Topical calcipotriol/betamethasone dipropionate for psoriasis vulgaris: A systematic review

INTRODUCTION

Psoriasis is a common, chronic inflammatory cutaneous disease that affects 1-3% of the world population. ^[1] The pathogenesis is multifactorial and there are various triggering factors. It may lead to a low quality of life and reduces physical and mental functioning. ^[2] Psoriasis vulgaris is the most common form of psoriasis. Mild to moderate psoriasis vulgaris is usually treated topically with agents that may include vitamin D derivatives and corticosteroids. ^[3]

Calcipotriol and betamethasone dipropionate have been used as topical therapies in psoriasis vulgaris for many years. ^[4],[5],[6] Treatments are often used in combination to improve symptom control and tolerability. It was postulated that a combination of topical calcipotriol and corticosteroid may have an additive or synergistic treatment effect due to their different mechanisms of action. This is expected to be more efficacious and better tolerated than monotherapy with either drug. ^[7] However, calcipotriol and corticosteroids are usually not compatible because of their different pH requirements.

A compound with calcipotriol (50 ug/g) and betamethasone (0.5 mg/g) was introduced and recommended for mild-to-moderate psoriasis in 2001. ^[8] This formulation, available as both an ointment and a gel, combined the action of vitamin D3 analogues on keratinocyte differentiation with the anti-inflammatory effect of steroids. This reduced the side effect profile that was seen with single topical agents. ^[9],[10] A study in a human disease model showed that the ointment and gel formulations had comparable anti-psoriatic effects. ^[10],[11] Previous studies have used this compound, either alone or combined with other therapies, for the treatment of mild-to-moderate psoriasis. ^{[9],[12],[13],[14],[15],[16],[17],[18],[19],[20]} The primary aim of our systematic review was to examine the efficacy and tolerability of calcipotriol/betamethasone dipropionate in the treatment of psoriasis.

Materials and Methods

Eligibility criteria

We searched for studies regardless of the language or publication status, that met all of the following criteria: (i) randomized controlled trials involving psoriasis vulgaris patients; (ii) undergoing calcipotriol/betamethasone dipropionate ointment/gel therapy in the treatment group, without any other simultaneous treatment; (iii) undergoing calcipotriol or betamethasone ointment/gel therapy in the control group, without any other simultaneous treatment; (iv) psoriasis on the body, with or without scalp lesions.

Search strategy

PubMed, China National Knowledge Infrastructure and Cochrane library were independently searched by two investigators using the open search strings "calcipotriol," "betamethasone," "psoriasis", "random," "randomized control trial" and "randomized controlled trial." All studies that matched the search criteria were included until April 2015. The reference lists of prior reviews, systematic reviews and trials were also checked.

Study selection and data extraction

Two investigators independently screened all studies for inclusion into the review. Eligible studies were determined and retrieved. Disagreements were resolved by consensus. They independently extracted the data from included studies with the help of standardized forms. A third investigator was assigned the checking process. The study data included the country/region of participants, interventions, number of participants with age and gender distribution, the affected sites, baseline score, mean duration of disease, duration of treatment, evaluation time, efficacy and safety.

Quality assessment

The criteria recommended by the Cochrane Collaboration Handbook were used to assess the methodological quality of included trials. It focused on the description of randomization (sequence generation progress), allocation concealment, blinding, addressing of incomplete outcome data, reporting of selective outcome and other potential threats to validity. ^[21] The judgment for each entry was based on the answer of a question with "Yes" indicating "low risk of bias," "No" indicating "high risk of bias" and "unclear" indicating "either lack of information or uncertainty on the potential for bias." Disagreements were resolved by group consensus.

Outcome measures

The primary outcomes were the percentage reduction of the PASI score, the PASI score, and the proportion of patients who achieved PASI 75 score. The secondary outcomes included the proportion of "marked improvement or clearance" by investigator assessment and occurrence of any adverse events.

Data analysis and statistical methods

The statistical analyses were performed by both investigators using the duplicate data entry facility of Revman 5.0. In addition to 95% confidence intervals, mean differences were used for continuous outcomes. The I² statistic was calculated to determine the proportion of between-study variation due to heterogeneity. The value ranges from 0% to 100% and high values indicate strong heterogeneity. If the heterogeneity was low (P > 0.1, I² < 50%), a fixed-effect model was used for analysis, otherwise a random-effect model or describe analysis was used.

RESULTS

Eligible studies

Altogether, 391 papers were identified by a systematic literature search. After screening the titles and abstracts, 378 non-relevant papers were excluded. The full text of the 13 remaining papers was retrieved. After review, 10 randomized controlled trials were finally included. ^{[9],[12],[13],[14],[15],[16],[17],[18],[19],[20]} The study selection procedure is illustrated in a flowchart [Figure - 1].

