2018: Year in Review
This year, there have been several major breakthroughs in the field of dermatology. We cover the highlights in the latest advances and discoveries in 2018.
There is a strong association between psoriasis and inflammatory bowel disease (IBD), with a relative risk of 2.85 for Crohn disease in patients with severe psoriasis and 1.96 for ulcerative colitis in patients with severe psoriasis.1 In a recent review article, researchers evaluated the treatment options for psoriasis and concurrent IBD by performing a systematic review of biologic and systemic medications used between 1947 and 2017. Randomized, double-blinded, controlled trials were selected when available, and when unavailable, the next highest level of evidence was used. A total of 2282 articles were identified, however, only 132 articles met the inclusion criteria. The findings showed that only adalimumab (Humira) and infliximab (Remicade) have demonstrated efficacy in phase 3 clinical trials for the treatment of psoriasis, psoriatic arthritis, Crohn disease, and ulcerative colitis. Certolizumab pegol (Cimzia) is efficacious for the treatment of psoriatic arthritis and Crohn disease, while ustekinumab (Stelara) has shown efficacy for psoriasis, psoriatic arthritis, and Crohn disease. Golimumab (Simponi) has demonstrated efficacy for psoriatic arthritis and ulcerative colitis. Brodalumab (Siliq) and guselkumab (Tremfya) are efficacious for treating psoriasis though brodalumab worsens symptoms of Crohn disease.1
There is some level of evidence supporting that etanercept, ixekizumab (Taltz), and secukinumab (Costentyx) may also worsen Crohn disease. Cyclosporine is FDA approved for the treatment of psoriasis but not psoriatic arthritis or IBD. Methotrexate has demonstrated efficacy in randomized controlled trials (RCTs) for the treatment of psoriasis, psoriatic arthritis, and Crohn disease but not for ulcerative colitis.1 While this review is extremely helpful in identifying the existing data for treatment of psoriasis and IBD, there are some limitations such as extrapolating this data to identify the risk of IBD exacerbation as some of the studies did not include IBD data.
An observational cohort study evaluated the risk of cardiovascular (CV) disease events in patients with psoriasis treated with tumor necrosis factor (TNF) inhibitors vs phototherapy.2 For the study, 23,843 adult patients with psoriasis were selected from the Truven Health Analytics MarketScan Database, a large US administrative claims database, from 2000-2014. They were placed in 1 of 2 cohorts, those who were treated with TNF inhibitors (etanercept [Enbrel], adalimumab, and infliximab) and those who were treated with phototherapy. The investigators used multivariate Cox proportional hazard models to compare the risk of CV events between the 2 cohorts. CV events were defined as an inpatient stay with a diagnosis of myocardial infarction, stroke or transient ischemic attack, or unstable angina. Cumulative exposure to TNF inhibitors and phototherapy were based on treatment persistence.
The results demonstrated that patients with psoriasis who were treated with TNF inhibitors had a lower risk of CV events compared with those who received phototherapy with an adjusted hazard ratio (HR) of 0.77 (P<.05).2 Each incremental 6-month period of cumulative exposure to TNF inhibitors was associated with an increasingly statistically significant reduction in CV event risk. This was not the case for the phototherapy cohort. Other studies have shown similar findings for patients with inflammatory conditions such as psoriasis and rheumatoid arthritis suggesting that TNF inhibitors reduce the risk of CV events in a cumulative exposure dependent manner.
Efficacy of Certolizumab Pegol
CIMPACT is a phase 3, multicenter, randomized, double-blind study that evaluated certolizumab pegol(CZP) for the treatment of chronic plaque psoriasis compared with etanercept and placebo. CZP is a Fc-free, PEGylated, anti-TNF biologic that demonstrated promising results in a phase 2 study.3 In the phase 3 trial, 559 patients with moderate to severe plaque psoriasis for 6 months were randomized to CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks, or placebo every 2 weeks for 16 weeks, or etanercept 50 mg twice weekly for 12 weeks. The primary endpoint was responder rate defined as a 75% reduction in Psoriasis Area and Severity Index from baseline score at week 12 vs placebo and etanercept. Those treated with CZP who had a response at 16 weeks were re-randomized to either CZP or placebo for 32 weeks. Secondary endpoints evaluated various responses at weeks 12, 16, and 48. There was a significantly greater responder rate in CZP-treated patients vs placebo-treated patients at week 12.3 Additionally, CZP 400 mg was superior and CZP 200 mg was noninferior to etanercept at week 12. Through week 48, responder rates were significantly greater in those re-randomized to CZP compared with placebo. CZP 400 mg every 2 weeks had higher response rates than CZP 200 mg every 2 weeks, though both demonstrated efficacy. The safety profile of CZP is similar to that of other anti-TNF biologics with nasopharyngitis and upper respiratory tract infections most frequently reported.3 This phase 3 trial demonstrates that CZP is a promising novel treatment option for patients with chronic plaque psoriasis as it has demonstrated clinically meaningful, statistically significant improvement in chronic plaque psoriasis.
