Options available for patients with urticaria whose omalizumab therapy fails

Key takeaways:

• Guidelines suggest increasing the frequency or amount of dosing when treatment fails.
• Tacrolimus and mycophenolate are options, and dupilumab and remibrutinib have potential.

SAN ANTONIO — Patients with urticaria who do not respond to omalizumab have other options for treatment, David A. Khan, MD, said during the 16th Annual Allergy, Asthma & Immunology CME Conference.

Urticaria typically improves with 300 mg of omalizumab (Xolair; Genentech/Novartis) every 4 weeks for 3 to 6 months, Khan, professor of medicine and pediatrics and allergy and immunology program director at UT Southwestern Medical Center, said during his presentation.

“I think people can go a little bit longer, but at some point, you have to say it’s not working,” he said. “If omalizumab doesn’t work, then you can crank up the dose.”

International guidelines recommend shortening the interval to every 2 weeks, increasing the dose to a maximum of 600 mg, or both. But Khan cautioned that there are no data from controlled trials to support these high doses for patients who fail with standard doses.

“There’s lots of retrospective studies,” he said. “How many people have seen patients who get better when you give them more than 300 mg every 4 weeks? We all see it, but there’s not good, robust evidence.”

Alternatives to omalizumab are available and they have been studied, Khan said, but these studies have involved very few people, and none of them have examined patients who have failed treatment with high doses of omalizumab.

“We’re in very uncertain territory,” he said.

Off-label alternatives to omalizumab include anti-inflammatories, immunosuppressants and biologics, Khan said. Anti-inflammatories include hydroxychloroquine, dapsone, sulfasalazine, colchicine and methotrexate.

“Some people put in vitamin D as well,” he said.

Immunosuppressants include cyclosporine, tacrolimus, mycophenolate and sirolimus. Biologics include dupilumab (Dupixent; Regeneron, Sanofi), rituximab (Rituxan, Genentech), TNF-inhibitors, intravenous immunoglobulin and anakinra (Kineret, Swedish Orphan Biovitrum).

“Don’t forget about narrowband UVB therapy,” Khan said. “There are actually randomized controlled trials in chronic urticaria showing benefit using UV light therapy, so that’s something that you can certainly think about.”

Tacrolimus

Khan called tacrolimus, which is a calcineurin inhibitor that primarily affects T cells, his “go-to” treatment for patients who have failed high-dose omalizumab. He said it is exactly like cyclosporine, except it does not cause hirsutism or gingival hyperplasia.

“Most patients with hives are women, and they probably don’t want to be shaving,” he said. “Otherwise, the side effects are pretty similar.”

Tacrolimus and cyclosporine have the same monitoring protocols, Khan said, noting that he mostly is interested in kidney function. In the long term, he advised monitoring lipids and hyperglycemia as well.

Doses are different. Khan begins with 1 mg of tacrolimus twice a day and then ranges up to 4 mg a day as necessary.

“Very, very rarely do you need any more than that,” he said, adding that he measures blood levels to ensure doses do not enter a toxic range. “People metabolize these drugs dramatically differently. The lower it is, the better.”

Common side effects include headaches and gastrointestinal issues including dose-related nausea. Renal toxicity is rare at these doses, he continued, and it is very reversible when it does occur.

Treatment can take between weeks and months, Khan said, with most patients improving and some achieving remission in his experience.

“People who started therapy stopped therapy. They no longer had hives. And I think there are some medications that do this. Omalizumab is not one of them,” he said. “It’s a smaller percentage of patients, but there are some patients. I think certain of these immunosuppressants truly change the course of the disease.”

Mycophenolate

Although many physicians do not use it, Khan called mycophenolate another option, as it works on T and B cells and has a better safety profile than tacrolimus. Initial doses can be 1,000 mg twice a day, with Khan usually starting lower than that due to its common GI effects such as dose-related nausea, cramping and diarrhea.

“They’ll let you know, and many patients will put up with enough of it, and then you can lower the dose,” Khan said.