Figure 1: The flow chart of the study selection process

Risk of bias assessment and study characteristics

All studies reported random allocation of study participants, eight of them adequately described the randomization method. ^{[9],[12],[13],[14],[16],[17],[19],[20]} Six trials adequately mentioned the allocation concealment. ^{[9],[12],[13],[14],[17],[19]} Five trials performed blinding of participants and researchers and three trials mentioned blinding of outcome assessment. ^{[12],[13],[14],[17],[19],[20]} Nine trials addressed incomplete outcome data. All the ten trials addressed selective outcome reporting [Figure - 2] and [Figure - 3]. ^{[9],[12],[13],[14],[15],[16],[17],[18],[19]}

Figure 2: The judgments about each risk of bias item, for each included study

Figure 3: The judgments about each risk of bias item, presented as percentages across all included studies

Ten randomized controlled trials involving 6590 participants with psoriasis vulgaris were included in this systematic review. Five studies focused on Europeans and North Americans, two studies focused on Asians and the other three studies did not describe the origin. ^{[9],[12],[13],[14],[15],[16],[17],[18],[19],[20]} The mean age of patients was between 40-50 years. Men were relatively more affected than women. The duration of disease was more than ten years in most of the studies. The duration of treatment ranged from four to eight weeks. The characteristics of the included studies are depicted in [Table - 1].

Table 1: Characteristics of included studies

Efficacy evaluation

Comparison of calcipotriol/betamethasone dipropionate with calcipotriol [Table - 2]

Table 2: The protocols and efficacy of treatment group and control group

We identified ten trials for this comparison, involving a total of 4628 participants. ^{[9],[12],[13],[14],[15],[16],[17],[18],[19],[20]} The frequency of application was once daily calcipotriol/betamethasone versus once daily calcipotriol in three studies, once daily calcipotriol/betamethasone dipropionate versus twice daily calcipotriol in five studies, and twice daily calcipotriol/betamethasone dipropionate versus twice daily calcipotriol in two studies. ^{[9],[12],[13],[14],[15],[16],[17],[18],[19],[20]}

The treatment duration was 4 weeks in seven studies. ^{[9],[12],[14],[15],[16],[18],[20]} Six studies evaluated the percentage reduction of PASI score at the first week and fourth week. They showed a higher reduction in the calcipotriol/betamethasone dipropionate group (about 40% at week 1, and about 70% at week 4) compared to those in the calcipotriol group (P < 0.001). ^{[12],[14],[15],[16],[18],[20]} Two of those studies conducted a meta-analysis and showed that calcipotriol/betamethasone dipropionate was more effective than calcipotriol at all evaluation time-points (Week 1: mean difference = 8.29, 95% [4.78-11.80], P < 0.001; Week 2: mean difference = 10.85, 95% [6.98-14.73], P < 0.001; Week 4: mean difference = 10.20, 95% [6.25-14.14], P < 0.001). ^[15],[18] One study also demonstrated that the PASI 75 score was observed in over 70% (111/152) of patients with calcipotriol/betamethasone dipropionate therapy in contrast to only about 40% (72/149) of patients with calcipotriol treatment (P < 0.01) at week 4. ^[15] Another study calculated the PASI scores and showed lower values in the calcipotriol/betamethasone dipropionate group (3.81 ± 3.27 at week 2, 2.5 ± 2.5 at week 4) than those in the calcipotriol group (5.47 ± 3.47 at week 2, 4.07 ± 3.33 at week 4) (P < 0.001). ^[9] Four studies evaluated the proportion of "marked improvement or clearance" by the investigators assessment at week 4. ^{[12],[14],[16],[20]} All those studies showed a higher proportion of improvement in the calcipotriol/betamethasone dipropionate group (once daily being nearly 60%, and twice daily being around 70%) compared to those in the calcipotriol group (P < 0.001 or P = 0.033).

The treatment duration was eight weeks in three studies. ^{[13],[17],[19]} All the studies evaluated the percentage reduction of PASI score at week 4 and week 8 and showed a higher reduction in calcipotriol betamethasone dipropionate group (about 50% at week 4 and over 55% at week 8) than those in the calcipotriol group (P < 0.001). Two studies also demonstrated a PASI 75 score in about 20% patients at week 4 and in 40% patients at week 8 treated with calcipotriol/betamethasone dipropionate therapy. This was in contrast to a PASI 75 score seen in only about 6% patients at week 4 and 20% patients at week 8 treated with calcipotriol (Week 4, P < 0.001; Week 8, P < 0.05). These studies also evaluated the proportion of "marked improvement or clearance" by investigator assessment. They showed a higher proportion of improvement in the calcipotriol/betamethasone dipropionate group (about 15% at week 4 and 30% at week 8) compared to that seen in the calcipotriol group (Week 4, P = 0.019, P = 0.003; Week 8, P = 0.002, P = 0.009). ^[13],[19]

