Etanercept is a fusion protein of the p55 receptor for TNF bound linked to a constant region, antibody backbone. It was the first anti-TNF agent approved for the treatment of psoriasis. Etanercept is dosed as a 50 mg subcutaneous injection given twice weekly for the first 3 months of treatment followed by weekly dosing. Etanecept is also approved for the treatment of psoriatic arthritis.

The primary endpoint of the pivotal phase III clinical trials with etanercept was after 12 weeks of therapy, when 49 % of subjects reached a PASI 75 at that time point [30]. Higher rates of response, including PASI 90, and complete clearance were not reported. At 6 months, with the continued 50 mg twice weekly schedule, the PASI 75 rate increased to 59 % [30]. However, with the indicated dosing schedule and dose reduction after 3 months, PASI 75 rates only reach 54 % [31]. Additional studies with 25 mg twice weekly resulted in only 51 % of patients reaching a PASI 75 [32]. Longer-term analysis has not been done in these clinical trials. Additional studies have shown that etanercept can be successful in treating scalp psoriasis [33].

Infliximab was the second medication in this class to be approved for psoriasis and is also approved for psoriatic arthritis. It is dosed as an IV infusion, usually over 2 h starting at a dose of 5 mg/kg given weeks 0, 2, 6 and then every 8 weeks. Infliximab is a chimeric, monoclonal antibody that maintains a primarily murine binding site.

Since its approval to very recently, infliximab has had the highest short term efficacy of any biologic immunotherapy. At the 10 week primary endpoint of the phase III clinical trials, infliximab had a PASI 75 of 80 % and a PASI 90 of 57 %, and complete clearance of 26 % [34]. However, due to a number of potential factors including a rapid decrease in blood levels due to the decrease in the frequency of dosing in maintenance therapy and/or immunogenicity of the medication, the clinical efficacy of infliximab decreases significantly over the first year. At 1 year, the efficacy decreases to only 61 % of patients achieving a PASI 75 from the original highs [34].

Adalimumab was the most recent anti-TNF agent to be approved for the treatment of psoriasis. This medication is a human monoclonal antibody that is dosed as a 40 mg sub-cutaneous injection given as 80 mg week 1, 40 mg week 2, then 40 mg every other week. Like the other anti-TNF agents, it is approved for the treatment of psoriatic arthritis, as well.

The primary endpoint of the phase III clinical trials of adalimumab were 16 weeks. Inclusive in these trials was the Champion trial, the first biologic therapy comparator trial, comparing adalimumab with methotrexate. The PASI 75 in these trials was 79.6 % with a reported PASI 90 of 51.3 % and complete clearance of 16.7 %. In the Champion trial, adalimumab was markedly superior to methotrexate. Long term efficacy of adalimumab is, unfortunately, difficult to ascertain as the primary trials were done with a withdrawal and retreatment structure [35]. However, it is clear that there is some loss of effect of adalimumab over time [36]. Studies of adalimumab in palmar-plantar psoriasis have also shown benefit [37].

While there are variances in safety outcomes between the anti-TNF agents, the general issues associated with them are present across the class. In understanding anti-TNF safety, it is critical to remember that this is the only class of psoriasis biologics that was initially developed for other indications, Crohn’s disease and rheumatoid arthritis. Most of the reports of safety concerns with these medications stem from use in these other indications. An analysis by Burmester and colleagues showed that the rates of medication associated side effects for adalimumab were markedly lower for psoriasis in clinical trials than for other indications [38]. This finding may be due to a healthier clinical trial population, younger age, and/or the presence of other immune suppressive medication. Yet it makes comparison of the side effect profiles of anti-TNF agents with other agents approved only for psoriasis extremely difficult.

The primary risk associated with anti-TNF agents is infection. Anti-TNF agents have been associated with slight but increased risk of serious infections, opportunistic infections, and reactivation of tuberculosis and hepatitis B in the general populations studied. However, when psoriasis is studied exclusively, no increased risk of infection can be identified in short-term treatment when compared to placebo [39]. Nonetheless, it is likely that there is an infectious risk associated with anti-TNF agents for psoriasis, especially for non-serious infections [40]. Screening for latent tuberculosis should be done regularly and prior to starting patients should be screened for exposure to hepatitis B [41, 42].

