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Long-term Safety of Oral Systemic Therapies for Psoriasis: A Comprehensive Review of the Literature

Abstract

Oral systemic therapies are important treatment options for patients with moderate-to-severe psoriasis, either as monotherapy or in therapy-recalcitrant cases as combination therapy with phototherapy, other oral systemics or biologics. Long-term treatment is needed to maintain sufficient disease control in psoriasis, but continuous use of systemic treatments is limited by adverse events (AEs) and cumulative toxicity risks. The primary aim of this comprehensive literature review was to examine the long-term safety profiles of oral agents commonly used in the treatment of adults with psoriasis. Searches were conducted in EMBASE and PubMed up to November 2018, and 157 relevant publications were included. Long-term treatment with acitretin could be associated with skeletal toxicity and hepatotoxicity, although evidence for skeletal toxicity is mixed and hepatotoxicity is rare, particularly at low doses. Other safety issues include hyperlipidaemia and potential for teratogenicity up to 2–3 years after discontinuation of treatment. There is a paucity of data on long-term treatment with apremilast. Continued exposure to apremilast does not seem to increase the incidence of common AEs, such as gastrointestinal (GI) AEs, upper respiratory tract infections and headache, while the long-term risks for depression, suicidal thoughts and weight loss are unknown. Long-term ciclosporin treatment is associated with renal toxicity, hypertension, non-melanoma skin cancer, neurological AEs and GI AEs. Long-term methotrexate treatment is associated with hepatotoxicity, GI AEs, haematological toxicity, renal toxicity and alopecia. Finally, long-term treatment with fumaric acid esters (FAE) is associated with GI AEs, flushing, lymphocytopenia, proteinuria and elevated liver enzymes. Median drug survival estimates varied considerably: ~  2.9–9.7 months for apremilast; ~ 5.4 months for ciclosporin; ~ 8.6 months for acitretin; ~ 12.1–21.6 months for methotrexate; and ~  54.8 months for FAE. These long-term safety profiles may help to guide clinicians to select the optimal oral systemic treatment for the long-term treatment of psoriasis in adults.

FormalPara Key Summary Points
Due to the chronic nature of psoriasis, long-term systemic treatment is often needed to maintain sufficient disease control. It is clinically important to consider the potential adverse events and cumulative toxicity risks associated with the long-term use of oral systemic therapies.
This comprehensive literature review discusses the long-term safety profiles and adverse events frequently associated with oral systemic therapies and the ways in which these can be managed.
Drug survival estimates differed considerably between treatments and may have been influenced by inter-study variability.
Understanding the differential risks associated with the long-term treatment of psoriasis will serve to improve risk–benefit assessment and therapeutic decision-making for clinical practice.
Further work is needed to better define ‘long-term’ therapy and standardise safety reporting to enable more accurate comparisons between agents.

Introduction

Oral systemic therapies represent an important component of the psoriasis treatment regimen, particularly for patients with moderate-to-severe disease and for those with mild disease who do not respond sufficiently to topical agents and/or phototherapy [1, 2]. When response to a single treatment is not sufficient, two or more treatments with different mechanisms of action and compatible safety profiles may be combined to achieve better disease control while limiting toxicity [3,4,5]. Such treatment strategies may include combinations of two oral systemic agents or use of an oral systemic agent together with phototherapy or a biologic. Several oral agents are currently licensed for the management of psoriasis; systemic agents with a long history of use include the so-called ‘conventional’ psoriasis treatments methotrexate (first used in the USA in 1958 [6]), acitretin (approved in Germany in 1992 [7]), ciclosporin (approved in Germany in 1993 [8]) and formulations of fumaric acid esters (FAE; approved in Germany in 1994 [7]) [9, 10]. More recently, two small-molecule drugs have also been approved in Europe for plaque psoriasis treatment: apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor, in 2014; and dimethylfumarate (DMF), a novel FAE monotherapy, in 2017 [11, 12]. Some of the conventional agents were developed prior to the current era of evidence-based medicine and, consequently, safety and efficacy data have been obtained predominantly from wide clinical experience, rather than from high-quality randomised controlled trials (RCTs) [2]. In contrast, for the biologic therapies in psoriasis high-quality evidence is available in support of their efficacy and safety.

In clinical practice, the question of when to choose an oral treatment versus a biologic is mostly dictated by national treatment guidelines and reimbursement criteria. In general, a patient with psoriasis is considered to be a valid candidate for systemic therapy when the affected area exceeds 10% of the body surface area, the disease involves special areas, such as scalp or genitalia, and/or topical therapy has failed [13]. Current treatment guidelines recommend a conventional oral drug as first-line systemic treatment for moderate-to-severe psoriasis, whereas a biologic is applied as second-line treatment in case of treatment failure, intolerance or contra-indication to an oral therapy [14]. In line with this, real-world registry data demonstrate that a significant proportion of patients on systemic therapy are treated with an oral agent [9, 10]. Observations in daily clinical practice have shown that many patients discontinue and switch to an alternative psoriasis therapy during the course of their treatment. In a retrospective, longitudinal cohort study of patient data from a USA health claims database, 23% of patients switched treatment in the previous year [15]. In addition, results from a retrospective chart review of 166 patients with moderate-to-severe psoriasis indicated that on average there were 1.2 treatment changes per year, most commonly due to poor disease control or flare of psoriasis [16]. Furthermore, adverse events (AEs) are often a reason for premature discontinuation of conventional oral systemic psoriasis treatments in clinical practice [17].

Given that psoriasis is a chronic disease and all available treatments are only immune modulating, long-term treatment is often necessary to maintain sufficient disease control. However, due to the potential risks of AEs and cumulative toxicity associated with long-term treatment with systemic agents, a risk–benefit assessment individualised for each patient is required before treatment initiation. The risk–benefit ratio of systemic agents is dependent upon several factors, including drug efficacy, toxicity profiles and individual patient characteristics [18]. To allow optimal risk–benefit analysis and well-balanced decision-making for long-term psoriasis management, insight into the long-term safety profiles of the available oral systemic therapies is essential. However, a clinically oriented overview of the long-term safety profile of oral psoriasis treatments, including a comprehensive assessment of recently published data, is lacking.

The aim of this comprehensive review of the literature is to examine the long-term safety of five common oral systemic agents that are used in the management of moderate-to-severe psoriasis and are recommended in the current European psoriasis guidelines [7].

Methods

Scientific publications relating to the long-term safety of the systemic agents used for the treatment of psoriasis were identified through a comprehensive search of the literature, focussing on long-term safety (defined here as ≥ 6 months), risk–benefit profile and drug survival (defined as how long a patient remains on a given therapy continuously). Types of articles included were: primary manuscripts; review articles; case series; clinical trials; comparative studies; meta-analyses; and observational studies. Exclusion criteria were: congress abstracts; publications not in English; pre-clinical studies, including animal studies; articles in which combination treatments were used; articles describing indications other than psoriasis; articles in which patients were treated for < 6 months.

In November 2018, literature searches were conducted in EMBASE (Table 1) and PubMed (using the filter ‘publication date from 2018/10/01’; Table 2) to obtain the most recent literature. Additional references were found using hand searches and screening of the reference lists of identified articles.

Table 1 Abbreviated EMBASE search strategies (search date 7 November 2018)
Table 2 Abbreviated PubMed search strategies (search date 19 November 2018)

Citations were screened by title and abstract, and additional focussed criteria were applied to narrow down the number of articles remaining for full-text screening at the next stage. Focussed criteria for inclusion were: adults with moderate-to-severe plaque psoriasis treated with monotherapy; European or North American population; exclusion of single-case studies. The full-text articles of the resulting publications were further screened before inclusion.

This article does not contain any studies with human participants or animals performed by any of the authors; therefore, ethics committee approval was not required.

Results

After screening the full-text articles, 157 were included in this comprehensive review of the literature (Fig. 1; Table 3; [2, 14, 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]). In this section, we describe the long-term safety profile of each of five common oral systemic agents (acitretin; apremilast; ciclosporin; methotrexate; FAE, including DMF) used to treat moderate-to-severe psoriasis in adults.

Fig. 1
figure 1

Search results. *Focussed criteria for inclusion were: adults with moderate-to-severe plaque psoriasis treated with monotherapy; European or North American population; articles available in English language; exclusion of single-case studies. Note that articles may appear in more than one drug category. FAE Fumaric acid esters

Table 3 Summary of long-term safety profiles of oral systemic therapies in adult patients with psoriasis

Acitretin

Acitretin is a second-generation retinoid [23] that elicits its anti-psoriatic activity via modulation of keratinocyte proliferation and downstream anti-inflammatory pathways [36]. As per the label, acitretin is indicated for severe cases of psoriasis that do not respond to other treatments (Table 3; Electronic Supplementary Material [ESM] 1) [48, 49], but some experts recommend the use of acitretin in patients with moderate-to-severe psoriasis [7] where methotrexate and ciclosporin are not appropriate [50]. In addition, acitretin is indicated for palmoplantar pustulosis [20, 25]. It has been suggested, based on clinical experience and in the absence of head-to-head RCTs, that acitretin monotherapy is less effective for psoriasis than other conventional systemic agents [2]. Because of this, acitretin may work best when combined with ultraviolet B light, psoralen and ultraviolet A light (PUVA) or other systemic therapy, or in sequential regimens [20, 21].

Skeletal toxicity, specifically hyperostosis, is thought to be the main cumulative AE of acitretin therapy [19,20,21, 51, 52], with some early retrospective studies reporting an increased risk of skeletal hyperostosis following long-term treatment; however, evidence for this is mixed [21]. A more recent retrospective study of acitretin given at a commonly used dosage (average 27.1 mg/day) over an average of 2.13 years found no evidence of skeletal hyperostosis [53]. In line with this finding, more recent prospective studies indicate a lower risk of acitretin-induced skeletal toxicity than previously reported [21].

There is mixed evidence for a risk of hepatotoxicity [19, 21, 24, 54] and abnormal findings on liver function tests with acitretin therapy, both of which appear to be rare at the initial doses commonly used in clinical practice (25–30 mg/day) [20, 21, 23, 26, 49, 54, 55]. A small retrospective study found minimal risk of hepatotoxicity, with six (14%) patients showing transient elevation in aspartate aminotransferase levels to > 41 units/L [53]. In addition, a prospective 2-year study of acitretin (25–75 mg/day) showed no biopsy-proven hepatotoxicity [55].

