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.
Acitretin is a second-generation retinoid  that elicits its anti-psoriatic activity via modulation of keratinocyte proliferation and downstream anti-inflammatory pathways . 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  where methotrexate and ciclosporin are not appropriate . 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 . 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 . 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 . In line with this finding, more recent prospective studies indicate a lower risk of acitretin-induced skeletal toxicity than previously reported .
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 . In addition, a prospective 2-year study of acitretin (25–75 mg/day) showed no biopsy-proven hepatotoxicity .
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 ; 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 . Thus, acitretin should not be used in pregnant women , 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 . 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 ; 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 .
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 .
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 . 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) .
Due to the early appearance and dose-dependency of AEs, the dosing of acitretin is usually based on tolerability rather than efficacy . Long-term therapy may be limited due to the potential for teratogenicity, AEs and potential end-organ toxicity , 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 .
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 . 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 . 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 .
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 . AEs of depression were reported in 1.3% of patients in short-term (16-week) studies . 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 . 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 . Clinical vigilance for depression and suicidal thoughts is recommended [7, 30, 31].
Ciclosporin mediates its anti-psoriatic effects via selective inhibition of immunological pathways in T cells . 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 , 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 .
Long-term ciclosporin therapy may not be possible due to AEs (in particular, nephropathy and hypertension) and risks of end-organ toxicity . 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 . 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) .
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 . 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 , hypomagnesaemia , hyperbilirubinaemia [37, 91, 94] and decreased haemoglobin levels .
Ciclosporin is associated with an increased risk of infection . 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) . 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 , temperature hypersensitivity in extremities  and pulmonary AEs (cough, rhinitis and dyspnoea) .
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)  and by keeping the cumulative dosing time to < 2 years.
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 . 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 . As a DNA synthesis inhibitor, methotrexate has greater toxic effects on cells with higher division rates . 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 .
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 . 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 . Low-dose methotrexate rarely causes clinically significant liver damage in the absence of excessive alcohol intake . Therefore, alcohol use should be avoided and patients with hepatic inflammation should be monitored . 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 . 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  and the German S3 guidelines  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 , 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 . 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 .
Reported subjective AEs lasting longer than the first few days of drug administration include fatigue , headache [24, 40] and malaise . Haematological toxicity can occur, specifically pancytopenia [21, 23, 24, 26, 40]. Following dose reduction or temporary withdrawal, haematopoietic suppression usually improves .
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  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 . 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) .
Alopecia was seen in 4% of patients on long-term therapy [26, 40]. Severe skin reactions have also been associated with methotrexate treatment .
Other AEs that have been associated with methotrexate treatment—although not specifically with long-term therapy—include reactivation of phototoxic reactions  and ulcerative stomatitis . 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) .
Methotrexate may reduce the incidence of cardiovascular-related disease in patients with psoriasis . 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 .
Long-term therapy with methotrexate may not be possible due to AEs and end-organ toxicity potential  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 .
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 .
Methotrexate has been reported to have an acceptable risk–benefit profile ; however, this must be carefully evaluated and continuously monitored in each patient due to the potential for serious AEs . Taken together, with proper treatment monitoring and physician vigilance, methotrexate continues to play an important role as a systemic psoriasis therapy .
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 , and in 73% of patients in a study of patients with severe psoriasis with ≤ 14 years of follow-up . A 16-week RCT of FAE and DMF found a similar percentage of patients experiencing AEs (84.1 and 83.9%, respectively) . A prospective follow-up study of DMF found that 86% of patients experienced AEs over a median period of 28 months .
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 . 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 . A retrospective cohort study found that 42% of patients experienced diarrhoea and 55% experienced flushing over ≤ 14 years of treatment with FAE . 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 . A real-world study of FAE reported GI disturbances in 25% of patients and flushing in 12% . 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) . 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 .
Abnormalities in monitoring blood tests or urinalysis were observed in 45% of patients in an 8-month study of FAE . 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 .
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 . A retrospective cross-sectional study of FAE reported that 41% of patients experienced lymphopenia after 24 months . 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) . A real-world study of FAE reported lymphopenia in 10% of patients . Regular monitoring of lymphocyte counts (every 4 weeks for FAE ; every 3 months for DMF ) and discontinuation of DMF treatment if counts fall to < 700/µL  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 . 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 .
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 . Reduced leucocyte levels (< 3000/µL) were observed in 5% of patients in a retrospective observational study (mean FAE duration 3.6 years) .
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 . 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) . German guidelines for psoriasis treatment conclude that eosinophilia is temporary and generally observed between weeks 4 and 10 of therapy . 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 . 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 . 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) .
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  (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 .
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 ; 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) .
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 .
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 .
Taken together, FAE therapy is associated with a favourable risk–benefit profile  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 .
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.
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 . 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 .
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 . 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) .
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) . 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 .
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 . After 18 months, 50% of patients treated with a systemic agent had discontinued therapy (due to contraindication, AE or treatment success) . 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)  and differing healthcare insurance systems . 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  and that 68% of patients discontinued methotrexate after an average of ~ 4.2 months . 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) . 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 .