Comparison of calcipotriol/betamethasone dipropionate with betamethasone [Table - 2]

We identified five trials for this comparison, involving a total of 3471 participants. ^{[12],[13],[16],[19],[20]} The frequency of application was once daily calcipotriol/betamethasone dipropionate versus once daily betamethasone in three studies, and twice daily calcipotriol/betamethasone dipropionate versus twice daily betamethasone in two studies. ^{[12],[13],[16],[19],[20]}

Three studies treated the patients for four weeks. ^{[12],[16],[20]} The evaluation of percentage reduction of PASI score showed a higher reduction in the calcipotriol/betamethasone dipropionate group compared to that in the betamethasone group (P < 0.001). A once daily application showed nearly 40% reduction and the twice daily application showed a reduction of around 50% at week 1. There was a reduction of 70% at week 4 with both once daily and twice daily applications. The studies also showed a higher proportion of "marked improvement or clearance" by investigator assessment in the calcipotriol/betamethasone dipropionate group (once daily being 60%, and twice daily being 70%) compared to that seen in the betamethasone group (P < 0.001) at week 4.

Two studies treated the patients for eight weeks and evaluated the percentage reduction of the PASI score. ^[13],[19] There was a higher reduction of the PASI score in the calcipotriol/betamethasone dipropionate group (about 50% at week 4) compared to that seen in the betamethasone group (P = 0.037 and P = 0.038). However, the results of PASI score reduction was not consistent at week 8. Although one study showed better efficacy in the calcipotriol/betamethasone dipropionate group versus the betamethasone group (P < 0.001), the other study showed no significant difference (P = 0.17). These two studies compared the rate of patients who achieved a PASI 75 score. One study showed no significant difference between groups at Week 4 (P = 0.07). More patients achieved a PASI 75 score in the calcipotriol/betamethasone dipropionate group when compared to the betamethasone group at week 8 (P = 0.004). However, another trial did not show such a difference at week 8 (P = 0.18). These two studies also evaluated the proportion of "marked improvement or clearance" by investigator assessment. A higher proportion of improvement was seen in the calcipotriol/betamethasone dipropionate group compared to that seen in the betamethasone group at week 8 (P = 0.03 and P = 0.008). Improved results were seen earlier at week 4 in one study. ^[13]

Comparison of calcipotriol/betamethasone dipropionate once daily with calcipotriol/betamethasone dipropionate twice daily [Table - 2]

A four week trial was carried out for this comparison, with a total of 384 participants. ^[14] The study evaluated the percentage reduction of the PASI score at week 1 and week 4, and the proportion of "marked improvement or clearance" by investigator assessment at week 4. No statistically significant differences regarding any outcomes were seen between the two treatment protocols at any time point (P = 0.3 and P = 0.052).

Adverse effects

The incidence of adverse effects ranged from 0% to 42.5% with once daily calcipotriol/betamethasone dipropionate, 5.3-38.3% with calcipotriol monotherpay, 3.1-48.2% with betamethasone monotherapy and 26.8-29.6% with twice daily calcipotriol/betamethasone dipropionate. Lesional and perilesional cutaneous adverse drug reactions were recorded meticulously. The most common adverse effect noted in all groups was pruritus. Other adverse effects included pain, folliculitis, rash, pustules, dermatitis, exfoliation, erythema, aggravation of psoriasis, skin irritation, telangiectasia, etc. The proportion of patients reporting cutaneous adverse effects to calcipotriol/betamethasone dipropionate was similar across once daily (0-10%) and twice daily (8-10%) applications. The incidence of cutaneous adverse effects ranged from 11-20% with calcipotriol monotherapy, and 0-9% with betamethasone monotherapy. The proportion of patients reporting adverse effects to calcipotriol/betamethasone dipropionate was significantly less than those only on calcipotriol. The main reasons for withdrawal from the treatment protocol included unacceptable adverse effects, unacceptable treatment efficacy, poor compliance, patient being lost to follow-up or complete resolution of lesions. The percentage of patients who withdrew from treatment due to adverse effects was about 1% in the once-daily calcipotriol betamethasone dipropionate recipients, 1-10% in calcipotriol recipients, 1-6% in betamethasone recipients and 7.5% in the twice-daily calcipotriol betamethasone dipropionate recipients. The adverse effects usually resolved in a few weeks. The adverse effects are listed in [Table - 3].