Cancer risk of anti-TNF agents is more controversial. Concerns of an increased risk of lymphoma and certain solid tumors are common. No good information on these long-term risks exist in psoriasis patients treated with anti-TNF agents. However, in meta-analysis analysis of rheumatoid arthritis patients treated with TNF alpha inhibitors, lymphoma risk does not seem to be any higher in anti-TNF treated populations than in comparably severe patients treated with other modalities [43]. Likewise, the incidence of solid tumors as well as recurrence or cancer in patients who are treated with anti-TNF’s does not seem to be increased [40]. In a recent prospective long term study of etanercept users, the rates of malignancies excluding NMSC and lymphoma were not higher than the rates of the general psoriasis population [44]. The possible exception to these findings are non-melanoma skin cancer and, possibly, melanoma, that seem to be a bit higher in anti-TNF treated patients [40].

Other risks associated with anti-TNF therapy, including worsening of demyelinating disease and congestive heart failure come from attempts to treat these conditions with this type of therapy [39, 41]. Anti-TNF agents did not seem to show benefit in these conditions and treatment seemed to worsen some patients. Thus, anti-TNF therapy should be avoided in patients who suffer from or are at high risk for these conditions.

The next step in the simplified sequential model of psoriasis pathogenesis is the activation of Th17 cells after stimulation with IL-23. Ustekinumab is a human monoclonal antibody directed against the p40 sub-unit protein shared by IL-12 and 23. Interestingly, it was initially postulated to be of use in psoriasis based on the older Th1 model through its impact on IL-12. Subsequently, the belief is that it is the impact on IL-23 that is most important [18, 45–47]. Ustekinumab has been shown to markedly down regulate gene expression in the Th17 pathway emphasizing its mechanism consistent with the sequential model [46].

Ustekinumab is given as either a 45 or 90 mg dose depending whether the patient is greater than or less than 100 kg. The primary endpoint of the initial phase III clinical trials with ustekinumab was PASI 75 at 12 weeks of therapy. Rates of response were around 67 % for those receiving 45 mg and 66–76 % for those receiving 90 mg dosing [48, 49]. In long-term extension trials, response was maintained with no evidence of significant safety signals [50]. One concern with blocking IL-12 was that this would induce immune deviation and increase the risk of infection. However, 5 year follow up in clinical trials does not seem to lend credence to this theory with no increase in infection rates seen [51]. However, trials with another IL-12/23 inhibition, briakinumab suggested increased rates of infectious risk, skin cancers, and major adverse cardiac events suggesting that continued attention needs to be paid to safety outcomes [52, 53].

Despite the evidence suggesting the safety of ustekinumab, the data on briakinumab as well as theoretical concerns has led to the development of biologic medications that bind only to the p19 subunit of IL-23. This mechanism would leave IL-12 intact. Moreover, trials with these agents would answer a fundamental question, whether the IL-12/Th1 pathway that was the focus of the initial immunological models of psoriasis, has a therapeutic role at all in the treatment of this disease. At the time of this writing, phase II data on two medications, guselkumab and tildrakizumab, have been published. Both of these agents have high-level responses [54, 55]. In fact, in a comparator trial with adalimumab, guselkumab was more efficacious for both short and year-long therapy from a phase II study (Gordon, NEJM, in press). Peak efficacy was seen with PASI 75 scores at week 16 of 81 % compared to 71 % for those patients receiving adalimumab. Tildrikizumab also showed high level responses in phase II trials with PASI 75 results reaching 72 % (in press British Journal Of Dermatology). This high level efficacy continued through week 52. While safety is impossible to evaluate in small, phase II trials, it is difficult to imagine that the safety record will be inferior to that seen with ustekinumab. Thus, these trials validate the present model of psoriasis with a minimal to no role for the Th1 pathway and suggest more specific pathways for the treatment of psoriasis.