Mucocutaneous AEs are seen relatively often [19, 24, 25, 56]. Many of the AEs reported following acitretin therapy result from a weakening of the epithelia [22]; these include dryness of skin [23, 26, 56] and mucous membrane [19, 23, 27], pruritus [26, 56], peeling of the palms/soles [26, 57] and alopecia [19, 23,24,25,26,27, 56].

Acitretin has teratogenic potential [19,20,21,22,23,24,25]; it is associated with foetal abnormalities, with the greatest risk reported to be at weeks 3–6 of gestation. Acitretin may also be associated with increased rates of spontaneous abortions and stillbirths [21]. Thus, acitretin should not be used in pregnant women [20], and pregnancy must be avoided through the use of effective contraception for the duration of treatment and for at least 2 years after acitretin discontinuation. Some regulatory authorities (e.g. in Germany) require effective contraception for up to 3 years [19,20,21,22, 49, 58].

Hyperlipidaemia is a potential AE of acitretin [19, 20, 25,26,27, 59]; however, this is based mainly on reviews and short-term studies. In a clinical trial, two-thirds of patients developed hypertriglyceridaemia, one-third developed hypercholesterolaemia and 40% of patients had temporary reductions in high-density lipoproteins [28]. A longer-term retrospective study found no increases in total cholesterol of clinical significance and very little impact on low-density lipoprotein cholesterol over approximately 2 years of treatment [53]; 60% of patients demonstrated an increase in triglyceride levels of > 20 mg/dL, which was similar to that seen in clinical trials, with 80% of these having triglyceride levels > 200 mg/dL. Elevated lipids induced by acitretin may contribute to coronary heart disease if not managed effectively [53].

Other AEs that are attributed to acitretin, but not specifically to long-term treatment, include myalgias [19, 23, 24], arthralgia [19, 24, 27] and pseudotumour cerebri (benign intracranial hypertension) [19, 24]. Depression and other psychiatric symptoms have been reported with other retinoids, and patients should be made aware to be vigilant for possible psychiatric symptoms [28].

An advantage of acitretin is the lack of immunosuppressive AEs. A study using data from the BIOBADADERM registry (Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases) compared infection rates with different systemic drugs [60]. Of the non-biological therapies, acitretin showed the lowest risk of infection [crude risk ratio (RR) vs. methotrexate 0.6, 95% confidence interval (CI) 0.42–0.86] and a significantly lower risk of recurrent infections (adjusted RR vs. methotrexate 0.45; 95% CI 0.23–0.87; p < 0.05) [60].

Due to the early appearance and dose-dependency of AEs, the dosing of acitretin is usually based on tolerability rather than efficacy [22]. Long-term therapy may be limited due to the potential for teratogenicity, AEs and potential end-organ toxicity [61], such as hepatotoxicity and skeletal toxicity, although evidence for end-organ toxicity is mixed.

The risk–benefit ratio of acitretin should be considered on an individual basis, along with AE monitoring [62].

Apremilast

Apremilast is a small molecule inhibitor of PDE-4, an enzyme which degrades cyclic adenosine monophosphate, thereby promoting increased anti-inflammatory cytokine production and preventing synthesis of pro-inflammatory cytokines [34]. Apremilast is indicated for patients with moderate-to-severe chronic plaque psoriasis who have failed or who have a contraindication to other systemic therapy (Table 3; ESM 2) [30, 34].

Long-term clinical trials of apremilast with up to 3 years’ follow-up have shown that the most common AEs include gastrointestinal (GI) AEs (nausea, diarrhoea); infections (upper respiratory tract infection, nasopharyngitis); and headache [33, 63,64,65]. No apparent increase in the incidence of these common AEs has been noted with continued exposure [33, 63, 66]. Infrequent and transient changes in laboratory values have been reported [66]. Real-world experience has reported similar AEs, including GI events and headache, during 7–9 months of follow-up [67,68,69]. A recent study reported that while apremilast is generally well tolerated in a real-world setting, the proportion of AEs resulting in treatment withdrawal was greater than that reported in RCTs [70].

Apremilast may be associated with an increased risk for depression, suicidal thoughts and behaviour and weight loss [7, 30, 31]. Uncommon cases of suicidal ideation and behaviour have been reported in clinical studies and from post-marketing experience, and completed suicide has been reported in post-marketing surveillance studies [34]. AEs of depression were reported in 1.3% of patients in short-term (16-week) studies [71]. Yet during long-term studies, the incidence of depression (reported by 2.8% of patients) did not increase over time, and the mean change in baseline body weight was only − 1.53 kg over 3 years [63]. Therefore, the long-term risks for depression and suicidal thoughts are unclear.

The risk–benefit profile of apremilast is deemed favourable when the lack of increase in common AEs with continued exposure is taken into account [33, 63, 66]; in addition, no standard blood monitoring is required [34]. Clinical vigilance for depression and suicidal thoughts is recommended [7, 30, 31].

Ciclosporin

Ciclosporin mediates its anti-psoriatic effects via selective inhibition of immunological pathways in T cells [36]. This immunosuppressant medication is indicated for the treatment of severe psoriasis when conventional therapy is ineffective or inappropriate (Table 3; ESM 3) [38, 72]. It is recommended for use as a short-term therapy [14, 36] before the initiation of more conventional, slow-acting treatments [73], as a low-dose (1.25–3 mg/kg/day) maintenance therapy and as part of a rotational strategy or combination treatment [73,74,75]. Occasionally, ciclosporin may be used for continuous long-term therapy for ≤ 2 years [20, 36]. However, an open cohort study showed that intermittent treatment had an improved safety profile compared with continuous treatment over 2 years [76].

Long-term ciclosporin therapy may not be possible due to AEs (in particular, nephropathy and hypertension) and risks of end-organ toxicity [61]. In addition, ciclosporin is associated with increased risks of nonmelanoma skin cancer (NMSC) and photocarcinogenic potential during long-term treatment (> 1–2 years) [14, 31], particularly in patients who have received high cumulative doses of PUVA [14, 36, 77, 78]. Another disadvantage is that ciclosporin treatment requires relatively frequent blood monitoring [35, 36, 38].

AEs with ciclosporin are common, are usually dose related and can be serious. One of the key concerns is renal dysfunction [21,22,23,24, 26, 27, 35, 37, 79,80,81,82,83,84,85,86,87,88,89,90,91,92,93] (reversible at doses ≤ 5 mg/kg/day [94, 95]; however, ciclosporin-induced nephrotoxicity can result in irreversible damage). Structural renal changes may be related to > 2 years of therapy (which worsen after 4 years [37, 79]) or doses > 5 mg/kg/day [35]. The most common effects include increased serum creatinine [81, 84, 90, 94, 96, 97] and urea levels [23, 94, 97].

Hypertension is more frequently experienced with longer-term ciclosporin treatment [22,23,24, 26, 27, 35, 37, 51, 82, 86, 87, 93, 94, 98, 99], with an incidence of 9–10% [91, 95].

Ciclosporin may also be associated with an increased risk of malignancies [especially squamous cell carcinoma (SCC) in patients with a previous history of PUVA treatment] [23, 35, 77, 78, 94, 100,101,102]. A prospective long-term (≤ 5 years) cohort study found that > 2 years of treatment (compared with < 2 years) was associated with a higher risk of malignancy (particularly NMSC) [77].

Neurological AEs, including headache [26, 35, 37, 87, 91, 103, 104], paraesthesia [23, 26, 35, 37, 91, 94, 103, 104] and tremor [35, 37, 87, 94, 104], are also seen with long-term therapy. Pseudotumour cerebri has been reported in very rare cases [103]. Finally, GI AEs, such as nausea [37, 91, 104] and GI discomfort [26, 35, 87, 94, 103], may be apparent with long-term therapy.

Abnormal values from laboratory tests can also occur, including measurements indicating hypercholesterolaemia [35, 37], hypertriglyceridaemia [35, 37, 87], hyperkalaemia [23], hypomagnesaemia [23], hyperbilirubinaemia [37, 91, 94] and decreased haemoglobin levels [94].

Ciclosporin is associated with an increased risk of infection [23]. A multicentre, prospective cohort study with a mean follow-up of 3.3 years showed a 58% higher risk compared with methotrexate (adjusted RR 1.58, 95% CI 1.17–2.15) [60]. Other ciclosporin AEs, although not always specifically associated with long-term treatment, include hypertrichosis [23, 24, 26, 35, 37, 82, 87, 93, 94, 103,104,105], gingival hyperplasia [23, 24, 26, 37, 87, 93, 94, 98, 104, 105], fatigue [37, 82, 91, 104, 105], myalgia [37], temperature hypersensitivity in extremities [37] and pulmonary AEs (cough, rhinitis and dyspnoea) [103].

Ciclosporin treatment has a risk–benefit ratio that is considered acceptable for short-term treatment [20, 73] or in cases for which there are limited treatment options. Ciclosporin may be less acceptable for patients who are at increased risk of some of the serious AEs, including renal impairment or hypertension (e.g. elderly patients) [20, 83]. The risk–benefit ratio of ciclosporin could be improved by changing the dose strategy, by using ciclosporin in combination with other psoriasis treatments (e.g. topical therapies) [106] and by keeping the cumulative dosing time to < 2 years.

Methotrexate

Methotrexate is presumed to alleviate psoriasis symptoms via the inhibition of DNA and RNA synthesis in activated T cells and keratinocytes, thereby initiating anti-proliferative and immunomodulatory mechanisms [36]. Methotrexate is indicated for the treatment of severe psoriasis (Table 3; ESM 4) [42, 107] and is also used to treat moderate-to-severe psoriasis [7]. As a DNA synthesis inhibitor, methotrexate has greater toxic effects on cells with higher division rates [108]. When used in a treatment regimen, methotrexate requires expert supervision because it can have severe wide-ranging AEs leading to GI, kidney, liver and lung toxicity. Liver enzymes and leucocyte counts need to be periodically monitored [109, 110].

