To date, there is no report of the use of ustekinumab for pediatric JIA, uveitis, or BD. Of note, there is one case report of the successful use of ustekinumab for the treatment of BD in a 39-year-old woman with concurrent psoriasis and hidradenitis suppurativa. After a flare-up of psoriasis, she was prescribed 45 mg of subcutaneous ustekinumab at weeks 0, 4, and 12, and achieved PASI-50 in 4 weeks and PASI-75 by 3 months. During this time, her symptoms of hidradeni-tis suppurativa and BD both resolved and she remained in remission for at least 3 years. As stated earlier, with the possible association of IL-17 and IL-23 with pediatric-onset BD, it is possible that ustekinumab, and other biologic agents, may in the future play a role in the treatment of this poorly characterized disease.
Through week 12 of the PHOENIX 1 trial in adults with psoriasis, the most common AEs from ustekinumab were nasopharyngitis (8.2%-10.2%), upper respiratory tract infection (6.3%-7.1%), and headache (5.1%-5.5%). Serious AEs (SAEs) occurred in two patients on the 45 mg dose, four patients on the 90 mg dose, and two patients in the placebo group. There were three serious infections, one cardiovascular event, and no cutaneous or noncutaneous cancers. By week 76, 5.1% of patients had developed antibodies to ustekinumab.
Through week 12 of PHOENIX 2, the most common AEs from ustekinumab in adults with psoriasis were nasopharyngitis (6.8%-7.3%), headache (4.6%), and upper respiratory tract infection (2.9%-4.4%). SAEs occurred in eight patients in the 45 mg dose group, five patients in the 90 mg dose group, and eight patients in the placebo group. There were three serious infections, two cutaneous cancers, one noncutaneous cancer, and one cardiovascular event. By week 52, 5.4% of patients had antibodies to ustekinumab.
Although the clinical trials highlighted the efficacy of ustekinumab, one of the major concerns was the long-term safety, especially with regards to malignancies. Here, we will briefly review the 1- to 5-year follow-up data in adults with psoriasis treated with ustekinumab.
Pooled safety data from Phase II and III clinical trials showed that during the placebo-controlled periods (12-20 weeks), there were comparable rates of AEs between patients on the 45 mg dose (57.6%), 90 mg dose (51.6%), and placebo (50.4%). The rates of overall infections and malignancies were also similar between patients on the 45 mg dose, 90 mg dose, and placebo. There were no reports of TB or demyelinating conditions. Apart from nonmelanoma skin cancers, the rates of malignancies were similar to those observed in the general US population. Importantly, by the third year, the rates of overall infections, AE, SAE, and malignancies remained stable over time.
Five-year follow-up studies in adult patients with psoriasis enrolled in the PHOENIX 1 and 2 trials individually demo nstrated favorable safety profiles. In the PHOENIX 1 study, the data revealed comparable rates of AEs, SAEs, infections, malignancies, and major adverse cardiovascular events among those in the 45 and 90 mg dose groups. There was one case of disseminated cutaneous herpes zoster but no reports of active TB, atypical mycobacterial, systemic fungal or salmonella infections, anaphylaxis, or serum-sickness-like reactions. Only 5.2% of patients developed antibodies and none reported injection-site reactions.
Safety monitoring of PHOENIX 2 until week 264 showed that cumulative rates of AEs and SAEs were similar among patients in the 45 mg dose group, 90 mg dose group, and the general population. Importantly, there was no increase in the rates of SAEs, serious infections, nonmelanoma skin cancers, other malignancies, or major adverse cardiovascular events. The most common serious infections were diverticulitis (seven cases), cellulitis (five cases), and cholecystitis (three cases), with no reports of active TB, atypical mycobacterial, systemic fungal or salmonella infections, anaphylaxis, or serum-sickness-like reactions.
Pooled safety data from PHOENIX 1 and 2, as well as their 5-year follow-up studies, demonstrated that the rates of overall mortality and malignancies (excluding nonmelanoma skin cancers) were found to be comparable to those in the general US population. The event rates for overall AEs, SAEs, serious infections, nonmelanoma skin cancers, other malignancies, and major adverse cardiovascular events were comparable between patients on the 45 and 90 mg doses. The rates of AEs were found to be comparable to other biologics used to treat psoriasis, and the study did not show evidence of cumulative toxicity up to 5 years.
