Novel and Emerging Strategies
Fumaric acid esters. Fumaric acid is a naturally occurring acid first isolated in 1832 from Fumaria officinalis L., a member of the poppy family. Plants in this family have been used medicinally since ancient times (European Commission 2003). More recently, fumaric acid esters, including dimethylfumarate and salts of monoethylfumarate, have shown promise in treating dermatologic conditions, including psoriasis. In 1994, a combination of dimethylfumarate and three salts of monoethylfumarate, Fumaderm, was approved in Germany for the treatment of psoriasis (Dunn 2013). Fumaric acid esters have been described as safe and effective for the treatment of psoriasis and other dermatologic diseases, and are used off-label to treat psoriasis in many countries (Wollina 2011; Atwan 2015).
Fumaric acid esters can be taken orally and have been shown to be mostly safe, with mild side effects such as flushing and gastrointestinal disturbance (Atwan 2015). A 2014 meta-analysis (pooled analysis of published data) showed fumaric acid treatment was as effective as methotrexate for the treatment of psoriasis (Schmitt 2014). Also, a 2004 trial on 40 psoriasis patients found that fumaric acid esters, particularly dimethylfumarate, led to complete clinical remission in 82.5% of participants at 6 months (Carboni 2004).
In a retrospective study of data from 127 adolescents treated with fumaric acid esters for up to 60 months, researchers found average improvements of up to 66% on standardized psoriasis severity scales. These results were achieved by 36 months, though significant improvements were observed by 6 months (Reich 2016). A trial on 13 psoriasis patients (10 of whom completed the trial) showed that fumaric acid ester treatment for 24 weeks led to significant improvements is psoriasis severity in 80% of participants. Two of three subjects who had insulin resistance at baseline showed normal insulin responsiveness at the end of the study, and highly sensitive C-reactive protein (hs-CRP, a marker of systemic inflammation) improved by a median of 25% among participants who showed clinical psoriasis improvement. The treatment also appeared to ameliorate cardiovascular risk, as endothelial function improved by the end of the treatment period. The researchers suggested future trials investigate the potential of fumaric acid esters to improve cardiovascular outcomes in psoriasis patients (Boehncke 2011).
A 13-week randomized controlled trial on 143 psoriasis patients showed that oral fumaric acid esters plus topical calcipotriol (a vitamin D analog) outperformed fumaric acid esters alone. The combination treatment was more effective and faster acting than standalone fumaric acid esters. Because the combination regimen allowed for a slightly lower dose of fumaric acid esters, the researchers concluded that the risk-benefit ratio favored calcipotriol plus fumaric acid esters over fumaric acid esters alone (Gollnick 2002).
Small molecules. Small molecule drugs such as tofacitinib (Xeljanz) and ruxolitinib (Jakafi) are emerging as therapeutic options for treating psoriasis. Whereas biologics are delivered by subcutaneous or intravenous injection, many small molecule drugs can be administered orally or topically. Also, unlike large, protein-based biologics, these small molecule drugs are less likely to provoke immune reactions (Bagel 2014; Gooderham 2013; Morrow 2004).
- Tofacitinib. Tofacitinib is an immunosuppressant approved for rheumatoid arthritis. This drug blocks enzymes called Janus kinases (JAKs), which is thought to result in suppression of the pro-inflammatory action of several interleukins, including interleukin-6 (IL-6) (Migita 2014; Garcia-Pérez 2013; Levy 2012; Bagel 2014; Patel 2012; Lundquist 2014).
In a 2015 trial, oral tofacitinib was superior to placebo and as safe and effective as etanercept, one of the most widely used injectable biologics, for the treatment of moderate-to-severe plaque psoriasis. Long-term studies are ongoing to confirm efficacy and safety (Bachelez 2015).
- Ruxolitinib. Ruxolitinib is a JAK inhibitor that can be administered topically. In a clinical study, application of ruxolitinib cream for 28 days significantly decreased the extent and severity of psoriasis lesions compared with placebo, with only mild side effects reported. Ruxolitinib is currently under development as a treatment for psoriasis (Gooderham 2013; Garcia-Pérez 2013; Levy 2012; Punwani 2012).
Biologics. Several new biologics are under development for the treatment of psoriasis. These agents target various inflammatory cytokines and their receptors, including IL-17 and IL-12/23 (Garcia-Pérez 2013; Patel 2012).
- Brodalumab. Brodalumab is a human monoclonal antibody that blocks the action of IL-17 by binding to its receptor (Bagel 2014). In one clinical trial, brodalumab demonstrated clearance of nearly two-thirds of psoriasis lesions in patients with severe psoriasis within 12 weeks. Side effects such as upper respiratory infection, low white blood cell count, and suicidality necessitate more extensive trials to confirm safety (Papp 2012; Carroll 2015; Patel 2012).
- Ixekizumab. Ixekizumab is a humanized monoclonal antibody that blocks the actions of IL-17. In a clinical study, the highest injectable dose of ixekizumab (150 mg) completely cleared the skin of approximately 40% of psoriasis patients by 12 weeks, with no serious adverse effects reported. Ixekizumab is currently undergoing further clinical trials (Leonardi 2012; Declercq 2013; Patel 2012; Garcia-Pérez 2013).
- Briakinumab. Briakinumab is a human monoclonal antibody that inhibits the actions of IL-12/23 (Patel 2012; Garcia-Pérez 2013; Gordon 2012). In a large year-long clinical trial, briakinumab was effective in the treatment of moderate-to-severe psoriasis. This study confirmed a previous trial showing that briakinumab can provide considerable relief from psoriasis. Since some adverse effects such as serious infections and skin cancers were reported, additional evaluation of the safety profile of this drug is needed (Gordon 2012; Garcia-Pérez 2013; Patel 2012).