Long-term studies show that AEs occur in around 61–95% of patients treated with methotrexate [26, 40, 111, 112]. However, a meta-analysis based on 2763 patient-safety years reported that AEs were treatment-limiting in only 6.9% of patients treated for 6 months [113].

Progressive and dose-dependent hepatotoxicity is a concern with long-term methotrexate therapy [20,21,22,23,24, 26, 39, 74, 114,115,116,117,118,119]. Increases in hepatic enzyme levels occur in 23–33% of patients on long-term treatment with this medication [39, 40, 112]. A 2-year retrospective chart review showed a 23% incidence of severe hepatotoxicity and an association with increased risk for diabetes mellitus [39]. Liver toxicity is rare in the absence of key risk factors, including excessive alcohol intake, concomitant non-steroidal anti-inflammatory drug (NSAID) use, diabetes mellitus, obesity, hypoalbuminaemia and high total cumulative dose [111]. Low-dose methotrexate rarely causes clinically significant liver damage in the absence of excessive alcohol intake [115]. Therefore, alcohol use should be avoided and patients with hepatic inflammation should be monitored [120]. Acute increases in liver enzymes may indicate hepatic inflammation, and if alanine or aspartate aminotransferase levels exceed ≥ 3-fold the upper limit of normal, then methotrexate should be discontinued [120]. Liver biopsies can be subject to sampling error, intra- and inter-observer variability, procedural pain and morbidity; therefore, liver biopsies are not considered to be the test of choice and non-invasive tests should be sought as an alternative [121,122,123]. Accordingly, the latest guidelines have removed the requirement for liver biopsies for patients without risk factors (e.g. obesity and diabetes) [23, 43], and the British Association of Dermatologists [124] and the German S3 guidelines [7] no longer recommend liver biopsies to monitor methotrexate-induced hepatotoxicity.

GI symptoms [20, 24, 40, 112], including nausea [23, 26, 27, 40], vomiting [23, 40] and abdominal discomfort [23], are associated with long-term methotrexate therapy. Subcutaneous or intramuscular methotrexate administration may overcome some of the limitations of oral therapy regarding GI symptoms; however, to date no studies have directly compared these two routes of administration in patients with psoriasis [125]. Dose reductions of methotrexate may help to avoid GI symptoms and the addition of folic acid to the therapeutic regimen is also helpful, although high doses of folic acid can diminish the therapeutic effect of methotrexate [108].

Reported subjective AEs lasting longer than the first few days of drug administration include fatigue [40], headache [24, 40] and malaise [24]. Haematological toxicity can occur, specifically pancytopenia [21, 23, 24, 26, 40]. Following dose reduction or temporary withdrawal, haematopoietic suppression usually improves [40].

Kidney function was affected in around 3% of patients on long-term methotrexate therapy [40, 41]. Methotrexate is teratogenic and is contraindicated in pregnancy [2, 23, 24, 26, 126, 127]. Pulmonary toxicity is a risk of methotrexate therapy [20, 26, 108, 117, 118, 128]; lung fibrosis [23, 24] and pneumonitis [24] have been reported.

Treatment with methotrexate has been associated with an increased incidence of certain malignancies, such as lymphoma [24, 100] and SCC in patients having received PUVA [100]. A prospective study indicated that high-dose exposure to methotrexate was a significant independent risk factor for developing SCC (high versus low/no exposure: RR 2.1, 95% CI 1.4–2.8) [129].

Alopecia was seen in 4% of patients on long-term therapy [26, 40]. Severe skin reactions have also been associated with methotrexate treatment [20].

Other AEs that have been associated with methotrexate treatment—although not specifically with long-term therapy—include reactivation of phototoxic reactions [24] and ulcerative stomatitis [24]. Methotrexate is also associated with an increased risk of infections [20, 23, 130]; a multicentre, prospective cohort study with a mean follow-up of 3.3 years reported a 40% higher risk of infection versus acitretin (crude acitretin RR 0.6, 95% CI 0.42–0.86) and a 58% lower risk of infection versus ciclosporin (adjusted ciclosporin RR 1.58, 95% CI 1.17–2.15) [60].

Methotrexate may reduce the incidence of cardiovascular-related disease in patients with psoriasis [131]. Two different meta-analyses of observational studies concluded that low-dose methotrexate was associated with a decreased risk of cardiovascular events [132, 133]. These analyses included a study that showed a significantly reduced risk of vascular disease for those who were prescribed methotrexate compared with those who were not (RR 0.73, 95% CI 0.55–0.98) [132,133,134].

Interestingly, dermatology guidelines for methotrexate recommend more intensive monitoring than do rheumatology guidelines for methotrexate. Consequently, abnormal test results are observed more frequently in patients with psoriasis than in those with psoriatic arthritis [135].

Long-term therapy with methotrexate may not be possible due to AEs and end-organ toxicity potential [61] and administration should ideally be time-limited and carefully monitored [109, 110].

Another clinically relevant issue is potential interactions between methotrexate and other drugs, including drugs that may decrease methotrexate binding to serum albumin; probenecid, which may inhibit tubular secretion; drugs with known kidney or liver toxicity; and alcohol. In addition, certain NSAIDs should not be administered at the same time of day as methotrexate [14].

Clinicians prescribing methotrexate should be alert for potential dosing errors. Dosing errors may occur with methotrexate (in particular with oral dosing formulations) due to patient mistakes or prescribing/dispensing errors. Recent recommendations to avoid such errors include restricting who can prescribe methotrexate, changing the packaging/warnings and providing educational materials [136].

Methotrexate has been reported to have an acceptable risk–benefit profile [112]; however, this must be carefully evaluated and continuously monitored in each patient due to the potential for serious AEs [20]. Taken together, with proper treatment monitoring and physician vigilance, methotrexate continues to play an important role as a systemic psoriasis therapy [137].

Fumaric Acid Esters

A fixed combination of FAE that includes DMF and different monoethylfumarates is licensed in Germany as Fumaderm® (Biogen Idec) for the treatment of moderate-to-severe plaque psoriasis (hereafter referred to as FAE) [7, 46]. DMF [as monotherapy; marketed as Skilarence® (Almirall Limited)] is approved for the treatment of moderate-to-severe plaque psoriasis that requires systemic therapy (Table 3; ESM 5) [45, 138]. DMF, via its active metabolite monomethylfumarate, is believed to elicit its immunomodulatory effects through several pathways, including glutathione-mediated nuclear factor kappa-light-chain-enhancer of activated B-cell inhibition to promote downstream anti-inflammatory pathways [139, 140].

AEs with FAE occurred in 49% of patients in a retrospective analysis over a mean period of 3.6 (range 0.1–32.5) years [141], and in 73% of patients in a study of patients with severe psoriasis with ≤ 14 years of follow-up [142]. A 16-week RCT of FAE and DMF found a similar percentage of patients experiencing AEs (84.1 and 83.9%, respectively) [143]. A prospective follow-up study of DMF found that 86% of patients experienced AEs over a median period of 28 months [144].

The most commonly reported AEs with FAE and DMF are GI complaints [7, 16, 20, 46, 141, 143,144,145,146,147,148,149,150,151] (most commonly abdominal pain), flushing [7, 16, 20, 46, 141, 142, 144,145,146, 148,149,150,151] and white blood cell count abnormalities [7, 16, 141, 142, 149, 151, 152]. In an 8-month study of FAE, 68% of patients developed GI AEs and/or flushing; these AEs settled without intervention in most cases [146]. A retrospective analysis of  patients with ≤ 4 years of treatment found that at the beginning of treatment, GI complaints were the most frequent AEs with FAE; however, the authors do not state how this changed with longer-term treatment [147]. A retrospective cohort study found that 42% of patients experienced diarrhoea and 55% experienced flushing over ≤ 14 years of treatment with FAE [142]. Approximately 30% of patients experienced GI disorders and 14% experienced flushing in a retrospective observational study with a mean duration of FAE therapy of 3.6 years [141]. A real-world study of FAE reported GI disturbances in 25% of patients and flushing in 12% [149]. GI disorders were the most frequently reported AEs in a phase 3 trial with both FAE (63%) and DMF (63%); most events reported were considered ‘mild’ in intensity. Flushing was also commonly reported (16 and 18%, respectively) [143]. A prospective follow-up study of DMF found that 58% of patients experienced GI AEs and 65% experienced flushing over a median period of 28 months [144].

Abnormalities in monitoring blood tests or urinalysis were observed in 45% of patients in an 8-month study of FAE [146]. Transient proteinuria (defined as dipstick urinalysis positive and 24-h urine collection > 0.14 g protein) was seen in 13% of patients treated with FAE over a mean period of 3.6 years; however, only a few cases of disturbed renal function were documented [141].

The use of FAE may be associated with lymphopenia [7, 16, 141, 142, 149, 151, 152]. A retrospective cohort study found relative lymphopenia in 76% of patients over ≤ 14 years of treatment with FAE [142]. A retrospective cross-sectional study of FAE reported that 41% of patients experienced lymphopenia after 24 months [152]. Lymphopenia < 500/µL (grade 3 and 4) was observed at some point during treatment in 17% of patients in a retrospective observational study (mean FAE duration 3.6 years) [141]. A real-world study of FAE reported lymphopenia in 10% of patients [149]. Regular monitoring of lymphocyte counts (every 4 weeks for FAE [7]; every 3 months for DMF [45]) and discontinuation of DMF treatment if counts fall to < 700/µL [45] are recommended to avoid prolonged exposure to severe lymphopenia and to minimise the potential risk of opportunistic infections such as progressive multifocal leucoencephalopathy (PML). In patients with lymphocyte counts of 700–1000/µL, monthly monitoring is required until levels are ≥ 1000/µL [45]. A recent review of the literature identified 19 cases of PML (14 in patients with psoriasis) on FAE therapy, with the onset of symptoms occurring after a median of 31 months [153].

Leucopenia may be observed with long-term treatment with FAE [7, 141, 151, 152]. A retrospective cross-sectional study reported that 12% of patients experienced leucopenia after 24 months of treatment with FAE [152]. Reduced leucocyte levels (< 3000/µL) were observed in 5% of patients in a retrospective observational study (mean FAE duration 3.6 years) [141].