“The effective treatment dose is anywhere probably from 1 to 4 grams a day,” he said. “This works slower than the calcineurin inhibitors, so I will up-dose on a monthly basis.”

Khan said that he had one patient who developed lymphopenia, although it has been reported in other patients. He also said that he has had patients who have failed with cyclosporine who have seen successful outcomes with mycophenolate.

Cyclosporine with omalizumab

Khan noted a study of patients whose treatment failed with cyclosporine or omalizumab and whose failures continued when they switched treatment.

“Why don’t we give them both at the same time?” Khan said.

The researchers did not see any improvements until 4 months.

“You do need maybe a little more patience, and sometimes that’s hard for these patients who are really miserable to deal with,” Khan said. “I find myself guilty of moving on sometimes sooner, maybe, and this is something that we just need to be aware of.”

Sirolimus

As a mammalian target of rapamycin or mTOR inhibitor, sirolimus is another option that “works on a different pathway for T cells,” Khan said.

Few studies have investigated its use, Khan said. Effective dosing remains unclear, he continued, but he said that he starts at 1 mg a day, with effectiveness with 1 mg to 3 mg a day, “based on a handful of people.”

About half of these patients experience edema in their lower extremities, Khan said, calling it “weird.” He also said that he monitors kidney function and complete blood counts in patients who use it.

Khan further cited a retrospective series where five of six patients who had failed both omalizumab and tacrolimus or cyclosporine responded to sirolimus. Three of these patients developed lower extremity edema that improved or resolved with reductions in sirolimus dosing.

At 9 months, one patient stopped her sirolimus treatment and experienced urticaria remission.

“Was that natural history, or did the drug do it?” Khan said. “I don’t know, but I think this is probably another one that might be able to induce remission.”

Hesitation in using

Many physicians do not use these alternatives because they are uncomfortable with them due to a lack of training and experience, Khan said, and they are worried about harm.

GI symptoms account for most of the adverse effects, but there have been no cases of permanent harm, Khan continued.

“I think you can use these agents, as long as you know what you’re doing, you’re monitoring,” he said. “I cannot say that about prednisone.”

Prednisone causes severe osteoporosis and avuncular necrosis of the hips among other damage, Khan said, adding that patients with controlled urticaria and no other problems while on prednisone are very rare.

“Anything you do is better than prednisone,” he said. “We give prednisone out like candy because we’re comfortable with it, but that’s not the mindset we need.”

Other biologics

Considering the side effects and lack of quality data, Khan said that dupilumab (Dupixent; Regeneron, Sanofi) and remibrutinib (Novartis) also may be alternatives for patients whose omalizumab treatment fails.

For example, Khan cited a study that found a statistically significant benefit for patients who used dupilumab without any prior omalizumab for chronic spontaneous urticaria, although patients whose omalizumab treatment failed before using dupilumab did not see any similar benefits.

“That was disappointing,” Khan said.

Still, Khan said he expects that dupilumab eventually will be approved for treating urticaria.

“If we have more options, I think that’s a good thing,” he said. “But I would say it’s probably not something we’re going to be relying on.”

Remibrutinib, which is an oral Bruton’s tyrosine kinase inhibitor, is now moving through clinical trials with some early data published indicating that patients achieve complete response based upon a weekly Urticaria Activity Score of 0.

“I would argue that’s even higher that what we see with omalizumab,” Khan said. “This is pretty exciting.”

Khan said that remibrutinib may be available for patients with urticaria early next year.

Take-home advice

Khan outlined what physicians need to do as they determine the best treatment for patients with refractory chronic spontaneous urticaria.

“No. 1: make sure they have CSU in an adequate trial of high-dose omalizumab,” he said.

Physicians can use cyclosporine or tacrolimus in combination with omalizumab, or they can use the other alternatives he discussed, all of which are safer than chronic steroids.

Although results for dupilumab and remibrutinib are still early, Khan said he is optimistic about further developments in biologics.

“Things will get better. I think we’re going to have more options for other therapies,” he said. “There’s a very active research space now with chronic urticaria, which is great to see.”