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Long-term efficacy


clinically relevant questions. First, the patients participating in the clinical trials are pre-selected and problematic patients with multiple comorbidities or previous failures of another biologic tend to be excluded. This leads to an obvious selection bias. Second, psoriasis is a chronic disease, where life-long treatment is often indicated. The randomised trials do not provide any information about the long-term efficacy of the drug, as the duration is limited to 10–16 weeks. Third, the primary endpoint (PASI reduction) does not address other important clinical symptoms of psoriasis such as PsA, non-plaque forms of the disease or psoriasis involvement of the nails or cosmetically sensitive regions (genitals, hands, face). Fourth, it would be advantageous if the biologic treatment addressed comorbidities, such as the metabolic syndrome or cardiovascular diseases, which are overrepresented in psoriasis population.


Efficacy of biologics in psoriatic arthritis


Biologics have been extensively tested in PsA, which constitutes an independent indication for treatment. Ash et al3


have 18


recently performed a systematic meta- analysis of the efficacy in PsA. All anti-TNFa agents (etanercept, adalimumab, infliximab) showed comparable efficacy measured at 12–16 weeks by the American College of Rheumatology (ACR) 20, 50 and 70, supported by the reductions in the PsA Response Criteria score, number of tender and swollen joints, radiologic progression, pain and Health Assessment Questionnaire score. Although not shown in head-to-head studies, ustekinumab is more active than placebo but seems to have a lower rate of patients achieving ACR20 than do anti-TNF agents; however, further studies are needed to verify this point. The major limitations of these studies are that they primarily focused on the polyarthritis-type of PsA and there are no high-quality studies addressing the psoriatic spinal disease or monoarthritis. Dactylitis and enthesitis have been included as secondary endpoints and significant improvements have been seen with infliximab, ustekinumab and golimumab (the latter is not approved for plaque psoriasis).3 It will be interesting, from the point of view of a dermatologist, to understand the correlation between clinical responses in the skin and joints. Does the satisfactory skin response to a biologic predict the response with respect to PsA?


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Table 1: Known factors negatively affecting the long- term efficacy of biologics14


Duration of treatment (loss of efficacy in 10–20% patients/year)


Previous failure of the anti-TNFa agent Female gender Obesity


Discontinuation of treatment


Unfortunately, this type of analysis has not been performed.


Biologics for nail psoriasis Nail psoriasis is notoriously difficult to manage by conventional therapies and the observation of the striking effects of the biologics adds to their value in the therapeutic armamentarium. Unfortunately, the quality of evidence is quite weak. A recent Cochrane Review identified three trials (with golimumab, ustekinumab and infliximab) where nail responses measured by Nail Psoriasis Severity Index (NAPSI) were included as a secondary endpoint.5 Infliximab showed a 57.2% improvement in NAPSI at week 24 (sustained until week 50), which was comparable to the effect of golimumab at week 24 (50mg: 33% improvement; 100mg: 54% improvement) and ustekinumab at week 64 (45mg: 56.6 ± 43.2%; 90mg: 67.8 ± 37.5%).5


Biologics and health-related quality of life


The Dermatology Life Quality Index (DLQI) is a validated, self-administered ten-question questionnaire, which is believed to reflect accurately the impact of skin disease on the quality of life, ranging from 0 (no impairment) to 30 (the most severe impairment) points. There is agreement that scores below 5 reflect only a small life quality impairment, whereas scores of 10 or higher are interpreted as large, significant life quality impairment.6 The impact of biologic treatment on DLQI has been systematically studied in clinical trials. The baseline DLQI for untreated patients with moderate-to-severe psoriasis was in the range 9–12 and decreased to below 5 (range 3.0–4.4) after the treatment with adalimumab, etanercept, infliximab or ustekinumab. The reduction in DLQI has been comparable for the above-mentioned biologics.7


Long-term efficacy of biologics The most relevant question from the clinical point of view is whether the clinical responses in the skin observed after 10–16


weeks are maintained over longer periods of time. This question cannot be answered in the placebo-controlled trials, as it is not ethical (or realistic) to maintain the patient on placebo for prolonged periods of time. Therefore, most of our knowledge on long-term efficacy comes from the open-label extension (OLE) arms following the placebo-controlled period. Papp et al8


analysed the data for


etanercept from the OLE studies of the duration 3–48 months and found a gradual loss of efficacy from 45.3% of responders at the third month to 27.8% at the forty-eighth month of treatment. The one-year efficacy of infliximab has been reported by Reich et al,9


who found a 20%


decrease in the number of responders between weeks 24 and 50. These data suggest that continuous treatment with the biologic is associated with a considerable loss of efficacy. However, the OLE data published for adalimumab10 and ustekinumab11,12


loss of efficacy over years. Significant differences in the presentation of data for these two compounds mean that direct comparison is not possible. This discrepancy can partially be explained by the nature of the statistical analysis of OLE trials. The unavoidable loss of patients during the long-term follow-up is a formidable methodological challenge. The stringent analysis using the non-responder imputation intent-to-treat principle would grossly underestimate the efficacy. If used for the etanercept data,8


the 48-month


responder rate would only be 6.1%. Therefore, the usual analysis for OLE data is the last observation carried forward (LOCF), which unfortunately overestimates the response.13


For the 48-month


etanercept data, the efficacy measured by LOCF will be 27.8%. The true etanercept efficacy is thus somewhere between 6% and 28%, but a large span precludes making an educated guess. Depending on data handling and stringency of data processing, OLE data should be reviewed with care.


Another approach to the assessment of long-term efficacy is to measure the drug discontinuation rate (so-called drug survival) in a population of real-life patients. It is well known that the main reason for the discontinuation of a biologic in psoriasis is a loss of efficacy.14


show only a negligible


Therefore,


drug survival should approximately reflect the long-term efficacy, assuming that the patient (or the dermatologist) discontinuing the drug faced the suboptimal effect. Data from Denmark14


and Italy15 show that, over


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