In the second of a two-part article on treating psoriasis, Dr Priya Patel reviews the systemic treatment options available for the disorder and discusses some novel modalities
In part one of this article, which was published in the January 2018 issue of Aesthetics, I discussed the topical treatment options that are available for the chronic inflammatory disorder, psoriasis. Generally, patients are initiated on topicals and those with more severe or refractory symptoms may need dermatological assessment and systemic treatment, then biologics, depending on their disease severity and efficacy of the treatment. Many of these therapies have been used for years and are known to be safe and effective in most cases. However, newer therapies are emerging that are focusing on immunological pathways, which are showing promise and with time may be more cost-effective and safer than traditional systemics.
Across Europe, treatment of moderate to severe psoriasis varies, as there is limited data comparing therapies. One study from 1977-2000 demonstrated that only 8% of randomised control trials compared different systemics, with merely two trials comparing more than two systemics (ciclosporin vs. etretinate).1-3 The limitations to most of the trials are due to inconsistent data regarding doses, length of treatment, incomplete outcomes, short follow-up times and small patient samples.1,4,5 However, although many studies do not allow for effective comparison of treatments, they do demonstrate efficacy of systemics, as discussed below.
Ultimately, therapies should be chosen based on an individual’s comorbidities, psoriasis severity and patient choice after the benefits and risks are fully explained by the practitioner
Systemic therapies include ciclosporin, methotrexate, retinoids, hydroxyurea and fumaric esters. Although many of these therapies have shown to be effective, they have increased toxicities compared with topicals, limiting their long-term use.6 Additionally, many are utilised in rotations to minimise the side effects. However, the difficulty with this is that psoriasis can flare or return whilst off treatment or during transition. In many countries, there are discrepancies between which systemic should be used as a first-line treatment. Ultimately, therapies should be chosen based on an individual’s comorbidities, psoriasis severity and patient choice after the benefits and risks are fully explained by the practitioner.
Ciclosporin has been used throughout Europe since the early 80s because many clinical trials have found it to be effective.4,7-9 It primarily acts as an immunosuppressant, with doses ranging between 2-5mg/kg in divided doses and gradually incremented by 0.5-1mg/kg over two to four weeks.9,10
After six to 12 weeks, if no response is seen, then therapy should be discontinued. If effective, patients should remain on treatment for one to two years as ciclosporin cannot be used long-term due to its cumulative side effects. It does however, achieve remission quickly, hence therapy can then be switched to longer-term agents such as retinoids, fumarates and methotrexate.4,9,10
The side effect profile includes hypertension, nephrotoxicity and immunosuppression. Patients need regular blood tests and blood pressure checks (two per week for the first two months, then monthly thereafter) to monitor for adverse reactions; if they occur, ciclosporin must be discontinued.10,11-13 The risk of hypertension and nephrotoxicity increases with increased dose and duration of ciclosporin and generally desists on discontinuation.12,13 Additionally, ciclosporin metabolism is influenced by cytochrome p450 enzymes; therefore, many drugs can interfere and interact with it, such as steroids, amiodarone, erythromycin, phenobarbital, orlistat and the herbal remedy, St John’s Wort.9
This would limit ciclosporin use in elderly populations, given their comorbidities and polypharmacy. As ciclosporin is an immunosuppressant, patients have an increased risk of malignancies, with trials showing an estimated 2.2-3.8% increased risk.9,14 These risks were at the higher end if patients had a past history of psoralen and ultraviolet A (PUVA), methotrexate or other immunosuppressants.10,14 Therefore, ciclosporin is contraindicated in patients with malignancies, renal dysfunction, and uncontrolled hypertension or during lactation.9 Relative contraindications include active infections, immune-deficiencies, chronic organ failures or pregnancy.9
One randomised control trial with 85 patients (43 in the methotrexate group and 42 in the ciclosporin group) with moderate to severe psoriasis showed 60% and 71% PASI-75 responses for methotrexate (discussed below) and ciclosporin respectively.1,15 Therefore, both were effective with ciclosporin having higher clearance rates, but not at a statistically significant level (p value=0.29).15 However, the sample numbers were small and therefore small differences could be missed. Another trial indicated methotrexate potentially has a faster clearance rate compared to ciclosporin, but the efficacy of both drugs was similar, with the limiting factor being a small sample size of 30 patients.16 Trials demonstrate clinical inconsistencies due to varying patient sizes, disease severity and follow-up periods.4,7 No one trial has used very large sample sizes, making the true efficacy harder to estimate. Nonetheless, ciclosporin is known to be effective in treating psoriasis, but patients should be warned about variable responses.6
Methotrexate is a known immunosuppressant, which has been used to treat psoriasis successfully for more than 40 years, despite the exact method of action remaining unclear and with no large-scale randomised control trials conclusively proving its effects.4,17
Methotrexate is commonly given once per week as an oral dose based on weight, but can be given intravenously or intramuscularly, with a maximum dose of 30mg/week.18,19 However, the side effect profile is extensive; common side effects include gastrointestinal disturbance, headaches, bone marrow/blood dysfunction, fibrosis (pulmonary and hepatic are most common), hepatotoxicity, skin reactions or hypersensitivity and conditions associated with immunosuppression, such as malignancies or infections.7,18,20-22 Deaths have been reported with the use of methotrexate in the treatment of psoriasis due to fatal toxic reactions,18 however it is my understanding that these are uncommon.