Another potential AE of FAE treatment is eosinophilia, which is usually transient [7, 141, 142, 151]. A retrospective cohort study found transient eosinophilia in 14% of patients over ≤ 14 years of FAE treatment [142]. Similarly, transient abnormal eosinophil levels (25% above the upper limit of normal) were observed in 16% of patients in a retrospective observational study (mean FAE duration 3.6 years) [141]. German guidelines for psoriasis treatment conclude that eosinophilia is temporary and generally observed between weeks 4 and 10 of therapy [154]. Eosinophilia rarely leads to intervention or treatment discontinuation [141, 142].

Increases in liver enzymes and serum creatinine levels may be seen with long-term treatment with FAE [16, 141, 148, 152]. A retrospective cohort study found liver enzyme elevations in 25% of patients over ≤ 14 years of FAE treatment; these events were isolated elevations that mostly resolved spontaneously or with dose reduction [142]. A retrospective cross-sectional study of FAE reported that 13% of patients experienced liver enzyme increases after 3 months and 6% experienced an increase in creatinine levels after 24 months [152]. Additionally, abnormal creatinine levels (> 1.2 mg/dL) were observed in 12% of patients in a retrospective observational study (mean FAE treatment duration 3.6 years) [141].

In the context of potential drug–drug interactions, a preclinical in vitro assessment of DMF as an inhibitor of cytochrome P450 (CYP) enzymes did not find any inhibitory activity of DMF or its main metabolite monomethylfumarate, suggesting that DMF is unlikely to influence other compounds metabolised by CYP enzymes [155] (Almirall S. A., Barcelona, Spain; data on file). Therefore, DMF may be combined safely with other therapies metabolised via CYP enzymes. Accordingly, a retrospective study of patients treated with FAE and at least one other medication over a mean of 27.4 months reported no clinical drug–drug interactions with FAE [47].

A 2017 Cochrane systematic review and meta-analysis of systemic pharmacological treatments for chronic plaque psoriasis found no significant differences between FAE and placebo in terms of the risk of developing serious AEs [156]; over 1 year, FAE had a similar rate of serious AEs as other systemic drugs. In another study, the rates of AEs for FAE and other systemic drugs were also similar, with the exception of higher rates of GI disorders (13.1 vs. 8.4 per 100 patient-years, respectively) and blood and lymphatic disorders (4.1 vs. 1.0 per 100 patient-years) and lower infection rates (3.0 vs. 6.0 per 100 patient-years) [157].

Current guidelines recommend treatment with FAE for induction and long-term treatment [14, 150]. A European consensus group that was convened to deliver real-world guidance on the clinical use of DMF in moderate-to-severe chronic plaque psoriasis recommended managing patient expectations before starting treatment because AEs are mostly experienced during the onset of therapy. The consensus group considered the long-term safety profile of FAE treatment to be favourable [46].

Data from a phase 3 clinical trial indicate that DMF is superior to placebo in terms of efficacy and comparable to FAE in terms of efficacy and safety profile [143].

Taken together, FAE therapy is associated with a favourable risk–benefit profile [158] and may thus be a useful treatment option for patients with moderate-to-severe psoriasis, including those for whom potentially more toxic therapies are contraindicated [20].

Drug Survival

Taking into consideration that long-term AEs could negatively impact drug survival, we also reviewed drug survival estimates (Table 4; [17, 135, 157, 159,160,161,162,163,164,165,166,167,168]). Variability in drug survival rates in daily clinical practice may reflect important differences in the safety profile (the percentages of patients discontinuing due to AEs are presented in ESM 6), but also efficacy, patient treatment satisfaction, convenience and/or economic factors.

Table 4 Summary of drug survival rates for the systemic agents used to treat moderate-to-severe psoriasis

A multicentre, prospective cohort study of patients in the BIOBADADERM registry reported that drug survival probabilities in the first year of treatment were 23.3%, 42.3% and 50.3% for ciclosporin, acitretin and methotrexate, respectively [159]. A quarter of patients stopped treatment after 0.30, 0.22 and 0.38 years, respectively; the median survival times were 0.72, 0.45 and 1.01 years, respectively [159].

A retrospective assessment of drug survival rates found that 1-year survival rates ranged from 16% for ciclosporin to 37% for acitretin, 43% for methotrexate and 46% for FAE; the 5-year survival rates ranged from 10% for methotrexate, to 16% for acitretin and 25% for FAE. For ciclosporin the survival rate was 0% at 20 months [17]. A retrospective analysis of the Italian PsoReal registry data found that the average treatment duration of conventional agents (9.0 ± 10.0 months) and biologics (13.7 ± 11.6 months) was lower than that of FAEs (28.1 ± 20.1 months) [169].

Assessment of the factors associated with drug survival using a large public healthcare database (Clalit Health Services) in Israel found similar mean drug survival times for acitretin and methotrexate (25.5 and 25.9 months, respectively) [160]. Five-year drug survival rates were 23% for acitretin and 19.6% for methotrexate. Young age was a risk factor for treatment termination in both the acitretin and methotrexate treatment groups. This was attributed to concern for the potential of future morbidities, emergence of AEs, alteration in disease severity and teratogenic properties [160].

Additionally, a prospective analysis of drug survival of psoriasis treatments in the Swiss Dermatology Network for Targeted Therapies found mean drug survival times of 7.7 months for methotrexate and 9.3 months for FAE [167]. After 18 months, 50% of patients treated with a systemic agent had discontinued therapy (due to contraindication, AE or treatment success) [167]. Finally, median drug survival times reported for apremilast ranged from ~ 2.9 to ~ 9.7 months [161,162,163,164,165].

Differences in discontinuation rates may be accounted for by the fact that some studies have looked at drug survival in combination with additional systemic treatments (associated with better drug survival) [170] and differing healthcare insurance systems [163]. Drug survival estimates for methotrexate, for example, also vary considerably—likely indicating variable long-term tolerability. Data from a prospective Dutch registry of patients treated with methotrexate (MTX-CAPTURE) showed drug survival rates of 63%, 30% and 15% after 1, 3 and 5 years, respectively; the median drug survival was 1.8 years [166, 171]. Other studies showed the duration of the first treatment course to be, on average, 18.8 months [135] and that 68% of patients discontinued methotrexate after an average of ~ 4.2 months [172]. Median drug survival of FAE was measured in a 1-year registry study and was found to be 54.8 months compared with 51.1 months for other conventional systemic treatments (p = 0.40) [157]. Data from a retrospective, single-centre study from Ireland reported a 4-year drug survival rate of 60% for FAE; the mean length of treatment was 28 months [168].

Discussion

We have comprehensively assessed the literature on the long-term safety profiles of five commonly used oral systemic treatments for psoriasis. The characterisation of long-term safety profiles may help to guide therapeutic decision making for oral systemic therapy in clinical practice, allowing healthcare professionals to select the most optimal treatment for each individual. In addition, the information provided by this literature review has the potential to improve treatment-monitoring practices and management of AEs.

The clinical evidence to-date indicates that long-term treatment with acitretin and methotrexate may be limited due to potential cumulative organ-toxicity risks and must be avoided in female patients of reproductive age due to teratogenic potential [48, 107, 109, 110]; however, acitretin and methotrexate remain useful and widely used therapeutic options if patients are selected carefully and monitored regularly. Methotrexate should be avoided in patients who drink alcohol excessively and in patients with diabetes, obesity, concomitant NSAID use and hypoalbuminaemia due to increased risk of hepatotoxicity [111], while acitretin should not be used in pregnant women [20]. Apremilast has a favourable long-term safety profile; there is no increased risk in common AEs with continued exposure and no standard blood monitoring is required [7, 30, 31]. European guidelines do not recommend ciclosporin for the long-term treatment of psoriasis given its safety concerns; however, it may be used occasionally for ≤ 2 years. Ciclosporin may not be suitable for those patients, particularly the elderly, who are at increased risk for some of the more serious AEs, such as renal impairment or hypertension [20, 83]. FAE (including DMF) show a promising long-term efficacy and safety profile [138, 141, 144]. GI AEs (most commonly abdominal pain and diarrhoea) and flushing are an important concern for many patients; however, symptoms are generally mild-to-moderate and often resolve with continued treatment [141, 151]. Exposure to severe lymphopenia should be minimised to reduce the risk of PML; consequently, absolute lymphocyte counts should be monitored every 4 weeks for FAE and every 3 months for DMF, and treatment should be stopped if lymphocyte counts decrease to < 700/μL on two repeated measurements [45]. FAE should be avoided in patients with pre-existing leukopenia [7, 141, 152] and/or lymphopenia [7, 16, 141, 142, 149, 152].

Long-term safety profiles are also useful in the context of combination therapy, which might be used in patients with psoriasis who are recalcitrant to monotherapy with the aim of improving efficacy while limiting toxicity. Different strategies can be employed: two or more therapies with different mechanisms of action can be used in combination, or rotational therapy or sequential therapy may be used. Rotational therapy involves rotating psoriasis therapies every 2–3 years to minimise cumulative toxicity, while sequential therapy involves switching between different agents for rapid clearance versus long-term maintenance [3]. The European S3 guidelines provide recommendations on specific therapeutic combinations along with the benefits and limitations of each [14]. Recent guidelines from the American Academy of Dermatology and National Psoriasis Foundation focussing on the efficacy and safety of systemic non-biological treatments suggest that ciclosporin may be used as a bridge therapy for patients who are transitioning to a long-term treatment with an improved safety profile. Recommended combination therapies include methotrexate with tumour necrosis factor (TNF) inhibitors or narrow-band-UVB phototherapy, or acitretin with PUVA or broad-band-UVB phototherapy [173]. The Medical Board of the National Psoriasis Foundation indicated the following preferences for combination therapies with biologics: biologic + methotrexate, biologic + acitretin and biologic + phototherapy [5]. However, the number of available trials assessing the efficacy and safety of combination therapies in psoriasis is limited [3,4,5]; these are warranted in future research.

