| Relative values of different outcomes | The GDG considered the following outcomes:
clear/nearly clear (defined as at least 75% improvement, very mild or clear on a static scale) duration of remission (relapse rate and time to remission) withdrawal due to toxicity withdrawal due to lack of efficacy skin atrophy (reporting of skin atrophy was not by quantifiable methods).
The GDG prioritised the following outcomes for decision making:
Based on the clinical and cost-effectiveness evidence, the GDG recommended potent corticosteroids applied once daily plus vitamin D or a vitamin D analogue applied once daily (applied separately, one agent applied in the morning and the other in the evening) as the first topical intervention. This was the most cost-effective and clinically sensible option based on the investigator and patient assessment of achieving clear or nearly clear status after very potent steroids had been excluded owing to safety concerns. There was no clinically significant difference between most interventions in terms of withdrawal due to toxicity as the absolute numbers were low and clear evidence regarding duration of remission was lacking. |
| Trade off between clinical benefits and harms |
The superior efficacy of potent corticosteroids compared with vitamin D analogues might be outweighed by the risk of local side effects (e.g. irreversible skin atrophy), shorter duration of remission, destabilisation of psoriasis, and, although rare, the potential for systemic side effects of corticosteroid in those with extensive disease. It was also recognised that such risks might be compounded by repeat prescriptions being issued without assessment. The GDG discussed the risks and benefits of corticosteroids and considered that given their marked efficacy and cosmetic acceptability, potent corticosteroids could be recommended for the treatment of chronic plaque psoriasis in primary care in the context of appropriate review and patient education. However, very potent corticosteroids could not be recommended due to concerns about the rebound effect, irreversible skin atrophy, the risk of repeat prescriptions being issued without monitoring and lack of long-term safety data. Based on the duration of the trials (mostly up to 8 weeks for potent and 4 weeks for very potent corticosteroids) and in line with the clinical experience of the GDG, it was agreed that to ensure safe use, potent corticosteroids should not be used continuously for more than 8 weeks and very potent corticosteroids for more than 4 weeks. The data showed that the levels of skin atrophy at this point did not demonstrate clinically relevant harm and the treatment response was beginning to plateau. The majority of those who are likely to respond within 8 weeks to potent or very potent steroids would have done so by 4 weeks. Therefore, the initial treatment period recommended for these topical agents is 4 weeks. A break of 4 weeks between courses of potent or very potent corticosteroids was recommended, as the GDG were aware of data suggesting that 3–4 weeks is required for skin regeneration. Non-steroid based topical treatments are recommended to maintain disease control during this break, as there was evidence to suggest that vitamin D analogues could maintain response following short-term treatment with a combined product containing potent corticosteroid and vitamin D analogue. The GDG considered that appropriate assessment and review of efficacy and safety was critical. An early review to identify tolerability/side-effects and to identify complete non-responders is needed. Since the most rapid improvement is seen within the first 4 weeks, a review after 4 weeks was agreed. Those with little or no improvement at 4 weeks should be cycled on to the next stage of the topical treatment pathway. Although the combined product is not cost-effective for the average patient, it was considered an important third-line topical option. This was because in non-responders to topical treatment, concordance is often a problem and a once-daily, well-tolerated topical preparation would be of benefit in achieving clearance, so avoiding hospital referral and saving cost in this small group. Therefore, the GDG agreed to recommend once daily combined potent corticosteroid and vitamin D analogue in patients in whom twice daily potent corticosteroid or coal tar cannot be used and a once daily preparation would improve adherence.
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| Economic considerations | The GDG relied on a variety of sources in their consideration of the costs and benefits of alternative topical therapies in the treatment of patients with mild to moderate psoriasis. Limited evidence, both in terms of quantity and quality, was identified in the published literature. The available evidence showed:
short-contact dithranol likely to be more cost-effective than a vitamin D analogue 18; vitamin D analogue to be more cost-effective than potent and very potent corticosteroids 289; and two compound formulation steroid and vitamin D analogue to be more cost-effective than concurrent (morning/evening) application of the two topicals and more cost-effective than both potent steroids and vitamin D analogues applied alone 37
However, the GDG remained uncertain about the robustness of these conclusions.