Additionally, methotrexate is teratogenic and secreted during lactation; hence, patients must undergo pregnancy prevention schemes prior to drug administration
Similar to other systemics, the side effect profile increases with dose and duration, although this does not occur in all cases. Generally, side effects reverse with cessation or reduction of therapy.18,21 As the risks are extensive, it should only be considered in severe psoriasis that is refractory to topicals and the lowest doses possible should be used.21 It is contraindicated in patients with severe hepatorenal dysfunction and relatively contraindicated in bone marrow dysfunction, immunodeficiency and acute infections.18,20
Additionally, methotrexate is teratogenic and secreted during lactation; hence, patients must undergo pregnancy prevention schemes prior to drug administration.18 Furthermore, women should avoid pregnancy until one month post-discontinuation and men should not impregnate their partners until three months post-discontinuation.18,19 Alongside pregnancy prevention, patients must also have regular bloods tests – full blood count (FBC), urea and electrolytes (U+E) and liver function tests (LFT) – with additional liver biopsies if hepatotoxicity is suspected (note that this may not always show on routine blood tests).18,19,22 An additional test that can be performed is Type III procollagen aminopeptide (PIIINP), as normal levels indicate a lower risk of hepatic fibrosis and raised levels could warrant biopsy.23-25 Non-steroidal anti-inflammatories and salicylates can interact with methotrexate metabolism, increasing the risk of toxicity, thus concomitant use should be avoided, especially with existing renal dysfunction and folate deficiency.18,20,21,26 Overall, methotrexate patients should be carefully selected and monitored; however, it has been shown to be a relatively safe, well-tolerated and cost-effective medication.7,19,26-28
Smaller case series, reports or retrospective studies have suggested methotrexate can reduce psoriasis severity by 50% in more than 75% of patients.4 One small study of 85 patients with moderate to severe psoriasis showed a 50-60% reduction in PASI scores after four months of using 15mg methotrexate.15 Comparatively, another small study with 30 patients demonstrated faster clearance in one month using an average of 27.7mg/week of methotrexate.1,16
Retinoids are vitamin A derivatives, for which several formulations exist, but acitretin is widely approved in the US and Europe.29 Similarly to other systemics, its exact method of action has not been fully established; however, it acts as an anti-inflammatory, immunosuppressant and affects epidermal growth and differentiation.22,30 It has pharmacokinetic variability, thus the dose needs adjusting per patient but is usually given once/day at 25- 50mg.29,31 Retinoids are often used in combinations, such as PUVA, as they demonstrate poorer disease control as a monotherapy.6
Retinoids demonstrate variable half-lives, which is dependent on patient lifestyle and alcohol intake as this can prolong the half-life. The longest documented elimination half-life is 168 days, with three years for complete elimination of longer-acting retinoids.1
The major side effect is teratogenicity, hence it is contraindicated in pregnancy; it’s also contraindicated in women of child-bearing age as it interferes with oral progesterone contraception.29 Additionally, liver and lipid function can be affected, with clinical trials demonstrating 66% of patients developing hypertriglyceridaemia.1 Thus, patients with existing renal or liver failure or hypercholesterolaemia should not be given retinoids. Monitoring involves blood tests (FBC, U+E, LFTs, glucose and lipids) at least monthly during treatment.29
More commonly, retinoids cause mucocutaneous drying (xerosis, cheilitis and pruritus)7,30,31 with 75% of patients also experiencing drug-induced alopecia, which resolved on discontinuation.1,17 Some studies also demonstrate muscle and joint dysfunction with long-term therapy.7,31 Overall, retinoids are effective, but given their side effects, are poorly tolerated by patients, with 10-20% discontinuing treatment.32 They seem to have greatest benefit when used as maintenance for immunosuppressed patients or patients achieving clearance with other medications like ciclosporin, as it is cumulatively less toxic than other systemics.30,33
Clinical trials have shown retinoids to be effective. However, overall the data of trials is limited by variability in patients assessed (disease severity at baseline), retinoid dose and duration, use of other topical therapies and outcomes.4 Many trials collated into systematic reviews also have small patient numbers and short follow-up (two to four months).4 However, effective results have been seen in subtypes of psoriasis such as pustular and erythrodermic.33 Combinations with PUVA, discussed in Part One of this article, have shown good results whilst reducing the side effect profile of both therapies.4,34 One study of 135 patients utilising PUVA and retinoids demonstrated significant reduction in squamous cell carcinomas from 196 to 302 (p=0.002), although no difference in basal cell carcinomas was observed.35 Combination with narrow band UVB also showed efficacious treatment.4,34,36
Fumaric acid esters (FAEs)
