The results of this observational study describe, for the first time, the long‐term treatment of psoriasis with three different FAE therapy regimens (FAE monotherapy; FAEs + phototherapy; FAEs + MTX) in a real‐life setting. One strength of this study is that it is, to the best of our knowledge, the largest study of this kind to include a total study population continuously treated with FAEs for a mean of 3.6 years (43.9 months) and is therefore strongly representative of psoriasis patients treated with classic systemic therapies in everyday clinical practice. Each of the three therapy regimens was well characterized with a sufficiently large sample size and a relatively long observation period in many cases (Table 3); 27.1% of all 859 patients received FAEs in combination with phototherapy or MTX. To measure safety, we calculated AE rates and listed SAEs. To evaluate effectiveness, we measured reduction in sPGA and percentage reduction in PASI and aPASI as the outcomes of interest.44 In the long‐term treatment of patients with psoriasis, FAE monotherapy and combination therapies with phototherapy or MTX showed a favourable safety profile and satisfactory clinical effectiveness.

Safety aspects

In all treatment groups, the most frequent AEs were gastrointestinal symptoms, which were observed in approximately one‐third of treated patients (Table 5). In our experience, gastrointestinal symptoms typically occur within the first few weeks of FAE treatment and last for several minutes to half an hour after oral administration. Symptoms are generally mild to moderate and resolve with continued treatment. In this study, these symptoms were rarely so profound as to require treatment discontinuation. However, the comparatively low manifestation of gastrointestinal symptoms in our study defies explanation.45, 46 One can only speculate whether the great diversity in reports of treatment‐related gastrointestinal disorders is due in part to the wide heterogeneity in FAE dosage adjustments, which in real life are mainly based on the individual expertise of the treating physicians. The second most frequently reported AE was flushing of the skin (Table 5), which can range from a rapid sensation of heat to long‐lasting facial redness. This symptom was observed in up to 6–14% of patients, also typically in the earlier stages of treatment and with the tendency to resolve over time. This AE may be very unpleasant but is not serious and only very rarely represents a considerable burden for the patient, leading to treatment discontinuation. Improvement of this AE has been observed following treatment with acetylsalicylic acid.17, 19, 26 This treatment response has been later confirmed also by two randomized placebo‐controlled clinical trials (RCTs).47, 48 Haematologic disorders, primarily comprising leucopenia, lymphopenia and eosinophilia, were the third most reported AEs (Table 5). According to the literature, the proportion of patients who discontinue FAE treatment because of haematologic disorders ranges from 2.6% to 12%.5, 14, 30 Between 12% and 17% of patients in the three treatment groups developed severe lymphopenia or eosinophilia at some point during FAE therapy (Table 6). A retrospective case series reported that 26% of psoriasis patients (16/62) had a lymphocyte count <500/μL.49 Usually, these phenomena are transient and reversible14, 50-52 and may serve as a biomarker for drug efficacy of FAEs.53 The changes in leucocyte and lymphocyte counts observed in the present study (Table 7) compare well with those recently reported by Sondermann et al.54 In that study, which included a much smaller cohort of 105 patients with psoriasis, the median leucocyte count decreased by about 17.3% and the median lymphocyte count by about 35.8% in the first 6 months of FAE therapy. Over a maximum FAE treatment period of 112 months, that group observed severe lymphopenia (CTCAE grade 3 or 4) in 11.4% of patients. Although severe, persistent leucopenia and lymphopenia events were rare,49, 55 these AEs resulted relatively often in the physician's decision to discontinue treatment to decrease the risk of opportunistic infection.54 Although opportunistic infections are very rare, 19 cases of progressive multifocal leucoencephalopathy have been identified among patients treated with different FAE preparations to date;56, 57 14 of these occurred during therapy for psoriasis (11 patients used Fumaderm® and three patients used Psorinovo®, DMF, compounding pharmacy). All of these patients were lymphopenic and had been receiving FAE therapy for prolonged periods. Only patients with prolonged uncontrolled lymphopenia during FAE therapy seem to be at higher risk for this very rare but serious side‐effect of FAEs.7, 54 Additionally, fatal cases of West Nile encephalitis,58 generalized varicella zoster,59 and Kaposi sarcoma60 have been associated with FAEs.61 In our total cohort, we did not observe any severe or opportunistic infections leading to treatment discontinuation. Eosinophilia is frequently observed within the first 3 months of FAE therapy62, 63 and usually decreases to standard values with continued treatment,64 only rarely necessitating treatment discontinuation.7 Other frequent AEs among the three drug cohorts were hepatobiliary disorders (Table 5). A clinically relevant increase in liver enzymes was observed in up to 5% of patients (Table 6); increases were reversible after FAE dose reduction or treatment discontinuation. Mild‐to‐moderate elevations in liver enzymes (below twice the upper limit of normal) were reported in up to 40% of psoriasis patients taking FAEs but rarely necessitated discontinuation of therapy.18, 22, 50, 64 To date, no animal or human data have indicated any risk of permanent liver damage with FAE use. Although between 10% and 20% of patients in the three treatment groups showed increased serum creatinine levels and/or proteinuria (Table 6), only a few sporadic cases of disturbed renal function were documented as AEs in the ‘FAE monotherapy’ and ‘FAEs + phototherapy’ groups (Table 5). This result confirms again that treatment‐related renal disorders are reversible upon FAE dose reduction or treatment discontinuation.51, 65 According to our long‐term experience, increased serum creatinine levels and proteinuria very rarely lead to treatment discontinuation after FAE dose reduction. Other recorded AEs were comparatively rare or sporadic and were also reversible (Table 5). Given the above findings and the EMA's updated recommendations regarding lymphopenia during FAE therapy,66 patients receiving FAE therapy require regular and continuous clinical assessment and monitoring of all safety‐relevant laboratory parameters.54 Although we are currently adhering to the aforementioned EMA guidelines, which are based so far only on case‐report‐level evidence,49 we agree that their rigorous implementation should now be discussed on the basis of broader evidence.49, 54, 55