Original decision modelling was undertaken for the guideline and showed that there were relatively small differences in terms of benefit between different topical sequences, but large differences in terms of cost. Based on the mean costs and benefits of 118 compared sequences, the analysis suggests that treatment with potent corticosteroids or concurrent treatment with potent corticosteroid and vitamin D analogue (morning/evening application) was likely to be the most cost-effective option for the first and second-line treatment of patients with mild to moderate psoriasis.
The analysis specifically found twice daily potent corticosteroid to be highly cost-effective, but the GDG expressed concern that the well known side effects of potent corticosteroids (e.g. skin atrophy, rapid relapse) were not adequately captured in the economic model owing to a lack of data. Twice-daily potent corticosteroids were more cost-effective than once-daily, largely because the quantities of topical used for once and twice daily application were very similar, yet the network meta-analysis showed a non-significant trend toward twice daily being more effective in the investigator assessed outcomes used in the base case scenario (OR=1.807, 95% CrI 0.42 to 8.074). However, this trend was reversed for the patient-assessed outcome, i.e. twice-daily performed less well than once-daily (OR=0.714, 95% CrI 0.14 to 3.549). This finding is reflected in the results of the sensitivity analysis where patient-reported response was used, which show once-daily to be more cost-effective than twice-daily. The consensus of the GDG was that they were uncertain that twice-daily potent corticosteroids were more effective than once-daily potent corticosteroids. They concluded that even if twice daily application was more effective at inducing clearance or near clearance than once daily application, the risks of higher dose steroids were very likely to outweigh the potential benefits and make the intervention less cost-effective. The GDG recommend that in the choice of potent corticosteroid formulation, consideration be given to patient preference, cosmetic acceptability, practical aspects of application and the site(s) and extent of psoriasis to be treated. The lowest cost preparation might not be the most cost-effective one if adherence is low.
Concurrent treatment with potent corticosteroid and vitamin D analogue (morning/evening application) was also likely to be cost-effective in a range of scenarios. In some cases, it was found to be a cost-effective first line treatment; however, the GDG felt this was too aggressive a strategy to start with for the majority of people with mild to moderate psoriasis being seen in primary care. Based on that, they concluded that the addition of once daily vitamin D analogue to once daily application of potent corticosteroid should be the next treatment offered if a potent corticosteroid alone has failed to induce the desired level of response. The GDG specifically considered whether they should offer concurrent treatment (morning/evening) with two separate topicals or offer combined treatment in a single product for use just once daily. They considered the results of the cost-effectiveness analysis which showed that combined treatment (once daily TCF product) is not cost-effective compared with concurrent treatment. This is because the network meta-analysis found them to have similar efficacy, but TCF product is much more costly (unit cost of 120g combined product containing calcipotriol monohydrate and betamethasone dipropionate is between 2 and 4 times more costly than the combined unit cost of 100g of vitamin D analogue and potent corticosteroid each). This is true even when the most costly potent corticosteroid and vitamin D products and formulations are assumed to be prescribed. The GDG considered whether a once daily application of the combined product may be cost-effective when considering the problems many patients have adhering to twice daily treatment regimens. The results of a sensitivity analysis wherein 40% of patients prescribed concurrent therapy were assumed to apply only their potent corticosteroid once per day showed that the very small benefits of once daily combined product were still outweighed by its extra cost. The GDG concluded that the combined formulation product as first-line treatment produced enough additional benefit to justify its substantial additional cost.