Halobetasol and Tazarotene Lotion Efficacy and Safety
Two phase 3 RCTs evaluated the safety and efficacy of combined halobetasol with tazarotene (HP/TAZ lotion) treatment vs vehicle in the treatment of moderate to severe plaque psoriasis. Study participants were randomized to either HP/TAZ lotion or vehicle groups for once-daily application for 8 weeks. The primary endpoint was treatment efficacy as measured by 2-point reduction in Investigator’s Global Assessment score from baseline. At weeks 2, 4, and 8, those treated with HP/TAZ had a statistically significant improvement in signs and symptoms of plaque psoriasis compared with those receiving vehicle alone (35.8% and 45.3% in HP/TAZ vs 7% and 12.5% in vehicle alone reached the primary endpoint).4 Adverse events included contact dermatitis, application site pain, and pruritus. After completion of the study, rebound in disease activity was not seen upon discontinuing treatment with halobetasol. A previous study demonstrated that combined HP/TAZ treatment has synergistic effects with reduced application site reactions compared to either halobetasol or tazarotene alone.5
Methotrexate and Liver Cirrhosis
Janus Kinases Inhibitors for Alopecia Areata
There is emerging data supporting oral tofacitinib (Xelijanz), a Janus kinase (JAK) inhibitor, as a promising new treatment for alopecia areata (AA). This 24-week, open-label, single-center pilot study of 10 patients with AA evaluated the efficacy of topical 2% tofacitinib ointment applied twice daily in the treatment of AA. The patients were 18 years and older, had 2 patches of alopecia or total scalp hair loss, stable or worsening disease for 6 months, and no treatment for 1 month. Initially, tofacitinib was applied twice daily to half of the scalp. Once there was evidence of hair regrowth, it was applied to the entire scalp. Endpoints included scalp regrowth as measured by the Severity of Alopecia Tool (SALT) scores and time to hair regrowth. Three of the 10 participants experienced hair regrowth with a mean SALT score reduction of 34.6%.8 Adverse events included scalp skin irritation in 40% of participants and folliculitis in 10% of participants. The response to topical tofacitinib in this study was lower than that seen with oral tofacitinib but comparable to topical clobetasol under occlusion.8 Further studies with more participants are needed to better evaluate the role of topical tofacitinib in the treatment of AA.
While oral tofacitinib has shown promise as a pathogenesis-directed therapy for the treatment of AA in children aged 12 years and older, there has been a lack of data in pre-adolescent children.9 In one case series of 4 preadolescent children aged 8 to 10 years with AA, 3 children were treated with oral tofacitinib 5 mg twice daily which is the standard dose used in ongoing clinical trials for juvenile idiopathic arthritis in children and adults who weigh more than 40 kg. The fourth patient was initiated on 5 mg once daily to determine if any hair regrowth would occur at this lower dose, however, this was increased to 5 mg twice daily at 3 months due to no response to the lower once-daily dosing. Two patients demonstrated complete hair regrowth by 3 months and 6 months of therapy. The third patient had 62% hair regrowth by 6 months of treatment. The fourth patient only had scant regrowth of terminal hairs. Over the treatment period of 6 to 15 months, none of the participants experienced any adverse events or laboratory abnormalities.10 The results in this study demonstrate that oral JAK inhibitors are a promising therapeutic option for the treatment of AA in preadolescent children, however, long-term safety data in this population is warranted.
A recent survey of 900 physicians, including 300 dermatologists, indicated that 66% of them were recommending routine supplementation with biotin for skin, hair, and nail health. Biotin, also known as B7 or H, is an essential cofactor for many important metabolic pathways. It is known that biotin deficiency can result in neuromuscular dysfunction, alopecia, and dermatitis, however, deficiency is extremely rare given that a typical Western diet includes more than sufficient amounts of biotin.11
Routine recommendation of biotin supplementation in patients with normal biotin levels should cause the physician to pause and consider the implications as biotin can interfere with several laboratory assessments that use biotin as part of the immunoassay. The FDA recently issued a warning for interpreting laboratory results in patients taking biotin supplementation as it can cause falsely low troponins, thyroid stimulating hormone levels, N-terminal pro-brain natriuretic peptide, and parathyroid hormone levels, as well as elevated free triiodothyronine levels. Given its half-life, it is recommended that patients taking 10 mg/day of biotin stop taking it for 8 hours before scheduled laboratory tests. For those taking 100 to 300 mg of biotin daily, they ought to stop taking it for 3 days leading up to laboratory testing.11 The use of over-the-counter supplements such as biotin has become increasingly popular in the treatment of common conditions. The lack of evidence supporting biotin’s efficacy in treating dermatologic conditions and the potential for misinterpretation of important laboratory data should cause the clinician to pause before recommending its use.
Article continues on page 2