One major challenge when reviewing the literature was the definition of ‘long-term’ therapy. This review included articles that investigated safety over an arbitrarily chosen duration of ≥ 6 months; however, psoriasis is a lifelong condition that can require continuous treatment for many years. Variability in the definition of ‘long-term’ care, therefore, meant that comparison between agents was challenging. In addition, although long-term data are available for all of the conventional systemic agents, limited data are available on the newer agents, such as DMF and apremilast, which have not been extensively used over the long term. Hence, the availability of long-term safety data for these recently approved therapies was limited compared with that for conventional agents such as methotrexate and ciclosporin. Moreover, it was not always clear which AEs were due specifically to cumulative treatment over long periods of time and which were associated with very early treatment. An additional challenge was the collation of data in a meaningful way due to the reporting differences across publications. Direct inter-study and inter-agent comparisons should, therefore, be interpreted with caution. Finally, another potential limitation to this review is the small number of studies that were included, particularly for the newer agents.

In terms of the drug survival of these systemic agents, estimates varied considerably. Understanding the long-term safety profile will help to further elucidate the drivers of long-term drug survival, inform better treatment strategies and improve patient outcomes. Importantly, drug survival and RR estimates must be interpreted with caution because differences in study design, patient inclusion and selection introduce variability, thus influencing findings.

Conclusion

Oral systemic agents continue to play an important role in the long-term management of psoriasis. The characterisation of the long-term safety profile of oral systemic psoriasis treatments is essential to optimise risk–benefit analysis and well-balanced therapeutic decision-making and helps to guide adequate treatment-monitoring practices in clinical practice. In terms of improving future studies, a clearer definition of what constitutes ‘long-term’ therapy in psoriasis is needed to better define treatment regimens. Moreover, consistent reporting of safety data will better enable comparison and help to further elucidate the long-term safety profile of systemic agents.

References

  1. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011;65(1):137–74.

    PubMed  Article  Google Scholar 

  2. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85.

    CAS  PubMed  Article  Google Scholar 

  3. Nakamura M, Koo J. Safety considerations with combination therapies for psoriasis. Expert Opin Drug Saf. 2020;19(4):489–98.

  4. Gustafson CJ, Watkins C, Hix E, Feldman SR. Combination therapy in psoriasis: an evidence-based review. Am J Clin Dermatol. 2013;14(1):9–25.

    PubMed  Article  Google Scholar 

  5. Armstrong AW, Bagel J, Van Voorhees AS, Robertson AD, Yamauchi PS. Combining biologic therapies with other systemic treatments in psoriasis: evidence-based, best-practice recommendations from the Medical Board of the National Psoriasis Foundation. JAMA Dermatol. 2015;151(4):432–8.

    PubMed  Article  Google Scholar 

  6. Edmundson WF, Guy WB. Treatment of psoriasis with folic acid antagonists. AMA Arch Dermatol. 1958;78(2):200–3.

    CAS  Article  Google Scholar 

  7. Nast A, Amelunxen L, Augustin M, et al. S3 Guideline for the treatment of psoriasis vulgaris, update—short version part 1—systemic treatment. J Dtsch Dermatol Ges. 2018;16(5):645–69.

    PubMed  Google Scholar 

  8. European Medicines Agency. Scientific conclusions and grounds for the variation to the terms of the marketing authorisation. 2019. https://www.ema.europa.eu/en/documents/referral/sandimmun-article-30-referral-annex-ii_en.pdf. Accessed 25 Sep 2019.

  9. Augustin M, Spehr C, Radtke MA, et al. German psoriasis registry PsoBest: objectives, methodology and baseline data. J Dtsch Dermatol Ges. 2014;12(1):48–57.

    PubMed  Google Scholar 

  10. Iskandar IY, Ashcroft DM, Warren RB, et al. Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register. Br J Dermatol. 2015;173(2):510–8.

    CAS  PubMed  Article  Google Scholar 

  11. European Medicines Agency. EPAR summary for the public. Skilarence (dimethyl fumarate). 2017. https://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002157/WC500231110.pdf. Accessed 25 Sep 2019.

  12. European Medicines Agency. EPAR summary for the public. Otezla (apremilast). 2015. https://www.ema.europa.eu/documents/overview/otezla-epar-summary-public_en.pdf. Accessed 25 Sep 2019.

  13. Strober B, Ryan C, van de Kerkhof P, et al. Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council. J Am Acad Dermatol. 2020;82(1):117–22.

    PubMed  Article  Google Scholar 

  14. Nast A, Gisondi P, Ormerod AD, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris–update 2015–short version–EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2015;29(12):2277–94.

    CAS  PubMed  Article  Google Scholar 

  15. Armstrong AW, Koning JW, Rowse S, Tan H, Mamolo C, Kaur M. Initiation, switching, and cessation of psoriasis treatments among patients with moderate to severe psoriasis in the United States. Clin Drug Investig. 2017;37(5):493–501.

    PubMed  Article  Google Scholar 

  16. Smith D. Fumaric acid esters for psoriasis: a systematic review. Ir J Med Sci. 2017;186(1):161–77.

    CAS  PubMed  Article  Google Scholar 

  17. Arnold T, Schaarschmidt ML, Herr R, Fischer JE, Goerdt S, Peitsch WK. Drug survival rates and reasons for drug discontinuation in psoriasis. J Dtsch Dermatol Ges. 2016;14(11):1089–99.

    PubMed  Article  Google Scholar 

  18. Sadovsky R. Cyclosporine in the treatment of dermatologic disease. Am Fam Phys. 1997;55(6):2306–7.

    Google Scholar 

  19. Lee CS, Koo J. A review of acitretin, a systemic retinoid for the treatment of psoriasis. Expert Opin Pharmacother. 2005;6(10):1725–34.

    CAS  PubMed  Article  Google Scholar 

  20. Naldi L, Griffiths CEM. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol. 2005;152(4):597–615.

    CAS  PubMed  Article  Google Scholar 

  21. McClure SL, Valentine J, Gordon KB. Comparative tolerability of systemic treatments for plaque-type psoriasis. Drug Saf. 2002;25(13):913–27.

    CAS  PubMed  Article  Google Scholar 

  22. Dubertret L. Retinoids, methotrexate and cyclosporine. Curr Probl Dermatol. 2009;38:79–94.

    PubMed  Article  Google Scholar 

  23. Kaushik SB, Lebwohl MG. Review of safety and efficacy of approved systemic psoriasis therapies. Int J Dermatol. 2018;58(6):649–58.

    PubMed  Article  Google Scholar 

  24. Lebwohl M. A clinician's paradigm in the treatment of psoriasis. J Am Acad Dermatol. 2005;53(1 Suppl):S59–S69.

    PubMed  Article  Google Scholar 

  25. Geilen CC, Orfanos CE. Standard and innovative therapy of psoriasis. Clin Exp Dermatol. 2002;20(6 Suppl 28):S81–S8787.

    CAS  Google Scholar 

  26. Maryles S, Rozenblit M, Lebwohl M. Transition from methotrexate and cyclosporine to other therapies including retinoids, ultraviolet light and biologic agents in the management of patients with psoriasis. J Dermatolog Treat. 2003;14(Suppl 2):7–16.

    CAS  PubMed  Article  Google Scholar 

  27. Blauvelt A, Armstrong AW, Krueger GG. Essential truths for the care and management of moderate-to-severe psoriasis. J Drugs Dermatol. 2015;14(8):805–12.

    PubMed  Google Scholar 

  28. Stiefel Laboratories. Soriatane (acitretin) capsules. Package insert. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019821s027lbl.pdf. Accessed 25 Sep 2019.

  29. Nast A, Spuls PI, van der Kraaij G, et al. European S3-Guideline on the systemic treatment of psoriasis vulgaris—update apremilast and secukinumab—EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2017;31(12):1951–63.

    CAS  PubMed  Article  Google Scholar 

  30. National Institute for Health and Care Excellence. Apremilast. 2018. https://bnf.nice.org.uk/drug/apremilast.html. Accessed 25 Sept 2019.

  31. Volc S, Ghoreschi K. Pathophysiological basis of systemic treatments in psoriasis. J Dtsch Dermatol Ges. 2016;14(6):557–72.

    PubMed  Google Scholar 

  32. European Medicines Agency. Summary of the risk management plan (RMP) for Otezla (apremilast). 2014. https://www.ema.europa.eu/documents/rmp-summary/otezla-epar-risk-management-plan-summary_en.pdf. Accessed 25 Sep 2019.

  33. Crowley J, Thaçi D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77(2):310–17.e1.

    CAS  PubMed  Article  Google Scholar 

  34. Celegene Ltd. Summary of product characterisitics. Otezla 30 mg film-coated tablets. 2019. https://www.medicines.org.uk/emc/product/3648/smpc. Accessed 16 Nov 2019.

  35. Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010;63(6):949–72.

    CAS  PubMed  Article  Google Scholar 

  36. Pathirana D, Ormerod AD, Saiag P, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):1–70.

    PubMed  Article  Google Scholar 

  37. Feldman SR, Garton R. Cyclosporin in psoriasis: how? J Eur Acad Dermatol Venereol. 2004;18(3):250–3.

    CAS  PubMed  Article  Google Scholar 

  38. National Institute for Health and Care Excellence. Ciclosporin. 2018. https://bnf.nice.org.uk/drug/ciclosporin.html. Accessed 25 Sep 2019.

  39. Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol. 1996;10(6):369–75.

    CAS  PubMed  Article  Google Scholar 

  40. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 2000;14(5):382–8.

    CAS  PubMed  Article  Google Scholar 

  41. Rajnics P, Kellner VS, Kellner A, Karadi E, Kollar B, Egyed M. The hematologic toxicity of methotrexate in patients with autoimmune disorders. J Neoplasm. 2017;2(1):1.

    Article  Google Scholar 

  42. Nordic Pharma Ltd. Summary of product characterisitcs. Nordimet 25 mg solution for injection in pre-filled pen. 2018. https://www.medicines.org.uk/emc/product/2473/smpc. Accessed 25 Sep 2019.

  43. Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol. 2009;60(5):824–37.

    PubMed  Article  Google Scholar 

  44. Przekop PR Jr, Tulgan H, Przekop AA, Glantz M. Adverse drug reaction to methotrexate: pharmacogenetic origin. J Am Osteopath Assoc. 2006;106(12):706–7.

    PubMed  Google Scholar 

  45. Almirall Limited. Summary of product characteristics. Skilarence 120 mg gastro-resistant tablets. 2018. https://www.medicines.org.uk/emc/product/7480/smpc. Accessed 25 Sep 2019.