The base case cost-effectiveness analysis and sensitivity analyses showed that the choice of third line treatment in a given sequence was highly uncertain. Depending upon the data used and assumptions made, third line treatment with twice daily coal tar, twice daily vitamin D analogue or once daily TCF product was likely to be most cost effective. To reflect the uncertainties in the conclusions about cost-effectiveness and provide prescribers and patients with a degree of choice, the GDG chose to recommend all of these interventions if the patient has failed to achieve clearance or near clearance with potent corticosteroids alone or concurrent treatment with potent steroids and vitamin D analogue. They considered that some people may not choose to use coal tar as it has a pungent odour and that some people may prefer vitamin D analogues as they are generally safe for long term use. They considered that the combined potent corticosteroid and vitamin D analogue product was much more costly than other alternatives, but it may represent value for NHS resource in a select group of patients with resistant mild to moderate psoriasis. It also may be more cost-effective to offer if the alternative is referral and escalation of treatment to much costlier interventions (e.g. phototherapy, specialist applied topicals, systemic therapy, biologic therapy).
The cost-effectiveness analysis did not find short contact dithranol to be more cost-effective than other first, second and third line alternatives in the base case or any sensitivity analyses. The GDG did not want to rule dithranol out as a treatment option for some patients, but considered it only potentially cost-effective for patients who have failed to respond to other more efficacious and easy-to-use topical therapies. They emphasised the need for the healthcare professional to clearly explain proper application of dithranol for home use in order to maximise its effectiveness and reduce the inconvenience. They also considered that dithranol may be best delivered as part of treatment in a day care setting with specialist nurse supervision.
The cost-effectiveness of very potent corticosteroids was not evaluated as part of the decision-modelling, as the GDG did not consider it a safe treatment option for the management of mild to moderate psoriasis in primary care. They considered that based on its efficacy and relatively low cost (100g cream or ointment = £ 7.90), it was likely to represent good value for NHS resource so long as it is used with caution and under careful supervision of a specialist in secondary care.
In thinking about the potential risks of prescribing potent, and in select cases very potent corticosteroids, the GDG considered it essential to build in monitoring to assess efficacy and adverse events. The time horizon of the economic model was too short (1 year) to explicitly consider annual monitoring in the long term; however, it is very likely that the extra cost of an annual GP or specialist visit would be offset by the avoidance of irreversible adverse events that are associated with inappropriate and unsafe use of corticosteroids.
The cost-effectiveness of topical treatments for children was not explicitly considered in the decision modelling undertaken for the guideline; however, the GDG considered the results broadly applicable to this population. They considered that once-daily applications in children were likely to be more appropriate, and that evidence of effectiveness for combination strategies were lacking. Therefore, they concluded that for children with mild to moderate psoriasis, once daily application of potent corticosteroids or vitamin D analogue were likely to represent the best value for NHS resource. They also considered how infrequently psoriasis occurs in children and that referral to secondary care may be justified. |
| Quality of evidence | The GDG noted variations in methodology and reporting between the studies, in particular:
frequency of administration of treatment duration of follow-up within (left-and right-hand side comparison) and between patient randomisation topical formulation baseline disease severity -of the studies that reported disease severity at baseline, 16 studies included moderate to severe disease. This does not reflect clinical practice as monotherapy with topicals is usually used to treat mild/moderate disease, which was the population of interest for this question.
Note that within-and between-patient studies have been pooled together in the analysis, and none of the studies reported sufficient information to take account of the within-patient correlation in the analysis. It was often not possible to say if consistent differences were present as there was only one within patient study in the comparison. When it was possible to assess this, no consistent difference was seen for efficacy outcomes, although for vitamin D analogues vs. placebo there may be a difference for between-and within-patient studies for withdrawals due to adverse events or lack of efficacy. For withdrawals due to adverse events, 5/6 between patient studies favoured vitamin D analogues (RR = 0.54) compared with 5/5 within patient studies210,211,311,354,411 which favoured placebo (RR = 3.00). Conversely, for withdrawals due to lack of efficacy 3/3 between patient studies favoured vitamin D analogues (RR = 0.15) whereas 3/3 within patient studies showed no difference (RR=1.00). However, the absolute number of withdrawals was low so this difference is unlikely to be clinically meaningful.
