Calcipotriol/betamethasone dipropionate fixed combination for the treatment of psoriasis vulgaris: a systematic review and meta-analysis.

doi:10.21203/rs.3.rs-1443457/v1

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Calcipotriol/betamethasone dipropionate fixed combination for the treatment of psoriasis vulgaris: a systematic review and meta-analysis.

https://doi.org/10.21203/rs.3.rs-1443457/v1

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Psoriasis vulgaris has serious co-morbidities and impairs the quality of life. Vitamin D analogues and corticosteroids are widely used for treating psoriasis, but they have numerous effects. This review aims to assess the efficacy and safety of calcipotriol/betamethasone dipropionate (Cal/BD) as an alternative that may enhance patients' adherence. We searched PubMed, Cochrane, Web of science, and Scopus for reliable trials. The analysis was conducted by comprehensive meta-analysis (CMA) software using the Inverse-Variance method. The analysis showed that the fixed Cal/BD combination improves the psoriasis area and severity index score in body lesions (P<0.0001 at weeks one, two, four, and eight). It improves the total sign score (TSS) and achieves TSS-based response in scalp lesions (P<0.01 at eight weeks). Treatment success was achieved according to physician’s global assessment/investigator’s global assessment in scalp lesions (P<0.001 at weeks four, and eight), and according to patient’s global assessment in body (P=0.001 at week four) and scalp lesions (P<0.05 at weekss two, four, and eight). Adverse events were low for body (P<0.05 at weeks four, eight, and twelve) and scalp lesions (P<0.0001 at week eight). Our conclusion is that Cal/BD is effective and well-tolerated alternative therapy for psoriasis vulgaris.

Calcipotriol

Betamethasone dipropionate

Psoriasis vulgaris

Systematic review

Meta-analysis

Psoriasis is a chronic, recurrent, inflammatory skin disorder¹ that represents a major global health problem by affecting 0.09–11.4% of the world population.^2,3 It manifests in well-demarcated areas of thickened, erythematous, and frequently itchy plaques with silvery scales, these plaques usually involve the scalp, limbs, and the trunk¹ The histopathology of these plaques is characterized by epidermal hyperplasia with impaired differentiation of keratinocytes, infiltration of inflammatory cells in the epidermis and the dermis, as well as hypervascularity of the dermis^4,5 As a consequence of the systemic inflammation associated with psoriasis, there is an elevated risk of serious co-morbidities including cardiovascular diseases, diabetes, and psoriatic arthritis.^5,6 Psoriasis can impair patients' quality of life to a degree similar to diabetes and cancer.⁷ It is also associated with psychological issues such as depression, anxiety, feeling of stigmatization, and increased suicidal ideation.^6,8

Several therapeutic options are available for the treatment of psoriasis, such as topical therapy, phototherapy, and systemic therapies. According to guidelines, topical therapies are the mainstay for treating mild-to-moderate psoriasis.⁹ Topical therapy also represents an efficacious cost-saving alternative to systemic therapies for some patients with moderate-to-severe psoriasis. The current guidelines for this topical therapy recommended using topical corticosteroids and vitamin D analogues used together (either as monotherapies or fixed combination) as the first-line for treating psoriasis.⁹

Calcipotriol is an antipsoriatic vitamin D analogue that exerts its action by regulating epidermal proliferation and differentiation, inhibiting the inflammatory process, and through its antiangiogenic effect.¹⁰ However, calcipotriol has a slower onset of action, and it was associated with skin irritation and hypercalcemia when applied on high doses.^11,12 Betamethasone dipropionate is a potent synthetic corticosteroid used for the treatment of psoriasis. It suppresses various components of the inflammatory response; through inhibiting the recruitment and migration of the inflammatory cells, modulating cytokines (e.g. IL-2), releasing chemokines, and regulating DNA synthesis.¹³ Like other corticosteroids, the prolonged use of betamethasone dipropionate is limited by tachyphylaxis and steroids-associated side effects, which may include pathological adrenal suppression, clinical signs of Cushing’s syndrome, or local effects (e.g., skin atrophy, striae, and telangiectasia).¹⁴ Due to the incompatibility of the existing formulations of calcipotriol and betamethasone dipropionate, applying the two drugs simultaneously is not recommended. For the above-mentioned reasons, and because of psoriasis' chronic course, non-adherence to treatment constitutes a major challenge in the topical therapy. Non-adherence was estimated to range from 40 to 70%, this majorly reduces the treatment efficacy.¹⁵ Hence, there is a strong medical need for rapidly acting, highly efficacious, safe, cosmetically acceptable, and easy-to-use topical medication.