  46. Mrowietz U, Barker J, Boehncke WH, et al. Clinical use of dimethyl fumarate in moderate-to-severe plaque-type psoriasis: a European expert consensus. J Eur Acad Dermatol Venereol. 2018;32(Suppl 3):3–14.

    CAS  PubMed  Article  Google Scholar 

  47. Thaçi D, Weisenseel P, Philipp S, et al. Efficacy and safety of fumaric acid esters in patients with psoriasis on medication for comorbid conditions—a retrospective evaluation (FACTS). J Dtsch Dermatol Ges. 2013;11(5):429–35.

    PubMed  Google Scholar 

  48. National Institute for Health and Care Excellence. Acitretin. 2018. https://bnf.nice.org.uk/drug/acitretin.html. Accessed 25 Sep 2019.

  49. Genus Pharmaceuticals. Summary of product characteristics. Acitretin 10 mg capsules. 2016. https://www.medicines.org.uk/emc/product/5265/smpc. Accessed 25 Sep 2019.

  50. British Association of Dermatologists. Treatments for moderate or severe psoriasis. 2017. https://www.bad.org.uk/shared/get-file.ashx?id=124&itemtype=document. Accessed 25 Sep 2019.

  51. Koo J. Systemic sequential therapy of psoriasis: a new paradigm for improved therapeutic results. J Am Acad Dermatol. 1999;41(3 Pt 2):S25–S2828.

    CAS  PubMed  Article  Google Scholar 

  52. Vahlquist A. Long-term safety of retinoid therapy. J Am Acad Dermatol. 1992;27(6 Pt 2):S29–33.

    CAS  PubMed  Article  Google Scholar 

  53. Lee E, Loo J. Single-center retrospective study of long-term use of low-dose acitretin (Soriatane®) for psoriasis. J Drugs Dermatol. 2004;15(1):8–13.

    CAS  Google Scholar 

  54. Katz HI, Waalen J, Leach EE. Acitretin in psoriasis: an overview of adverse effects. J Am Acad Dermatol. 1999;41(3 Pt 2):S7–S12.

    CAS  PubMed  Article  Google Scholar 

  55. Roenigk HH Jr, Callen JP, Guzzo CA, et al. Effects of acitretin on the liver. J Am Acad Dermatol. 1999;41(4):584–8.

    PubMed  Article  Google Scholar 

  56. Murray HE, Anhalt AW, Lessard R, et al. A 12-month treatment of severe psoriasis with acitretin: results of a Canadian open multicenter study. J Am Acad Dermatol. 1991;24(4):598–602.

    CAS  PubMed  Article  Google Scholar 

  57. Gollnick HP. Oral retinoids—efficacy and toxicity in psoriasis. Br J Dermatol. 1996;135(Suppl 49):6–17.

    CAS  PubMed  Article  Google Scholar 

  58. Federal Institute for Drugs and Medical Devices. Acitretin and teratogenicity: extension of the period of pregnancy prevention to 3 years after the end of treatment. 2016. https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/EN/RI/2016/ri-acitretin.html. Accessed 25 Sep 2019.

  59. Gupta AK, Goldfarb MT, Ellis CN, Voorhees JJ. Side-effect profile of acitretin therapy in psoriasis. J Am Acad Dermatol. 1989;20(6):1088–93.

    CAS  PubMed  Article  Google Scholar 

  60. Dávila-Seijo P, Dauden E, Descalzo MA, et al. Infections in moderate to severe psoriasis patients treated with biological drugs compared to classic systemic drugs: findings from the BIOBADADERM Registry. J Invest Dermatol. 2017;137(2):313–21.

    PubMed  Article  CAS  Google Scholar 

  61. Gisondi P, Girolomoni G. Biologic therapies in psoriasis: a new therapeutic approach. Autoimmun Rev. 2007;6(8):515–9.

    CAS  PubMed  Article  Google Scholar 

  62. Aryal A, Upreti S. A brief review on systemic retinoids. Int J Pharm Sci Res. 2017;8(9):3630–9.

    CAS  Google Scholar 

  63. Reich K, Gooderham M, Green L, et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol. 2017;31(3):507–17.

    CAS  PubMed  Article  Google Scholar 

  64. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37–49.

    CAS  PubMed  Article  Google Scholar 

  65. Gooderham M, Papp K. Selective phosphodiesterase inhibitors for psoriasis: focus on apremilast. BioDrugs. 2015;29(5):327–39.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Reich K, Goodfield M, Green L, et al. Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment in the LIBERATE study. Ann Rheum Dis. 2017;76:1325–6 (abstract AB0771).

    Article  CAS  Google Scholar 

  67. Elise Kleyn C, Laws P, Chen KS, Eccles J, Cordey M, Griffiths CEM. UK and Ireland real-world experience with apremilast in psoriasis patients: analysis of 126 patients from the APPRECIATE study. Br J Dermatol. 2018;179:63.

    Article  CAS  Google Scholar 

  68. Mayba JN, Gooderham MJ. Real-world experience with apremilast in treating psoriasis. J Cutan Med Surg. 2017;21(2):145–51.

    CAS  PubMed  Article  Google Scholar 

  69. Cranwell W, Radulski B, Dolianitis C, Nicolopoulos J, Varigos GA. Experience with apremilast in a small cohort of patients with chronic plaque psoriasis. Australas J Dermatol. 2018;59(S1):51.

    Google Scholar 

  70. Ighani A, Georgakopoulos JR, Shear NH, Walsh S, Yeung J. Short-term reasons for withdrawal and adverse events associated with apremilast therapy for psoriasis in real-world practice compared with in clinical trials: a multicenter retrospective study. J Am Acad Dermatol. 2018;78(4):801–3.

    PubMed  Article  Google Scholar 

  71. Deeks ED. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2015;75(12):1393–403.

    CAS  PubMed  Article  Google Scholar 

  72. Novartis Pharmaceuticals UK Ltd. Summary of product characteristics. Neoral solution. 2018. https://www.medicines.org.uk/emc/product/5300/smpc. Accessed 25 Sep 2019.

  73. Capella GL, Della Casa-Alberighi O, Finzi AF. Therapeutic concepts in clinical dermatology: cyclosporine A in immunomediated and other dermatoses. Int J Dermatol. 2001;40(9):551–61.

    CAS  PubMed  Article  Google Scholar 

  74. Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol. 1993;28(3):454–9.

    CAS  PubMed  Article  Google Scholar 

  75. Koo J. Cyclosporine in dermatology: fears and opportunities. Arch Dermatol. 1995;131(7):842–5.

    CAS  PubMed  Article  Google Scholar 

  76. Ho VCY, Griffiths CEM, Berth-Jones J, et al. Intermittent short courses of cyclosporine microemulsion for the long-term management of psoriasis: a 2-year cohort study. J Am Acad Dermatol. 2001;44(4):643–51.

    CAS  PubMed  Article  Google Scholar 

  77. Paul CF, Ho VC, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol. 2003;120(2):211–6.

    CAS  PubMed  Article  Google Scholar 

  78. Marcil I, Stern RS. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet. 2001;358(9287):1042–5.

    CAS  PubMed  Article  Google Scholar 

  79. Zachariae H, Kragballe K, Hansen HE, Marcussen N, Olsen S. Renal biopsy findings in long-term cyclosporin treatment of psoriasis. Br J Dermatol. 1997;136(4):531–5.

    CAS  PubMed  Article  Google Scholar 

  80. Feutren G, Mihatsch MJ. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. International Kidney Biopsy Registry of Cyclosporine in Autoimmune Diseases. New Engl J Med. 1992;326(25):1654–60.

    CAS  PubMed  Article  Google Scholar 

  81. Magnasco A, Rossi A, Catarsi P, et al. Cyclosporin and organ specific toxicity: Clinical apects, pharmacogenetics and perspectives. Curr Clin Pharmacol. 2008;3(3):166–73.

    CAS  PubMed  Article  Google Scholar 

  82. Laburte C, Grossman R, Abi-Rached J, Abeywickrama KH, Dubertret L. Efficacy and safety of oral cyclosporin A (CyA; Sandimmun) for long-term treatment of chronic severe plaque psoriasis. Br J Dermatol. 1994;130(3):366–75.

    CAS  PubMed  Article  Google Scholar 

  83. Maza A, Montaudie H, Sbidian E, et al. Oral cyclosporin in psoriasis: a systematic review on treatment modalities, risk of kidney toxicity and evidence for use in non-plaque psoriasis. J Eur Acad Dermatol Venereol. 2011;25(Suppl 2):19–27.

    CAS  PubMed  Article  Google Scholar 

  84. Powles H, Porter C, Hulme F. Renal function after 10 years’ treatment with cyclosporin for psoriasis. Br J Dermatol. 1998;138(3):443–9.

    CAS  PubMed  Article  Google Scholar 

  85. International Kidney Biopsy Registry of Cyclosporin A (Sandimmun®) in Autoimmune Diseases. Kidney biopsies in control or cyclosporin A-treated psoriatic patients. Br J Dermatol. 1990;122(Suppl 36):95–100.

    Google Scholar 

  86. Lowe NJ, Wieder JM, Rosenbach A, et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol. 1996;35(5 Pt 1):710–9.

    CAS  PubMed  Article  Google Scholar 

  87. Mrowietz U, Farber L, Henneicke-von Zepelin HH, Bachmann H, Welzel D, Christophers E. Long-term maintenance therapy with cyclosporine and post-treatment survey in severe psoriasis: results of a multicenter study. German Multicenter Study. J Am Acad Dermatol. 1995;33(3):470–5.

    CAS  PubMed  Article  Google Scholar 

  88. Pei Y, Scholey JW, Katz A, Schachter R, Murphy GF, Cattran D. Chronic nephrotoxicity in psoriatic patients treated with low-dose cyclosporine. Am J Kidney Dis. 1994;23(4):528–36.

    CAS  PubMed  Article  Google Scholar 

  89. Powles AV, Baker BS, Valdimarsson H, Hulme B, Fry L. Four years of experience with cyclosporin A for psoriasis. Br J Dermatol. 1990;122(Suppl 36):13–9.