Vitamin D analogues vs placebo
The GDG noted that:
the Perez study gave an outlying result for the outcome of investigator’s assessment of global improvement (IAGI), and that there was a zero success rate in the placebo arm. This was considered unusual as emollients tend to have some level of efficacy. the Langner 1993 study used an unlicensed dose of calcitriol (15μg twice daily).
Vitamin D analogue vs. corticosteroid
There was heterogeneity between the studies for the outcome of investigator’s assessment of improvement. This could not be explained by excluding studies at higher risk of bias or by any of the pre-defined subgroups for investigation, as a statistically significant level of inconsistency still remained. However, it appeared that betamethasone valerate was less effective than betamethasone dipropionate when compared with vitamin D analogues. The GDG noted that the rates of remission were low for all interventions in the Fleming 2010A study but no clinical or methodological explanation could be found for this.
Vitamin D analogues vs. coal tar
There was significant heterogeneity between the studies. The heterogeneity may be explained by variation in treatment duration and coal tar taking longer to act than vitamin D analogue, so becoming relatively more effective at later timepoints. One of the studies (Pinheiro 1997) used a tar combination that includes a mild potency corticosteroid (alcoholic coal tar extract 5%, hydrocortisone 0.5%, allantoin 2%).
Maintenance therapy
Just two studies178,195,196 directly assessed maintenance treatment:
The Katz study had a maximum treatment period of 6 months with potent corticosteroid or placebo (using an intermittent regimen of 3 applications 12 hours apart once a week) among those who had achieved remission after 3–4 weeks treatment with a potent corticosteroid. The GRADE ratings for this study were low to moderate, and the definition of response was broader than that specified in the review protocol, which may over estimate efficacy (clear/slight improvement on a four point scale) but was included given the paucity of maintenance studies. The Kragballe study had a 52 week treatment period for as-needed application of either a combined potent corticosteroid and vitamin D analogue, the combination for 4 weeks then calcipotriol for 48 weeks, or alternating 4 week periods of the combination product and calcipotriol. The one year timeframe of this study reflects clinical practice; however, the study was primarily designed to investigate safety rather than efficacy.
Treatment regimens
There were also 3 studies (Kragballe 2004, Ortonne 2004 and Saraceno) that assessed different treatment schedules (e.g. combination of potent corticosteroid and vitamin D analogue then vitamin D analogue alone) but these were only 16–24 weeks in duration and therefore of limited relevance.
The GDG noted that there was inconsistency between the studies for time to relapse and relapse rates during a post-treatment withdrawal phase among those who had achieved remission, and that only 4 studies reported these data (Langley 2011A, Camarasa 2003, Alora-Palli 2010, and Christensen 1999) and one during a maintenance treatment phase following remission (Katz 1991). Additionally, in the placebo group the numbers who achieved remission and were followed-up were very few and they may have gone into spontaneous remission; therefore, the time to relapse in this group may be a spurious result. As such, the GDG gave little weight to these data. The GDG noted that, in accordance with clinical experience, relapse rates following use of vitamin D analogues appeared to be lower than that with potent corticosteroids (although the time to relapse was similar in both groups).
Time to maximum effect
The GDG noted the following variables between the studies investigating time to remission/maximum effect which made interpretation and synthesis of the results difficult: drug dosing formulation treatment duration outcome measure.
The GDG also noted that the majority of the trials were not long enough to see the maximum effect. The only longer term study (Perez) was a 12 month follow up after randomised phase of trial. However, it included small numbers of participants (22 at the start with 6 remaining at the end) and so was excluded from the review. The following maximum responses were noted: for vitamin D or vitamin D analogues -was seen at 8–12 weeks (most rapid improvement was seen over the first 4 weeks). for potent steroids -was not seen during the 8 week study period although continued improvement was likely to be minimal (most rapid improvement was seen over the first 2–4 weeks). for very potent steroids -was not seen by end of 4-week study period although continued improvement was likely to be minimal (most rapid effect is seen over the first 2 weeks). for the combined product -was at 12 weeks although the majority of this occurred within the first 4 weeks. it was not possible to be sure about when the maximum response to coal tar preparations is seen owing to the different results between preparations and the paucity of evidence so no time frame for use is stated.