Table 3: Adverse effects in treatment group and control group

DISCUSSION

We found several systematic reviews on topical calcipotriol/betamethasone dipropionate for the treatment of psoriasis. The current systematic review is conducted from various points of view. As calcipotriol/betamethasone dipropionate gel and ointment showed similar efficacies in previous studies, we included both formulations in our review. ^[10],[11] This is the main difference compared to previous systematic reviews. ^{[22],[23],[24]} Our study also paid close attention to the fixed compound formulation on body lesions, and not scalp lesions alone. ^{[22],[23],[24],[25]} A previous systematic review included both randomized controlled trials and non-randomized controlled trials. ^[24] As randomized controlled trials are considered to have a higher level of evidence, our review only included those studies. We included trials which had a duration of treatment ranging from four to eight weeks. Trials with a long term treatment duration of at least 24 weeks did not meet our inclusion criteria. ^{[22],[24],[25],[26]} Our review focused on the comparison of calcipotriol/betamethasone dipropionate with calcipotriol or betamethasone and was an update to the previous systematic reviews which included studies up to 2012. ^{[3],[25],[26],[27],[28]} According to the Cochrane library, a systematic review should be updated within 3 years. We believe that our systematic review will provide valuable and direct information about calcipotriol/betamethasone dipropionate in the treatment of psoriasis.

To assess the methodological quality, we used the criteria recommended by the Cochrane Collaboration Handbook. Of the ten studies, 80% adequately described the sequence generation and 60% described the allocation concealment so the selection bias was generally controlled. About 50% of studies performed double blinding of participants which indicates a moderate risk of performance bias. The risk of detection bias was moderately controlled as 30% of studies performed blinding of outcome assessment. Over 90% studies addressed incomplete outcome data and all studies reported the selected outcome. So, the attrition bias and reporting bias were well controlled. The overall methodological quality of included studies was moderate to high.

Our systematic review demonstrated that treatment with the two-compound formulation of calcipotriol/betamethasone dipropionate was more effective than either agent used alone. In the patients who were randomized to the calcipotriol/betamethasone dipropionate group, the percentage reduction of the PASI score was 40-48% at week 1, 50-74% at week 4 and remained at 55-73% at week 8. A higher reduction in the PASI score was observed after 1 week of treatment demonstrating the rapid onset of action of this compound. The improvement increased with continued application of the combination for four to eight weeks. The percentage of patients who showed marked improvement or clearance within 4 weeks was higher in the calcipotriol/betamethasone dipropionate group compared to the control groups, and increased further in eight weeks. All studies showed a high degree of consistency in the efficacy and tolerability results for calcipotriol/betamethasone dipropionate. ^{[9],[12],[13],[14],[15],[16],[18],[19],[20],[29]}

When once-daily calcipotriol/betamethasone dipropionate and twice-daily calcipotriol/betamethasone dipropionate were compared after four weeks of treatment, the percentage reduction of PASI score at week 1 and week 4 was not statistically or clinically significant. The proportion of "marked improvement or clearance" by investigator assessment at week 4 showed the same findings. ^[14] This result provides a useful reference for calcipotriol/betamethasone dipropionate application as once daily usage enables higher compliance and is economical too.

The adverse effect profile of calcipotriol/betamethasone dipropionate was similar across included studies with a comparable percentage of patients reporting cutaneous adverse reactions during treatment. The calcipotriol/betamethasone dipropionate combination was found to be safer than calcipotriol. No statistically significant differences existed between calcipotriol/betamethasone dipropionate and betamethasone, or once-daily calcipotriol/betamethasone dipropionate and twice-daily calcipotriol/betamethasone dipropionate. In a 52-week long-term study, treatment with calcipotriol/betamethasone dipropionate appeared to be safe and was well tolerated when used on its own or alternating every four weeks with calcipotriol. ^[30] Another six-month study showed high satisfaction and desire for repeated use of calcipotriol/betamethasone dipropionate in psoriasis vulgaris patients. ^[31] These results indicate a good safety profile of calcipotriol/betamethasone dipropionate.

CONCLUSION

Topical application of the two-compound product calcipotriol/betamethasone dipropionate provides good results for psoriasis vulgaris with only mild adverse effects. The optimal frequency of application is once daily. This combination is superior to either calcipotriol or betamethasone monotherapy when used for four to eight weeks, however longer durations of treatment are not recommended. We found that the studies included in this review were diverse and had limitations. Inconsistent treatment protocols, various outcome measurements, relatively short treatment duration and lack of long-term follow-up data were a few notable limitations. Randomized controlled trials that address these issues are needed in future studies.

Acknowledgement

The study was supported by skin disease research fund of China Society of Integrated Traditional Chinese and Western Medicine.

Financial support and sponsorship

Skin disease research fund of China Society of Integrated Traditional Chinese and Western Medicine.

Conflicts of interest

There are no conflicts of interest.