Sirolimus associated with improved outcomes in refractory chronic spontaneous urticaria
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Key takeaways:
- Four of six patients who used sirolimus had positive responses and discontinued systemic corticosteroids.
- Three eventually were hive-free, and the fourth’s hives were occasional and not burdensome.
Sirolimus may be a safe and effective alternative for patients with chronic spontaneous urticaria who do not respond to other treatments, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.
But the mechanism behind these results remains unknown, Gaytri Patel, MD, allergist at North Texas Allergy and Asthma Center, and David A. Khan, MD, member of the division of allergy and immunology at University of Texas Southwestern Medical Center, wrote.
Current guidelines for chronic spontaneous urticaria (CSU) recommend stepwise treatment with high doses of antihistamines, omalizumab (Xolair; Genentech, Novartis) or cyclosporine.
“Immunosuppressants such as cyclosporine tacrolimus and mycophenolate have been shown to be effective for the treatment of refractory chronic urticaria,” Patel told Healio.
Sirolimus (rapamycin), which is a mammalian target of rapamycin inhibitor, has similar indications for transplant rejection prevention, she continued.
“Given its immunosuppressant similarities, sirolimus was trialed in patients with severe refractory chronic urticaria,” Patel said.
Between June 2006 and June 2002, six patients (female, n = 5) with CSU were treated with sirolimus at a university allergy clinic. None of these patients had urticarial vasculitis as determined by their clinical features (n = 4) or a negative skin biopsy (n = 2), nor did any have symptoms concerning for chronic inducible urticaria.
Control was inadequate for all six patients even though they had been treated with high doses of antihistamines and oral calcineurin inhibitors. They also required systemic corticosteroids for control. Omalizumab treatment failed for five of the patients. The sixth was treated before the FDA had approved the biologic for CSU therapy.
These patients received between 1 mg and 4 mg of sirolimus each day. Providers performed laboratory monitoring including intermittent blood count and monthly blood urea nitrogen and creatinine. Once sirolimus therapy began, two patients increased their concurrent omalizumab doses.
Four patients responded to sirolimus therapy, the authors reported. The two patients who had Urticaria Control Tests saw their scores improve from 0 to 12 and from 3 to 15 after 3 months of treatment.
These four patients also discontinued their systemic corticosteroids within 1 to 5 months after beginning sirolimus, including three patients who used daily corticosteroids and one patient who used frequent bursts.
Further, three of the patients who responded to therapy were completely hive-free and the fourth had occasional hives that were not considered bothersome. One patient who had concomitant angioedema as well saw it resolve after 5 months.
One patient who did not respond to sirolimus increased its dose from 3 mg once a day to 2 mg twice a day and reported improvement during a brief telephone encounter but was lost to additional follow-up.
The other patient who did not respond did not experience any improvements with a dose of 4 mg once a day and discontinued treatment after 6 weeks. Urticaria then resolved with weekly subcutaneous immunoglobulin, but this patient was lost to follow-up after 4 months.
Treatment ranged from 1.5 to 34 months. Two patients are continuing therapy. Four patients reported adverse effects, including lower extremity edema (n = 3), metallic taste (n = 1) and arthralgia (n = 1).
The authors noted that the lower extremity edema was related to dosing, with symptoms improving for two of these patients once the doses were decreased. None of the patients discontinued treatment because of adverse effects.
Also, the researchers said that whether the response to treatment was due to a synergistic effect with higher doses of omalizumab among the two patients who used the biologic concurrently with sirolimus was unclear, although relapses in their CSU during lapses in their sirolimus regimen suggest omalizumab’s efficacy was secondary to sirolimus.
The researchers further cautioned that the mechanism behind the impact that sirolimus has on chronic urticaria remains unknown, although they noted that sirolimus significantly inhibits mast cell cytokine production, chemotaxis and cell survival and that the drug’s efficacy in CSU could be secondary to these effects.
“In chronic urticaria patients who are refractory to treatment with omalizumab, cyclosporine and other alternative agents, there is a more favorable potential for benefit compared with harm for treatment with sirolimus,” Patel said.
Based on these findings, the researchers concluded that sirolimus may be an effective and safe alternative for patients with severe refractory CSU, but more research is necessary.
“Further studies such as randomized controlled trials evaluating efficacy of sirolimus in severe chronic refractory urticaria patients are necessary,” Patel said. “Comparative studies evaluating effectiveness of sirolimus and calcineurin inhibitors would also be beneficial.”
For more information:
Gaytri Patel, MD, can be reached at gpatel@northtexasallergy.com.