The fixed combination of calcipotriol with betamethasone dipropionate was established in 2002 to treat psoriasis vulgaris.¹⁶ It showed improvement in the severity of psoriasis with rapid onset of action.¹⁷ Previous reviews emphasized the superiority of this combination over either ingredient alone.¹⁸ This superiority is achieved through the combined efficacy of the two ingredients, coupled with the rapid response of betamethasone dipropionate. Furthermore, betamethasone dipropionate counteracts the skin irritation caused by calcipotriol, and calcipotriol provides a steroid-sparing effect that reduces corticosteroid exposure.¹⁹ In this systematic review and meta-analysis, we aimed to achieve a conclusive, highly summarized evidence about the clinical efficacy and safety of calcipotriol/betamethasone dipropionate (Cal/BD) combination therapy in the treatment of psoriasis vulgaris.

Literature search results

Our search retrieved 1359 records after removing duplications, 61 of them were eligible for full-text screening according to our inclusion criteria. We included 28 trials in our final analysis.^16,20−47 Kragballe et al. 2006 reported data from the same population in two papers; one reported efficacy,²⁹ and the other reported safety.²⁸ The flow of data collection and screening process are shown in figure.1.

Summary of the included studies

Most of the trials included adult patients with plaque psoriasis for more than 6 months duration and more than 2% of the body or 10% of the scalp. They excluded patients with other forms of psoriasis rather than plaque psoriasis and excluded patients on current or recent treatment regimens with phototherapy, biological therapy, or any other medications that may affect psoriasis. Gel, ointment, aerosol foam, scalp formulation, and topical suspension are the topical therapy forms in the included studies. Summary of the included trials and baseline characters of enrolled subjects are shown in tables.1 and 2, respectively.

Quality assessment

All included single-arm trials were of good to fair quality according to the NIH assessment tool (Table S.1). Most of the included RCTs had low or unclear risk of bias regarding selection and detection biases, low risk of bias regarding performance, attrition, and reporting biases, and high risk of bias in the "other bias" domain. Figures S.1 and S.2 show the risk of bias graph and summary for the included RCTs, and Table S.2 shows the authors' judgment of each risk of bias domain with justification.

Outcomes

- Efficacy outcomes

PASI score change (body psoriasis)

The pooled estimate showed that Cal/BD significantly reduces PASI score at all measured time-points, but the results were heterogeneous (P < 0.0001, I² > 75%). At one week; MD=-3.444, 95% CI [-2.554, -4.334], P < 0.0001. At two weeks; MD=-4.301, 95% CI [-4.018, -4.584], P < 0.0001. At four weeks; MD=-5.841, 95% CI [-5.120, -6.561], P < 0.0001. At eight weeks; MD=-5.215, 95% CI [-3.169, -7.260], P < 0.0001 (Fig. 2).

PASI 75 (body psoriasis)

This analysis showed a low or insignificant rate of PASI 75 (patients achieving 95% PASI score improvement) with Cal/BD at different time points, and the results were heterogeneous (P < 0.02, I² > 80%) except at eight weeks (P = 0.776, I² = 0%). At one week; ER = 0.037, 95% CI [0.008, 0.146], P < 0.0001. At four weeks; ER = 0.415, 95% CI [0.296, 0.545], P = 0.199; heterogeneity was solved by excluding Langley et al. 2011³² (P = 0.233, I² = 29.85%) and the results remained insignificant; ER = 0.482, 95% CI [0.433, 0.532], P = 0.483. At eight weeks; ER = 0.342, 95% CI [0.303, 0.383], P < 0.0001. At 12 weeks; ER = 0.529, 95% CI [0.380, 0.674], P = 0.706 (figure.S.3).

Treatment success according to PGA/IGA

For body psoriasis, PGA/IGA –based treatment success rate was low or insignificant at measured timepoints, and the pooled trials were heterogeneous (P < 0.0001, I² > 40%) except for one week (P = 0.113, I² = 43.91%). At one week; ER = 0.042, 95% CI [0.027, 0.065], P < 0.0001. At two weeks; ER = 0.173, 95% CI [0.098, 0.287], P < 0.0001; heterogeneity was solved by excluding Koo et al. 2016²⁷ (P = 0.865, I² = 0%) and the results remained significant; ER = 0.101, 95% CI [0.066, 0.151], P < 0.0001. At four weeks; ER = 0.522, 95% CI [0.432, 0.611], P = 0.628. At eight weeks; ER = 0.411, 95% CI [0.298, 0.534], P = 0.153. At 12 weeks; ER = 0.505, 95% CI [0.291, 0.718], P = 0.964 (figure S.4).

