Symptoms resolve with dupilumab in patients with drug reactions
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Key takeaways:
- Patients with drug reactions with eosinophilia and systemic symptoms show increases in Th2-associated cytokines.
- Dupilumab dampens Th2 responses and may be an effective treatment for these patients.
Dupilumab may be a safe and effective therapy for patients with drug reactions with eosinophilia and systemic symptoms, or DRESS, according to a case series published in The Journal of Allergy and Clinical Immunology: In Practice.
Currently there are no standardized treatment protocols for DRESS, Nicholas Gulati, MD, PhD, assistant professor in the Kimberly and Eric J. Waldman Department of Dermatology at Icahn School of Medicine at Mount Sinai, and colleagues wrote.
“DRESS is thought to be underdiagnosed and underreported, but current estimates indicate that the syndrome occurs in about one in every 1,000 to 10,000 drug exposures,” Gulati, who also is director of the oncodermatology clinic and the early detection of skin cancer clinic at Mount Sinai, told Healio.
The authors defined DRESS as a type IV hypersensitivity reaction with internal organ involvement, lymphadenopathy, hematologic abnormalities and cutaneous lesions, often driven by allopurinol, anti-epileptics and antibiotics.
“Almost any medication can cause DRESS, but some of the more common ones include antibiotics and anticonvulsants,” Gulati said.
Although systemic corticosteroids usually are used to treat these cases, they may have negative side effects, especially with the prolonged use that DRESS often requires, according to the researchers.
Patients with DRESS exhibit increases in Th2-associated cytokines, the researchers wrote. Dupilumab (Dupixent; Sanofi Genzyme/Regeneron) may help treat DRESS by inhibiting IL-4 and IL-13 cytokines and dampening Th2 responses, the researchers continued, based on successful outcomes in two cases.
“Dupilumab, by inhibiting both IL-4 and IL-13 cytokines, broadly downregulates the Th2 axis of the immune system,” Gulati said. “Th2 immunity is what leads to the eosinophilia that characterizes DRESS, which is the likely reason why Th2 targeting with dupilumab benefited our patients.”
Case studies
Both patients had rashes and systemic involvement that are typical of DRESS, Gulati said.
After 2 weeks of treatment with trimethoprim-sulfamethoxazole, a man aged 37 years developed pharyngitis and lymphadenopathy, with subsequent morbilliform rash, facial edema and transaminitis, which the authors called consistent with DRESS.
After IV corticosteroids and an oral taper, the patient showed clinical improvement. But 5 days after the cessation of prednisone, he experienced recurrent erythematous papules and new-onset eosinophilia.
Physicians administered a 600 mg loading dose of dupilumab and a 300 mg maintenance dose 7 days later. The rash had resolved and his eosinophil count had normalized by his 14-day follow-up visit, and he received one more 300 mg injection.
The morbilliform rash returned 6 weeks later. Another 3-week course of 300 mg weekly doses of dupilumab was initiated. Rapid improvement followed and the patient took a break in medication.
However, another disease flare with an upper respiratory infection followed 3 weeks after that. Three more weeks of maintenance doses of dupilumab were prescribed, and remission was sustained for 16 weeks.
In the second case, a woman aged 45 years with chronic migraines was treated with monthly doses of galcanezumab (Emgality, Lilly.). But 23 days after her seventh dose, she developed a morbilliform eruption of the trunk with periocular edema and new-onset eosinophilia even though she was taking oral prednisone.
Clinicians suspected drug eruption based on biopsy results despite a lack of reporting associating galcanezumab with DRESS, although rashes have been documented. The patient then began dupilumab treatment.
With a 600 mg loading dose and a 300 mg maintenance dose 7 days later, cutaneous symptoms improved and eosinophilia normalized with no evidence of internal organ involvement. The patient discontinued prednisone treatment as well.
The patient’s symptoms remained clear with 5 weeks of dupilumab. But after a 7-week medication break, a faint morbilliform eruption occurred without galcanezumab or any new medications. With three more weekly 300 mg doses of dupilumab, symptoms resolved with 19 weeks of remission.