All treatment modalities demonstrated some efficacy by four weeks. The GDG agreed that based on the times to response, assessment at four weeks would be helpful to assess treatment efficacy, potential problems with use such as formulation, tolerability, cosmetic acceptability and to plan ongoing treatment strategy including treatment switch in the event of an inadequate response.
Relapse
From the evidence, relapse occurs in 20–80% of people following treatment withdrawal regardless of the specific topical treatment used, so the GDG agreed there should be an over-arching recommendation about offering strategies that recognise that repeat treatment is likely to be required and that patients need education on what to expect from treatment. Limited data on maintenance strategies precluded making separate recommendations on induction and maintenance of remission. In the absence of evidence, topical therapies should be continued to be prescribed and used ‘as needed’.
Treatment frequency
In considering differences between once and twice daily applications of potent corticosteroids, whilst there is generally a trend towards better efficacy with twice daily application, greater numbers of withdrawals due to adverse events were seen with twice daily potent corticosteroid compared with once daily. Therefore the GDG agreed that in view of convenience to the patient, potential cost benefit, and reduced risk of side effects especially in relation to corticosteroid use, once daily applications should be recommended in the first instance. Treatment could be escalated to twice daily if once daily is not effective.
Evidence gaps
The GDG noted important gaps in the evidence required to inform clinical practice. Psoriasis is a long term condition, but the vast majority of studies are 12 weeks or shorter in duration. Only limited data were available on longer term use, especially regarding the safety of very potent and potent steroids, treatment strategies for maintenance of disease control, relative benefits of the different interventions with respect to relapse and remission rates, and the value of early intervention (for example use of a topical treatment at first signs of disease occurrence). |
| Other considerations | Groups for special consideration
There are no groups of people who should not be offered topical therapy. For patients with severe chronic plaque psoriasis (i.e. BSA>10% and/or PASI >10), self-administered topical treatment alone is unlikely to provide adequate disease control, is difficult from a practical point of view, and application of potent corticosteroid over large areas of inflamed skin may increase the risk of both local and systemic side effects. It was therefore agreed that additional treatment strategies should be routinely offered to this group. Psoriasis is not common in children and therefore quicker escalation to secondary care may be appropriate. Giving GPs the option of using emollients and then referring without trying any active treatments was felt to be limiting. Plaques are usually thinner and less scaly in children. Topical calcipotriol is licensed for children above 6 years old. One study investigating calcipotriol in children found a smaller response compared to the adult studies, although this was one study with small numbers. From GDG experience, mild to moderate potency corticosteroids are also useful in children with or without tar but there was no evidence for this. Taking into consideration all of the above points, it was agreed that children should be reviewed after two weeks, as the plaques tend to be thinner and treatments should only be used within the licensed indications for trunk and limb psoriasis in children. For more information on dosing, in the absence of evidence, prescribers should refer to the BNF for Children. The GDG discussed the needs of older people, people with limited mobility and people with psoriatic arthritis. It was noted that specialist help with application can improve outcomes for these groups of people.
