The Role of Vitamin D in Chronic Urticaria and Angioedema Treatment

The purpose of this pilot, 12 week, clinical research study is to determine if
supplementation with Vitamin D will improve the clinical outcome in subjects with chronic
urticaria and angioedema (CUA). Vitamin D is a key element in the regulation of immune system
responses, and vitamin D could play an important role in the treatment of CUA. Recently, we
published that there is an important association with CUA and serum 25-hydroxy vitamin D
(25OHD). Namely, vitamin D levels in subjects with CUA were significantly lower as compared
to subjects with an alternative allergic disorder, allergic rhinitis. There is now one other
observational report that supplementation with vitamin D (50,000/wk) in subjects CUA resulted
in clinical improvement; however, there was only one treatment arm and optimal serum 25OHD
required to obtain benefit was not investigated.

This current study is a double-blinded, prospective, interventional study that seeks to
recruit adult subjects with physician-diagnosed CUA and randomize subjects to either the
recommended dietary allowance (Vitamin D 600 IU/day) or the recommended upper limit of intake
(Vitamin D 4000 IU/day). Subjects will answer a questionnaire to collect information
regarding demographics, previous diagnostic tests, medications, and complete an urticaria
severity score (USS). Information from the medical record: weight, height, body mass index
(BMI), thyroid stimulating hormone (TSH), free thyroxine (T4), thyroid autoantibodies,
urticaria autoimmune testing (CD203c results), anti-nuclear antibody (ANA), urinalysis, and
allergy skin prick testing, which are part of the CUA evaluation will be obtained. Subjects
will have research blood draws for serum 25OHD level, iPTH, calcium, phosphorus, albumin,
urine calcium, and vitamin D receptor (VDR) gene expression. All subjects will receive
standard-of-care therapy according to the 2009 Third International Consensus Meeting on
Urticaria position guidelines. Follow-up visits for medication usage, urticaria severity
score, and serum and urine safety monitoring will be at 6 and 12 weeks.

The hypothesis of this study is that high dosing of vitamin D will result in clinical
improvement in subjects with CUA. The primary clinical endpoint is medication usage, and the
secondary outcomes are urticaria severity score and prednisone rescue use. We will explore if
threshold serum 25OHD levels correlate and VDR expression correlate to clinical outcomes, and
to determine power analysis to conduct a larger scale study. Finally, the study aims to
determine if vitamin D supplementation is safe and well-tolerated in subjects with CUA.

Inclusion Criteria:

- Subjects will be included if they have physician-diagnosed chronic urticaria and/or
angioedema (CUA). CUA is defined by having urticarial wheals (hives) and/or angioedema
(dermal swelling) on a daily or almost daily for more than 6 weeks. Patients with CUA
also having signs of dermatographism and/or delayed-pressure urticaria will be
included in the study. Subjects with history of intolerance to non-steroidal
anti-inflammatory drugs will be included but warned not to take this drug class
(acetaminophen will be allowed instead).

Exclusion Criteria:

- Subjects will be excluded if:

1. They are not capable of answering the questionnaire.

2. Subjects with a pure physical or allergic urticarias, and/or hereditary and
acquired angioedema (C1 esterase inhibitor deficiency). These subjects will be
excluded as the etiology of their disease is known.

3. Pregnant or lactating women. All child-bearing women will be asked (verbally and
on the questionnaire) if they are pregnant or lactating. If they answer yes, they
will be excluded. As there is no risk or harm to the pregnant or lactating woman,
a urine pregnancy test will not be used.

4. Subjects with any clinically significant abnormality in biochemistry testing,
and/or hypercalcemia (calcium > 10.3 mg/dl) or renal insufficiency (GFR< 50
ml/min).

5. Subjects with a history of primary hyperparathyroidism, renal tubular acidosis,
sarcoidosis, granulomatous disease, or malignancy.