    PubMed  Article  Google Scholar 

  90. Powles AV, Cook T, Hulme B, et al. Renal function and biopsy findings after 5 years' treatment with low-dose cyclosporin for psoriasis. Br J Dermatol. 1993;128(2):159–65.

    CAS  PubMed  Article  Google Scholar 

  91. Shupack J, Abel E, Bauer E, et al. Cyclosporine as maintenance therapy in patients with severe psoriasis. J Am Acad Dermatol. 1997;36(3 Pt 1):423–32.

    CAS  PubMed  Article  Google Scholar 

  92. Svarstad E, Helland S, Morken T, et al. Renal effects of maintenance low-dose cyclosporin A treatment in psoriasis. Nephrol Dial Transplant. 1994;9(10):1462–7.

    CAS  PubMed  Google Scholar 

  93. Grossman RM, Chevret S, Abi-Rached J, Blanchet F, Dubertret L. Long-term safety of cyclosporine in the treatment of psoriasis. Arch Dermatol. 1996;132(6):623–9.

    CAS  PubMed  Article  Google Scholar 

  94. Feutren G. The optimal use of cyclosporin A in autoimmune diseases. J Autoimmun. 1992;5(Suppl A):183–95.

    PubMed  Article  Google Scholar 

  95. Feutren G, Abeywickrama K, Friend D, von Graffenried B. Renal function and blood pressure in psoriatic patients treated with cyclosporin A. Br J Dermatol. 1990;122(Suppl 36):57–69.

    PubMed  Article  Google Scholar 

  96. Korstanje MJ, Van de Staak WJBM. Long-term treatment of psoriasis with cyclosporin A–side-effects, minimal effective dose and cyclosporin blood levels. Clin Exp Dermatol. 1991;16(1):8–10.

    CAS  PubMed  Article  Google Scholar 

  97. Mason J. The effect of cyclosporin on renal function. J Autoimmun. 1992;5(Suppl A):349–54.

    PubMed  Article  Google Scholar 

  98. Altomare G, Ayala F, Bardazzi F, et al. Consensus on the use of cyclosporine in dermatological practice. G Ital Dermatol Venereol. 2014;149(5):607–25.

    CAS  PubMed  Google Scholar 

  99. Lebwohl M, Ellis C, Gottlieb A, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol. 1998;39(3):464–75.

    CAS  PubMed  Article  Google Scholar 

  100. Geller S, Xu H, Lebwohl M, Nardone B, Lacouture ME, Kheterpal M. Malignancy risk and recurrence with psoriasis and its treatments: a concise update. Am J Clin Dermatol. 2018;19(3):363–75.

    PubMed  PubMed Central  Article  Google Scholar 

  101. Naldi L. Malignancy concerns with psoriasis treatments using phototherapy, methotrexate, cyclosporin, and biologics: facts and controversies. Clin Dermatol. 2010;28(1):88–92.

    PubMed  Article  Google Scholar 

  102. van de Kerkhof PCM. Consistent control of psoriasis by continuous long-term therapy: The promise of biological treatments. J Eur Acad Dermatol Venereol. 2006;20(6):639–50.

    PubMed  Article  Google Scholar 

  103. Vassantachart JM, Jacob SE. Cyclosporine in the treatment of psoriasis. J Dermatol Nurses Assoc. 2017;9(2):98–101.

    Article  Google Scholar 

  104. Colombo D, Banfi G, Cassano N, et al. The GENDER ATTENTION observational study: gender and hormonal status differences in the incidence of adverse events during cyclosporine treatment in psoriatic patients. Adv Ther. 2017;34(6):1349–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Christophers E, Mrowietz U, Henneicke HH, Färber L, Welzel D. Cyclosporine in psoriasis: a multicenter dose-finding study in severe plaque psoriasis. The German Multicenter Study. J Am Acad Dermatol. 1992;26(1):86–90.

    CAS  PubMed  Article  Google Scholar 

  106. Korstanje MJ. How to improve the risk–benefit ratio of cyclosporin therapy for psoriasis. Clin Exp Dermatol. 1992;17(1):16–9.

    CAS  PubMed  Article  Google Scholar 

  107. National Institute for Health and Care Excellence. Methotrexate. 2018. https://bnf.nice.org.uk/drug/methotrexate.html. Accessed 25 Sep 2019.

  108. Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate: an old new drug in autoimmune disease. Expert Rev Clin Immunol. 2014;10(11):1519–30.

    CAS  PubMed  Article  Google Scholar 

  109. Ajmani S, Preet Singh Y, Prasad S, et al. Methotrexate-induced pancytopenia: a case series of 46 patients. Int J Rheum Dis. 2017;20(7):846–51.

    CAS  PubMed  Article  Google Scholar 

  110. Kozub P, Simaljakova M. Systemic therapy of psoriasis: methotrexate. Bratisl Lek Listy. 2011;112(7):390–4.

    CAS  PubMed  Google Scholar 

  111. Cuellar ML, Espinoza LR. Methotrexate use in psoriasis and psoriatic arthritis. Rheum Dis Clin N Am. 1997;23(4):797–809.

    CAS  Article  Google Scholar 

  112. Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10068):528–37.

    CAS  PubMed  Article  Google Scholar 

  113. West J, Ogston S, Foerster J. Safety and efficacy of methotrexate in psoriasis: a meta-analysis of published trials. PLoS ONE. 2016;11(5):e0153740.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. Weinstein G, Roenigk H, Maibach H, et al. Psoriasis-liver-methotrexate interactions. Arch Dermatol. 1973;108(1):36–42.

    Article  Google Scholar 

  115. Lanse SB, Arnold GL, Gowans JD, Kaplan MM. Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis. An acceptable risk/benefit ratio. Dig Dis Sci. 1985;30(2):104–9.

    CAS  PubMed  Article  Google Scholar 

  116. Robinson JK, Baughman RD, Auerbach R, Cimis RJ. Methotrexate hepatotoxicity in psoriasis. Consideration of liver biopsies at regular intervals. Arch Dermatol. 1980;116(4):413–5.

    CAS  PubMed  Article  Google Scholar 

  117. Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol. 1988;19(1 Pt 1):145–56.

    PubMed  Article  Google Scholar 

  118. Said S, Jeffes EW, Weinstein GD. Methotrexate. Clin Dermatol. 1997;15(5):781–97.

    CAS  PubMed  Article  Google Scholar 

  119. Zachariae H, Søgaard H. Methotrexate-induced liver cirrhosis. A follow-up. Dermatologica. 1987;175(4):178–82.

    CAS  PubMed  Article  Google Scholar 

  120. Boffa MJ, Chalmers RJG. Methotrexate for psoriasis. Clin Exp Dermatol. 1996;21(6):399–408.

    CAS  PubMed  Article  Google Scholar 

  121. Strober BE. Methotrexate-induced liver toxicity: replacing the liver biopsy. JAMA Dermatol. 2014;150(8):862–3.

    PubMed  Article  Google Scholar 

  122. Barker J, Horn EJ, Lebwohl M, et al. Assessment and management of methotrexate hepatotoxicity in psoriasis patients: Report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic. J Eur Acad Dermatol Venereol. 2011;25(7):758–64.

    CAS  PubMed  Article  Google Scholar 

  123. Eswaran R, Mahesh AR, Premkumar K, et al. Transient elastography monitoring for liver complications of long-term methotrexate use in psoriasis patients. Hepatol Int. 2018;12(2):S221.

    Google Scholar 

  124. Warren RB, Weatherhead SC, Smith CH, et al. British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol. 2016;175(1):23–44.

    CAS  PubMed  Article  Google Scholar 

  125. Vena GA, Cassano N, Iannone F. Update on subcutaneous methotrexate for inflammatory arthritis and psoriasis. Ther Clin Risk Manag. 2018;14:105–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Shen S, O'Brien T, Yap LM, Prince HM, McCormack CJ. The use of methotrexate in dermatology: a review. Australas J Dermatol. 2012;53(1):1–18.

    PubMed  Article  Google Scholar 

  127. Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38(3):478–85.

    PubMed  Article  Google Scholar 

  128. Phillips TJ, Jones DH, Baker H. Pulmonary complications following methotrexate therapy. J Am Acad Dermatol. 1987;16(2 Pt 1):373–5.

    CAS  PubMed  Article  Google Scholar 

  129. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study Cancer. 1994;73(11):2759–64.

    CAS  PubMed  Google Scholar 

  130. Guenther L, Langley RG, Shear NH, et al. Integrating biologic agents into management of moderate-to-severe psoriasis: a consensus of the Canadian Psoriasis Expert Panel. J Cutan Med Surg. 2004;8(5):321–37.

    PubMed  Article  Google Scholar 

  131. Liu B, Schwartz RA. Potential cardio-protective effects of psoriasis medications. Acta Dermatovenerol Croat. 2018;26(3):249–54.

    CAS  PubMed  Google Scholar 

  132. De Vecchis R, Baldi C, Palmisani L. Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data. Anatol J Cardiol. 2016;16(1):2–9.

    PubMed  Google Scholar 

  133. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108(9):1362–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Prodanovich S, Ma F, Taylor JR, Pezon C, Fasihi T, Kirsner RS. Methotrexate reduces incidence of vascular diseases in veterans with psoriasis or rheumatoid arthritis. J Am Acad Dermatol. 2005;52(2):262–7.

    PubMed  Article  Google Scholar 

  135. Busger op Vollenbroek FTM, Doggen CJM, Janssens RWA, Bernelot Moens HJ. Dermatological guidelines for monitoring methotrexate treatment reduce drug-survival compared to rheumatological guidelines. PLoS ONE. 2018;13(3):e0194401.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. European Medicines Agency. PRAC recommends new measures to avoid dosing errors with methotrexate. 2019. https://www.ema.europa.eu/en/news/prac-recommends-new-measures-avoid-dosing-errors-methotrexate. Accessed 25 Sep 2019.

  137. Lucas J, Ntuen E, Pearce DJ, Fleischer AB Jr, Feldman SR. Methotrexate: understanding the risk in psoriasis patients. J Dermatolog Treat. 2009;20(5):311–3.

    CAS  PubMed  Article  Google Scholar 

  138. National Institute for Health and Care Excellence. Dimethyl fumarate. 2018. https://bnf.nice.org.uk/drug/dimethyl-fumarate.html. Accessed 25 Sep 2019.

