiated based on the levels of complement and anti-C1q antibodies, with the latter presenting with low complement levels and high anti-C1q antibodies. HUV syndrome is diagnosed based on evidence of multiorgan systemic findings that are not a sequalae of another condition. Generally, it is reported that 10% to 30% of patients with systemic vasculitis will develop ocular involvement. In this case, the patient was found to have low complement low C3, C4 and CH50 with high C1q-binding antibodies in the setting of recurrent urticarial exanthem and sclerouveitis, suggesting a diagnosis of HUV/anti-C1q vasculitis. This form of vasculitis is uncommon, and associated ocular involvement is even rarer, with only a few cases ever reported in the literature.
This condition has also been shown to be associated with paraneoplastic syndromes. Therefore, a comprehensive workup for underlying malignancies should be started promptly when this diagnosis is suspected. Treatment for HUV can be challenging and requires a multidisciplinary approach. Depending on the severity of systemic involvement, timely initiation of immunomodulatory therapy is recommended to avoid permanent damage. In this case, the patient was started on omalizumab for initial treatment of urticaria. Omalizumab is a monoclonal anti-immunoglobulin (Ig) E antibody. Its mechanism of action is not fully understood, but the combination of decreased IgG, IgE and IgE receptor activity along with downregulation of mast cell receptors results in resolution of IgE/IgG-mediated disease. It has typically been found to be effective in chronic spontaneous urticaria, which is diagnosed by episodes of spontaneous recurrence of wheals and/or angioedema typically lasting for more than 1 year. It is often caused by breakdown in the IgE/mast cell pathway. On the other hand, urticarial vasculitis is defined by urticaria as well as systemic findings. Its disease process is complex including not only IgE/mast cell irregularities but also leukocytoclastic vasculitis as well as formation of immune complexes. This explains why initiation of omalizumab did not fully resolve the patient’s symptoms.
HUV/anti-C1q vasculitis has been rarely associated with ocular conditions such as episcleritis, scleritis and uveitis. When patients present with recurrent urticaria in the setting of persistent ocular symptoms, it is imperative to conduct a thorough workup and consider the possibility of HUV/anti-C1q vasculitis especially in nonresolving cases that were previously diagnosed as chronic spontaneous urticaria. Early identification of this disease process could uncover an underlying paraneoplastic syndrome and prevent irreversible multiorgan injury.
References:
- Berry EC, et al. BMJ Case Rep. 2021;doi:10.1136/bcr-2020-240041.
- Corwin JM, et al. Am J Ophthalmol. 1982;doi:10.1016/0002-9394(82)90202-1.
- Kaplan AP, et al. Allergy. 2017doi:10.1111/all.13083.
- Kolkhir P, et al. JAMA. 2024;doi:10.1001/jama.2024.15568.
- Thorne JE, et al. Am J Ophthalmol. 2002;doi:10.1016/s0002-9394(02)01814-7.
- Wang RX, et al. Immunol Allergy Clin North Am. 2024;doi:10.1016/j.iac.2024.03.006.
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Edited by William W. Binotti, MD, and Julia Ernst, MD, PhD, of New England Eye Center, Tufts University School of Medicine. They can be reached at william.binotti@tuftsmedicine.org and julia.ernst@tuftsmedicine.org.