Our results support the reported safety profile of FAEs. In their systematic review, Balak et al.46 identified 37 observational studies between 1987 and 2015 with a total of 3457 patients. Eighteen studies analysed long‐term FAE treatment over a period of up to 14 years.18 No treatment‐related deaths or SAEs were reported. The most frequently reported AEs were gastrointestinal symptoms and flushing of the skin. Frequently reported laboratory abnormalities included lymphopenia, elevated liver enzymes and eosinophilia. Overall, 45% to 87% of patients experienced an AE. The proportion of patients discontinuing FAE treatment because of AEs ranged from 6% to 47%. The most frequent causes of early treatment discontinuation were intolerable gastrointestinal symptoms and, far less frequently, severe flushing symptoms. Only a few reported treatment discontinuations resulted from laboratory abnormalities.

The general goal of combining FAEs with phototherapy was to induce a faster and improved therapeutic response to FAEs.20, 67 In a first prospective non‐interventional multicentre study (‘FAST’ study), Weisenseel et al.21 investigated the combination of FAEs with various phototherapies in 363 patients over a shorter observation period of 12 months. Tolerability and safety of this combination were good. Only 7% of patients experienced AEs, all of which were within the spectrum of known FAE‐related adverse reactions. However, the final statement of the authors that a phototherapy duration >3 months may not be advisable, not least because of its oncogenic potential,21 is not supported by our long‐term safety data. Without doubt, uncontrolled long‐term use of phototherapy may result in UV damage and premature ageing of the skin.67 UV exposure increases the risk of non‐melanoma skin cancer, hence careful clinical monitoring of patients under phototherapy must be ensured. However, none of the patients in our ‘FAEs + phototherapy’ subcohort experienced these serious side‐effects, even in one case where continuous twice‐weekly phototherapy lasted for 16 years.

With an observed drug interaction rate of <5%,30 FAEs appear not only suitable for comorbid patients with psoriasis but also usable in combination with other systemic antipsoriatic agents. Off‐label combination of FAEs and MTX has a reasonably long tradition, not just in our dermatology clinic.22-24 Additional administration of MTX seems especially justified if FAE monotherapy lacks efficacy, or in cases with new onset of psoriatic arthritis during FAE monotherapy.23 In psoriatic arthritis, MTX remains the first drug of choice.28 In their meta‐analysis of RCTs involving adult patients with moderate‐to‐severe plaque psoriasis, Schmitt et al.68 found that FAEs were equally as efficacious as MTX, with similar rates of AEs and treatment discontinuations. It is therefore reasonable to assume that there might be an additive antipsoriatic effect of adding MTX, without any new or additional safety concerns.28 Transient and reversible hepatotoxicity was the most common limiting factor during combination therapy.7