Adherence
The GDG considered factors that may impact on treatment adherence and outcomes including cosmetic acceptability and local side effects. For pragmatic reasons, the GDG had agreed that data on the impact of formulation on treatment outcomes would not be considered. However, it was agreed that formulation should always be considered when prescribing topical therapy to optimise treatment adherence and minimise local adverse effects. For example, a light cream or lotion may be appropriate for widespread, multiple small plaques to cover requisite large areas, lotions/solutions for hair bearing areas and ointments for scaly areas. It was noted that knowledge in primary care may be limited in this regard and simple guidance would be helpful. The GDG agreed that a specific recommendation about the need to consider formulation and cosmetic acceptability when prescribing topical therapy was justified. Non-concordance should be considered if there is no response to treatment in line with ‘Medicines adherence’ (NICE clinical guideline 76) 265
Safety and toxicity
There is enduring concern amongst clinicians and patients about potential risks of corticosteroids for the treatment of psoriasis including local skin atrophy, rapid relapse/rebound on treatment cessation, destabilisation of disease (for example induction of pustular psoriasis) and potentially systemic side effects in people with very widespread psoriasis, especially given that for chronic plaque psoriasis at most body sites (excluding face, flexures) potent or very potent corticosteroids are required to achieve clearance. From GDG knowledge, vitamin D analogues, tar and dithranol do not cause skin atrophy whereas corticosteroids do. The majority of the data on withdrawals and skin atrophy across all comparisons showed low event rates that gave very imprecise relative estimates, but in absolute terms demonstrated precise evidence of no clinically relevant difference between the interventions because the numbers involved were so low Overall, the evidence did not indicate any statistically significant increased risk of steroid atrophy with corticosteroid use (potent and very potent) and the numbers of cases of skin atrophy reported were very low. The majority of cases of skin atrophy that were reported were in patients who received corticosteroids. However, this outcome was not reported in all studies and no study reported having used a reliable quantitative measure to assess the level of atrophy. It was noted that the lack of a significantly increased risk may be due to lack of appropriately designed studies of sufficient duration and power rather than lack of risk. The GDG discussed whether extrapolation from the amount of steroid likely to be used if the Finlay fingertip unit was adhered to (i.e. 0.5g covers the equivalent of 2% BSA (or 2 ‘hands worth’)) could inform the likely safety of the recommendations made. Based on the fact that potent corticosteroid would only be the main treatment option in people with localised disease, with secondary care escalation immediately if BSA is >10%, a conservative assumption would be that anyone with a BSA of <10% may be managed with corticosteroids alone. Therefore, once daily application to 10% BSA (based on the fingertip unit) is equivalent to 2.5g daily application (75g per month). The GDG agreed that this is in keeping with dermatology practice that >100g month indicates potentially dangerous amounts of steroid and is less than the volumes used in the RCTs reviewed, which had few cases of atrophy. Therefore, the GDG were satisfied that based on the available evidence and current expert opinion the recommendations should not cause an increase in steroid-related toxicity in people with psoriasis. Some patients may prefer to use topical therapies that do not contain corticosteroids (tar, dithranol, vitamin D analogues) due to concerns about corticosteroid side effects. Tazarotene may be unpleasant to use. It causes burning and irritation of the skin (which was indicated by the evidence for a statistically significantly higher number of withdrawals due to adverse events among those treated with tazarotene compared with placebo in 2 studies), and shows only limited efficacy (approximately 6% achieved clearance or near clearance). Dithranol is difficult to use at home due to staining, risk of burning unaffected skin and difficulties with self application, but is useful for large, thick, treatment resistant plaques. Educational support is required when prescribed.
Current practice
In primary care topical vitamin D analogues are considered the standard treatment. Combined potent corticosteroid/vitamin D analogue preparation is not in most GP formularies due to the cost. Most patients benefit from an emollient to relieve pruritus and scaliness. PASI and DLQI are not used in primary care so could not be recommended for assessment of response to treatment. In addition sensitivity to change with PASI is poor in mild to moderate disease.
Other considerations from the evidence
The evidence suggested that time to relapse was shorter with potent and very potent corticosteroids compared to vitamin D analogues, tar and dithranol. The GDG noted that in studies that compared various treatment sequences (e.g. combined product containing calcipotriol monohydrate and betamethasone dipropionate followed by either vitamin D alone or alternating vitamin D alone and combined product containing calcipotriol monohydrate and betamethasone dipropionate) with vitamin D alone for the full trial period if a combined product containing calcipotriol monohydrate and betamethasone dipropionate was present anywhere in the sequence, even just for the first 4 weeks, the efficacy was improved compared with vitamin D alone. The data suggested that this increased efficacy could be maintained by subsequent use of vitamin D analogue alone.
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