BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.
Sara Freeman/MDedge News
Dr. Md Yuzaiful Md Yusof
Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.
“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.
“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.
B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.
There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.
The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.
Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.
Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.
Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.
The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.
“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”
In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.
“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.
“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.
Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.
“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.
The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.
SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.