  139. Brück J, Dringen R, Amasuno A, Pau-Charles I, Ghoreschi K. A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis. Exp Dermatol. 2018;27(6):611–24.

    PubMed  Article  CAS  Google Scholar 

  140. Mrowietz U, Morrison PJ, Suhrkamp I, Kumanova M, Clement B. The pharmacokinetics of fumaric acid esters reveal their in vivo effects. Trends Pharmacol Sci. 2018;39(1):1–12.

    CAS  PubMed  Article  Google Scholar 

  141. Dickel H, Bruckner T, Altmeyer P. Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study. J Eur Acad Dermatol Venereol. 2018;32(10):1710–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Hoefnagel JJ, Thio HB, Willemze R, Bouwes Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol. 2003;149(2):363–9.

    CAS  PubMed  Article  Google Scholar 

  143. Mrowietz U, Szepietowski JC, Loewe R, et al. Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm®- and placebo-controlled trial (BRIDGE). Br J Dermatol. 2017;176(3):615–23.

    CAS  PubMed  Article  Google Scholar 

  144. Lijnen R, Otters E, Balak D, Thio B. Long-term safety and effectiveness of high-dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single-blinded follow-up study. J Dermatolog Treat. 2016;27(1):31–6.

    CAS  PubMed  Article  Google Scholar 

  145. Atwan A, Ingram JR, Abbott R, et al. Oral fumaric acid esters for psoriasis. Cochrane Database Syst Rev. 2015;2015(8):CD010497.

    PubMed Central  Google Scholar 

  146. Burden-Teh E, Lam M, Cohen S. Fumaric acid esters to treat psoriasis: experience in a UK teaching hospital. J Am Acad Dermatol. 2013;68(4, Suppl 1):AB52.

    Google Scholar 

  147. Philipp S, Wolk K, Sterry G, Sterry W, Sabat R. Analysis of patients under long term treatment with fumaric acid esters for upto 4 years. Exp Dermatol. 2010;19(2):195.

    Google Scholar 

  148. Shear NH. Fulfilling an unmet need in psoriasis. Do biologicals hold the key to improved tolerability? Drug Saf. 2006;29(1):49–66.

    CAS  PubMed  Article  Google Scholar 

  149. Mason KJ, Lunt M, Hunter HJ, et al. Real-world use of fumaric acid esters in psoriasis: Results from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Br J Dermatol. 2017;177(5):e272–e273.

    Google Scholar 

  150. Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol. 1999;141(3):424–9.

    CAS  PubMed  Article  Google Scholar 

  151. Reszke R, Szepietowski JC. A safety evaluation of dimethyl fumarate in moderate-to-severe psoriasis. Expert Opin Drug Saf. 2020;19(4):373–80.

  152. Reich K, Thaci D, Mrowietz U, Kamps A, Neureither M, Luger T. Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis—a retrospective study (FUTURE). J Dtsch Dermatol Ges. 2009;7(7):603–11.

    PubMed  Google Scholar 

  153. Gieselbach RJ, Muller-Hansma AH, Wijburg MT, et al. Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol. 2017;264(6):1155–64.

    CAS  PubMed  Article  Google Scholar 

  154. Nast A, Kopp IB, Augustin M, et al. Evidence-based (S3) guidelines for the treatment of psoriasis vulgaris. J Dtsch Dermatol Ges. 2007;5(Suppl 3):1–119.

    PubMed  Article  Google Scholar 

  155. Aubets J, Jansat JM, Salva M, et al. No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P-glycoprotein (P-gp) drug transporter. Pharmacol Res Perspect. 2019;7(6):e00540.

    PubMed  PubMed Central  Article  Google Scholar 

  156. Sbidian E, Chaimani A, Garcia-Doval I, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev. 2017;12:CD011535.

    PubMed  Google Scholar 

  157. Augustin M, Mrowietz U, Radtke MA, et al. Effectiveness, drug survival and safety of fumaric acid esters for moderate-to-severe psoriasis in routine care: results from the German Psoriasis Registry PsoBest. Br J Dermatol. 2017;177(5):e246–e247247.

    Google Scholar 

  158. Mrowietz U. Advances in systemic therapy for psoriasis. Clin Exp Dermatol. 2001;26(4):362–7.

    CAS  PubMed  Article  Google Scholar 

  159. Dávila-Seijo P, Dauden E, Carretero G, et al. Survival of classic and biological systemic drugs in psoriasis: results of the BIOBADADERM registry and critical analysis. J Eur Acad Dermatol Venereol. 2016;30(11):1942–50.

    PubMed  Google Scholar 

  160. Shalom G, Zisman D, Harman-Boehm I, et al. Factors associated with drug survival of methotrexate and acitretin in patients with psoriasis. Acta Derm Venereol. 2015;95(8):973–7.

    CAS  PubMed  Article  Google Scholar 

  161. Papadavid E, Rompoti N, Theodoropoulos K, Kokkalis G, Rigopoulos D. Real-world data on the efficacy and safety of apremilast in patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2018;32(7):1173–9.

    CAS  PubMed  Article  Google Scholar 

  162. Lee EB, Amin M, Wu JJ. Drug survival of apremilast in patients treated for psoriasis in a real-world setting. J Am Acad Dermatol. 2018;79(4):760–1.

    PubMed  Article  Google Scholar 

  163. Santos-Juanes J, Velasco L, Munguía-Calzada P, Lozano A, Gómez-Díez S. Comment on “Drug survival of apremilast for psoriasis in a real-world setting”. J Am Acad Dermatol. 2018;79(4):e83–e8484.

    PubMed  Article  Google Scholar 

  164. Vujic I, Herman R, Sanlorenzo M, et al. Apremilast in psoriasis—a prospective real-world study. J Eur Acad Dermatol Venereol. 2018;32(2):254–9.

    CAS  PubMed  Article  Google Scholar 

  165. Vujic I, Herman R, Sanlorenzo M, et al. Apremilast in psoriasis-a prospective real-world study. J Invest Dermatol. 2017;137(10):S195 (abstract 014).

    Article  Google Scholar 

  166. Otero ME, van den Reek JM, Seyger MM, van de Kerkhof PC, Kievit W, de Jong EM. Determinants for drug survival of methotrexate in patients with psoriasis, split according to different reasons for discontinuation: results of the prospective MTX-CAPTURE. Br J Dermatol. 2017;177(2):497–504.

    CAS  PubMed  Article  Google Scholar 

  167. Maul JT, Djamei V, Kolios AGA, et al. Efficacy and survival of systemic psoriasis treatments: an analysis of the Swiss Registry SDNTT. Dermatology. 2016;232(6):640–7.

    CAS  PubMed  Article  Google Scholar 

  168. Ismail N, Collins P, Rogers S, Kirby B, Lally A. Drug survival of fumaric acid esters for psoriasis: a retrospective study. Br J Dermatol. 2014;171(2):397–402.

    CAS  PubMed  Article  Google Scholar 

  169. Damiani G, Cazzaniga S, Naldi L, PsoReal Study Group. Use of fumaric acid derivatives (FADs) in Italian reference centres for psoriasis. G Ital Dermatol Venereol. 2019. https://doi.org/10.23736/S0392-0488.18.06032-7.

  170. Lee EB, Amin M, Wu JJ. Reply to: “Comment on ‘Drug survival of apremilast for psoriasis in a real-world setting’”. J Am Acad Dermatol. 2018;79(4):e85.

    PubMed  Article  Google Scholar 

  171. Kirby B. Drug survival of methotrexate in psoriasis. Br J Dermatol. 2017;177(2):345–6.

    CAS  PubMed  Article  Google Scholar 

  172. Au S, Levin AA, Gottlieb AB. Psoriasis drug failure rates of biologics compared to conventional systemic therapies. J Invest Dermatol. 2014;134(Suppl 1):S9 (abstract 047).

    Google Scholar 

  173. Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic non-biological therapies. J Am Acad Dermatol. 2020;82(6):1445–86.

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Acknowledgements

Funding

This work and the journal’s rapid service fee was supported by Almirall S.A.

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All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article and take responsibility for the integrity of the work as a whole. All authors participated in the development of the research questions and contributed to the literature search. All authors contributed to the development and critical review of the manuscript and approved the final version.

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Medical writing assistance was provided by Hannah Clarke and Jen Lewis at Bioscript Medical, Macclesfield, UK and funded by Almirall.

Disclosures

Deepak M. W. Balak is a consultant/speaker for AbbVie, Almirall, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis and Sanofi Genzyme, and has received research grants from LEO Pharma. Sascha Gerdes has been an adviser for and/or received speakers’ honoraria and/or received grants from, and/or participated in clinical trials for Abbott/AbbVie, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, Amgen, Anaptys Bio, Baxalta, Bayer Health Care, Biogen Idec, Bioskin, Boehringer Ingelheim, Celgene, Centocor, Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, Incyte Inc., Isotechnika, Janssen-Cilag, Johnson & Johnson, Kymab, LEO Pharma, Medac, Merck Serono, Mitsubishi Tanabe, Mölnlycke Health Care, MSD, Novartis, Pfizer, Polichem S.A., Principia Biopharma, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, Schering-Plough, Sienna Biopharmaceuticals, Takeda, Teva, Trevi Therapeutics, UCB Pharma, VBL Therapeutics and Wyeth Pharma. Aurora Parodi has received speaker grants from and/or participated in clinical trials for AbbVie, Almirall, Celgene, Galderma, Jannsen-Cilag, LEO Pharma, Lily, Novartis, Pfizer and UCB. Laura Salgado-Boquete has received fees from AbbVie, Almirall, Celgene, Janssen, LEO Pharma, Lilly, Novartis, MSD and Pfizer.

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Balak, D.M.W., Gerdes, S., Parodi, A. et al. Long-term Safety of Oral Systemic Therapies for Psoriasis: A Comprehensive Review of the Literature. Dermatol Ther (Heidelb) 10, 589–613 (2020). https://doi.org/10.1007/s13555-020-00409-4

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Keywords

  • Adverse events
  • Drug survival
  • Long-term
  • Psoriasis
  • Safety
  • Systemic therapy