FAEs are chemical compounds that are only approved in a few European countries, such as Germany or the Netherlands, and are not used as a first-line treatment given their side-effect profile.6,4,37 They can be utilised in the UK, but only on an individual basis, usually with refractory psoriasis and contraindications to other therapies.6 Additionally, doses and recommendations appear to vary across the world with no clear consensus.6,37,38 Hydroxyurea can be used to manage psoriasis; however, haematological abnormalities can occur with hydroxyurea, but will generally improve with dose reduction or cessation. Overall, it is a favourable drug to use, although it should be used as a last-line agent and larger studies with longer follow-ups are needed.39,40
FEAs are marketed as Fumaderm or Dimethyl fumarate, which immunomodulates peripheral T-cells and reduces keratinocyte proliferation.37,41 Side effects for FAEs include gastrointestinal disturbance, which occurs in 67% of patients, and flushing, which occurs in 33%.37 The side effects tend to be delayed and occur four to 12 weeks into therapy, but improve after a few weeks or can be alleviated with other medications such as antacids, anti-emetics or antispasmodics.37,38,42 However, if symptoms persist, either dose reduction or discontinuation should be considered, this occurs in approximately 30-40% of patients.32,37,38 Generally, FAE are monitored via blood tests, every two weeks for three months, then monthly, as they can cause high or low white blood cell count and eosinophilia as well as increased LFTs, U+Es and lipids.37,38,42
FAEs need to be gradually increased and not used with other FAEs, as there have been previous reports of renal failure (acute and chronic) when both oral and topical FAEs were used or were used for prolonged periods.37,38,43-46 It can be used with gradual increments as both short and long term therapy for less than two years, although smaller studies have used it in patients for 14 years.37,47 It is contraindicated in patients with severe hepatorenal syndrome or gastrointestinal disease or an abnormal blood profile.37,38 There have been no safety trials to assess FAE in pregnancy or lactation; hence it’s currently contraindicated in these groups. Currently, guidelines also advise against combination therapies with other systemic agents as there is an increased risk of organ dysfunction.37,38
Other studies have shown FEA used in combination with topical therapies such as calcipotriol have better outcomes compared to isolated use
FEA has shown efficacy in a systems review using pooled data from five randomised control trials.4 One study showed a statistically significant (P<0.01) reduction of body percentage of psoriasis from 21% to 6.7% after 16 weeks of treatment, with 50% of patients achieving complete clearance.4,48 However, the number of patients used in this study was small (12). For it to be applied to a wider population, further studies are needed, particularly comparing FEA with other systemics.
Other studies have shown FEA used in combination with topical therapies such as calcipotriol have better outcomes compared to isolated use.49 This combination showed 50% reduction in PASI in 143 patients after three weeks compared to nine weeks when used as a monotherapy.49
Newer agents, such as biologics, are a growing area for psoriasis treatment.6,50 Biologics are protein based chemicals cultured in laboratories from living cells.51 Many patients can be started on these if traditional methods have failed and their psoriasis is clinically and psychologically severe to warrant novel therapies.6,52 Some newer agents include tumour necrosis factor-? (TNF?) inhibitors (such as infliximab, etanercept or adalimumab).53-59 Anti-TNF?’s reduce the inflammatory process associated with psoriasis and have been shown to be comparable or better than ciclosporin.60
Other options include secukinumab, a human anti-interleukin-17A monoclonal antibody. A Taiwanese study of 51 patients showed 75% improvement in PASI after 12 weeks in 87.5% of patients compared to 0% of placebo.61 This has shown efficacy and safety during 52 weeks of follow-up and further trials are being conducted.
Other newer agents emerging include itolizumab, an anti-CD6 humanised monoclonal IgG1 antibody, which has recently been used in seven Indian patients, refractory to other therapies.62 In this study, five patients responded positively to therapy with a PASI-90 and the remaining two responded well to PASI-7.62
Lastly, apremilast has emerged. This is an oral phosphodiesterase inhibitor, which has anti-inflammatory properties and has a favourable safety profile seen in two to three year data analysis.63 However, it appears to be better in those with a lower PASI score (<20) and with a lower BMI as those with larger BMIs endured more gastrointestinal side effects.64 Apremilast has shown efficacy with PASI-75 being achieved in patients after 16 weeks and participants even demonstrated small improvements in psoriatic arthritis.65 Overall, the advantages of biologics are they have longer remission periods and are effective for refractory psoriasis and some have been effective in psoriatic arthritis.60 However, they are very costly and the long-term safety profile has not been fully established; although, more therapies are continually emerging with further evidence being produced.60
Generally, for mild to moderate psoriasis, emollients and topicals can be administered and managed in the community. However, complex cases will likely need dermatological assessment and review for possible systemics. Ultimately, failing all of the above, biologics can be considered in certain patients. At all times, a patient’s comorbidities and systemic disease associated with psoriasis must be assessed; with lifestyle recommendations given to prevent further complications. Lastly, the psychosocial impact of disease should not be overlooked and these burdens must be addressed for patients to feel valued and treated as a person not a disease.