Upon identification of IL-17 as the critical connection between the immune system and the keratinocyte reaction in psoriasis, a number of biologic immunotherapies have been developed to inhibit this key cytokine. There are a number of different ways this IL-17 can be inhibited [56]. There are multiple isoforms of IL-17 found in psoriatic skin. There is upregulation of IL-17A and IL-17 F, which can form 2 sub-unit homodimers or form an A/F heterodimer, as well as IL-17C [25, 57]. Additionally, IL-17C is produced by keratinocytes and may have an autocrine function in the skin [58]. Interestingly, all of these isoforms bind to the IL-17 receptor A to have their effector function. Thus, it is possible to inhibit this system either by making a biologic molecule that would bind the cytokines themselves or more generally block the pathway by inhibiting binding to the receptor.

There are three new biologic medications that are designed to specifically inhibit IL-17. The first of these to be approved by regulatory authorities is secukinumab, a molecule that binds IL-17A specifically. Similarly, ixekizumab acts specifically on IL-17A not binding IL-17 F or IL-17C. In contrast, brodalumab blocks this pathway at the receptor level, binding and blocking activity of the IL-17RA receptor and inhibiting all three isoforms. Therefore, two theoretical questions arise. First, would blockade of the entire system through the receptor give higher levels of efficacy and second, is more specific blockade of IL-17A alone a safer strategy? These questions can only be answered by clinical data.

Phase III data on all of these drugs has recent become available. At the time of this writing, secukinumab has the most extensive available data set. In a recent publication of two phase III studies, this medication shows PASI 75 responses at week 12 of 77–82 % with 300 mg dosing and 67–72 % with 150 mg dosing [59]. In phase III trials, ixekizumab, shows PASI 75 results of 87–89 % and PASI 100 results of 35–41 % (Lancet, in press and presented at World Congress of Dermatology (WCD) 2015). Brodalumab has extremely high responses, as well, with PASI 75 responses of up to 85 % and PASI 100 of up to 42 % (presented at WCD 2015). What is fascinating is that the responses to all these medications is extraordinarily fast. Theoretically, this rapid response is related to the blockade of IL-17 itself which, along with inhibition of continued immune responses, stops the binding of the cytokine that directly impacts keratinocyte responses. Thus, as we are measuring the severity of psoriasis through clinical changes associated with keratinocyte reactions to inflammation, directly modifying this response could lead to greater improvement in disease, faster.

As secukinumab and ixekizumab has only recently been approved and brodalumab is not yet in general clinical use, it is impossible to definitively judge long-term safety. However, the clinical trials for all these medications have very large data sets and thinking of them collectively gives a sense of any safety issues of the class. By considering the role of IL-17 in health, the production of local responses to invading organisms, one would predict that these medications would increase the risk for local staphylococcal infections and candida infections. In fact, all three of these medications show some increase in very mild candida infections in the clinical trials population [59–61]. However, other infectious or other safety risks do not seem to be present. One additional completely unpredicted safety concern is the possibility of worsening established Crohn’s disease. From a purely immunological point of view, blockade of IL-17 should induce a great improvement in Crohn’s. However, in clinical trials of patients with active Crohn’s disease, a number of subjects worsened. At present, this difference between the very high level responses seen in psoriasis and the worsening of Crohn’s remains a mystery though it has been ascribed to differences in the microbiome of the skin and the gut. Luckily, the effect on Crohn’s seems to have little impact on patients with psoriasis though caution should be taken in patients who have both conditions.

One final safety concern has recently been identified with brodalumab among this class of medications, specifically. Though the data have not been fully analyzed, there have been a small number of completed suicides in the clinical trials of brodalumab. To date, there have been no completed suicides in either the secukinumab nor the ixekizumab clinical development programs, leading to a concern that this finding may be specific for blockade of IL-17 receptor rather than the cytokine IL-17A itself. While this remains speculation, the lack of events in both secukinumab and ixekizumab are comforting for the clinical use of these agents.