Safety data from the TRANSIT trial was analyzed through week 52. The rates of AEs were comparable between patients on the 45 and 90 mg doses and only led to cessation of ustekinumab in 0.4% of these patients. There were four serious infections, two of which required cessation of ustekinumab (pneumonia and acute hepatitis B), and four malignancies (keratoacanthoma, cervical carcinoma in situ, breast cancer in situ, and metastatic prostate cancer). There were three major adverse cardiovascular events: one cerebrovascular accident, one myocardial infarction, and one death from cardiorespiratory arrest. The overall rates of serious infections, malignancies, and major adverse cardiovascular events were 0.85, 0.85, and 0.64, respectively, per 100 patient-years of treatment.
During the first 12 weeks of the ACCEPT trial comparing ustekinumab with etanercept for adult psoriasis patients, 66.0% of patients on ustekinumab and 70.0% of patients on etanercept reported at least one AE. In this time period, the most common adverse events were nasopharyngitis (8.6% of those on etanercept, 10.0% of those on 45 mg ustekinumab, and 9.8% of those on 90 mg ustekinumab), upper respiratory tract infection (5.8%, 6.2%, and 6.3%, respectively), headache (11.0%, 14.8%, and 12.1%, respectively), back pain (2.0%, 6.7%, and 4.3%, respectively), and injection-site reaction (24.8%, 4.3%, and 3.7%, respectively). The rate of infections as well as proportions of patients who stopped treatment due to adverse events were similar between the three treatment arms. Two patients receiving 45 mg ustekinumab and one patient receiving 90 mg ustekinumab were found to have nonmelanoma skin cancers.
Safety data was also reported through week 64 of the ACCEPT trial. Patients on 45 and 90 mg doses of ustekinumab had similar rates and types of common adverse events, with the exception of injection-site reactions. One patient in each treatment arm died (motor vehicle accident, gunshot wound, and multisystem organ failure and sepsis, the latter in a patient who received 90 mg ustekinumab). Serious infections occurred in four patients who received etanercept, two patients who received 45 mg ustekinumab, and ten patients who received 90 mg ustekinumab (P=0.23 when comparing the low- and high-dose ustekinumab groups). There were nine reports of nonmelanoma skin cancers, and five patients who received ustekinumab had other malignant conditions. Three patients experienced major adverse cardiovascular events (one patient in the 45 mg ustekinumab group, one patient in the 90 mg ustekinumab group, and one patient who had crossed over to ustekinumab after etanercept). Although 3.8% of patients developed antibodies to ustekinumab, it was not associated with injection-site reactions.
With regard to the use of ustekinumab in children, we have the pooled data of the five case reports and the CADMUS trial. Among the five previously described case reports, there was one report of elevated liver function tests and one report of intolerance necessitating treatment cessation. The addition of the CADMUS trial greatly expanded available safety data in adolescents; patients were monitored for adverse events though week 60. By week 12, the percentage of patients who had reported more than one AE was 44.4% in the SD, 51.4% in the HSD, and 56.8% in the placebo groups - no dose effect was noted. The most common AEs were nasopharyngitis (2.8% in SD, 13.5% in HSD, and 27% in placebo) and headache (8.3% SD, 10.8% HSD, and 5.4% placebo). One SAE (worsening of psoriasis) was reported in the HSD group.
By week 40, after the placebo group had crossed over and received ustekinumab, the most common side effects were nasopharyngitis (34.5%), upper respiratory tract infections (12.7%), and pharyngitis (8.2%). By week 60, an additional five SAEs were also reported - one transient incident of leukopenia, pyelonephritis, ear infection, allergic contact dermatitis from hair dye, and one death from a motor vehicle accident, as well as one injection-site reaction. Although nine patients had developed antibodies to the drug - six in the HSD group and three in the SD group - six reached PGA 0/1 and only one reported an injection-site reaction, which was mild. Importantly, through week 60, there were no reports of malignancies, opportunistic infections, active TB, anaphylaxis, or serum-sickness-like reaction.
The long-term safety of ustekinumab is also supported by data from PSOLAR - the Psoriasis Longitudinal Assessment and Registry that prospectively follows patients with plaque psoriasis being treated with biologic agents including ustekinumab. In 2014, Papp et al analyzed data accumulated from 12,093 patients: the unadjusted rates of serious infection were lower for ustekinumab (0.93 per 100 patient-years) as compared with infliximab (2.91 per 100 patient-years) and other biologic agents (1.91 per 100 patient-years). Importantly, no increased risk of malignancies, mortality, serious infections, or major adverse cardiovascular events were observed with the use of ustekinumab. Additional safety data accumulated from PSOLAR indicates a lower rate of serious infections with ustekinumab (0.83 per 100 patient-years) compared to etanercept (1.47 per 100 patient-years), adalimumab (1.97 per 100 patient-years), and infliximab (2.49 per 100 patient-years).