Conclusions, next steps
Both patients tolerated dupilumab well without any appreciable adverse effects, the researchers wrote, with rapid symptomatic improvement and possible impedance of internal organ involvement. The patients also had significantly less systemic corticosteroid use and no need for hospitalization or readmission.
“The current standard-of-care treatment for DRESS is systemic steroids given for at least 6 weeks, but often much longer. Particularly with long-term use, systemic steroids are known to have many dangerous side effects, including immunosuppression,” Gulati said.
By using dupilumab in these patients, Gulati said, he and his colleagues were able to wean the patients off their systemic steroids much more quickly than is typical.
“Since dupilumab has a strong safety profile established over years, and is not immunosuppressive, we feel that this is a much more appealing long-term treatment option for DRESS than systemic steroids,” Gulati said.
The authors cautioned that neither of these patients had RegiSCAR scores that qualified as definite disease, even though their cases were consistent with possible DRESS, and suggested that prolonged courses of dupilumab with or without increasing dose intervals for at least 6 months may be required in other DRESS cases.
Additionally, the authors noted that overlapping systemic corticosteroid use may have benefitted these patients and led to a possible overestimate of dupilumab’s efficacy. The authors believe that dupilumab probably had a positive clinical impact anyway, although they added that further research may be warranted.
“We have been and are continuing to treat more DRESS patients with off-label dupilumab, and the results are encouraging. We are in the process of setting up a clinical trial that will more formally assess the safety and efficacy of dupilumab to treat DRESS,” Gulati said.
Gulati also advised vigilance for physicians who are treating these patients.
“Although DRESS is an acute and life-threatening drug reaction often first encountered in the emergency room or hospital, it is important to remember that these patients can experience sequelae months to years afterwards,” he said.
“Therefore, it is critical for DRESS patients to have regular outpatient follow-up and a long-term treatment option that is both safe and effective,” he continued. “We hope that dupilumab will be able to fill this major unmet clinical need.”
For more information:
Nicholas Gulati, MD, PhD, can be reached at nicholas.gulati@mssm.edu.
Perspective
Back to TopI think it is both surprising and significant how quickly the patients’ symptoms of DRESS resolved, which may be related to dupilumab. I would like more controlled trials and data to support the use of dupilumab in treatment of DRESS syndrome.
However, I would more strongly consider using it based on these two case studies. I have not treated DRESS with dupilumab before, as this is not a typical therapy in treatment of DRESS. But it does seem to show some promise. This study demonstrates that dupilumab may be helpful in treatment of DRESS and supports the use of dupilumab on a more experimental basis on a larger number of patients to determine effectiveness and safety.
This is a limited study of only two patients, so dupilumab needs to be used on a larger number of patients with DRESS to demonstrate true effectiveness and safety. Additionally, trials need to be better controlled in the future, so that we can separate the effectiveness of steroids vs. dupilumab on resolution of DRESS syndrome.
Perspective
Back to Top
I think these two cases are very interesting and raise an idea that is worth exploring in clinical studies. The current treatment of DRESS syndrome requires corticosteroids and, in some cases, other immune suppressants. Dupilumab works by more selectively targeting allergic type T2 inflammation and does not suppress the immune system very much as a result. If dupilumab were to work well for DRESS syndrome, that would potentially be an improvement.
Dupilumab was approved for use in patients with eczema and asthma by the FDA because it does well at reducing allergic type T2 inflammation in the skin and the lungs and improving those conditions for a lot of patients. We do think of DRESS syndrome-type drug reactions as being consistent with severe T2-driven inflammation, although there are possibly some other types of inflammation as well, and that needs to be determined.
Use of dupilumab for DRESS syndrome does not seem outlandish to me as a result, but it would be off label. I think it is worth studying and reporting on further. I also think we should use these findings as a starting point toward better studies, including prospective studies with larger sample sizes and possibly clinical trials. Improving upon our current treatment of DRESS syndrome would be great.
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