For scalp psoriasis, the pooled estimate showed that PGA/IGA-based treatment success rates with Cal/BD was low at one week, insignificant at two weeks, and high at four and eight weeks. The drug effect appeared to be duration-dependent, and the pooled trials were heterogeneous (P < 0.03, I² > 80%). At one weeks ER = 0.333, 95% CI [0.205, 0.491], P = 0.039. At two weeks; ER = 0.564, 95% CI [0.473, 0.650], P = 0.168. At four weeks; ER = 0.664, 95% CI [0.566, 0.749], P = 0.001. At eight weeks; ER = 0.710, 95% CI [0.644, 0.769], P < 0.0001 (figure.S.5).

Treatment success according to PaGA

For body psoriasis, the pooled estimate showed high PaGA treatment success rate with Cal/BD at four weeks but it was insignificant at eight weeks of treatment. Pooled studies were heterogeneous (P < 0.0001, I² > 90%). At four weeks; ER = 0.658, 95% CI [0.564, 0.741], P = 0.001. At eight weeks; ER = 0.497, 95% CI [0.26, 0.73], P = 0.981 (figure S.6).

For scalp psoriasis, the pooled estimate showed high rates of PaGA-based treatment success with Cal/BD at all measured timepoints, but the results were heterogenous (P < 0.0001, I² > 85%). At two weeks; ER = 0.660, 95% CI [0.515, 0.780], P = 0.031. At four weeks; ER = 0.751, 95% CI [0.600, 0.859], P = 0.002. At eight weeks; ER = 0.766, 95% CI [0.698, 0.822], P < 0.0001 (figure S.7).

TSS change (scalp psoriasis)

The pooled estimate showed that Cal/BD significantly reduces TSS score at eight weeks; MD=-5.035, 95% CI [-5.443, -4.628], P < 0.0001. Pooled trials were heterogenous (P < 0.0001, I² = 98.35%) (Fig. 3).

Treatment success according to TSS (scalp psoriasis)

This analysis showed insignificant TSS-based treatment success rate with Cal/BD at eight weeks of treatment; ER = 0.469, 95% CI [0.307, 0.638], P = 0.725. Pooled trials were heterogenous (P = 0.001, I² = 85.07%). Heterogeneity was solved by excluding Gooderham et al. 2014²³ (P = 0.995, I² = 0%) and the results became significantly low; ER = 0.387, 95% CI [0.327, 0.450], P = 0.001 (figure S.8).

- Safety outcomes

The analysis results showed that Cal/BD has low rates of all studied adverse events for both body psoriasis and scalp psoriasis populations. Table 3 shows the detailed results of each studied adverse event.

Table 2

Baseline table. Data are presented as mean ± SD or number (percentage). Abbreviations: Cal/BD, calcipotriol/betamethasone dipropionate; PASI, psoriasis area and severity index. PGA/IGA, physician/investigator's global assessment.
Study ID	Subgroups	Subjects	Age (years)	White/Caucasian	Males	PASI score	Duration of psoriasis (years)	Total body surface psoriatic area (percentage)	PGA/IGA
Study ID	Subgroups	Subjects	Age (years)	White/Caucasian	Males	PASI score	Duration of psoriasis (years)	Total body surface psoriatic area (percentage)	Mild	Moderate	Severe/very severe
Lebwohl 2016³³	-	100	47.4 ± 14.8	93 (93)	53 (53)	8.8 ± 4.6	14.6 ± 13.8	6.7 ± 4.9	9 (9)	77 (77)	14 (14)
Paul 2017⁴⁰	-	185	54 ± 14.5	122 (86.5)	126 (68.1)	7.1 ± 4.5	19.3 ± 14.1	7.1 ± 5.7	54 (29.2)	109 (58.9)	22 (11.9)
Koo 2016²⁷	Foam	141	51 ± 10.5	122 (86.5)	87 (61.7)	7 ± 4.2	16.1 ± 8.3	7.7 ± 4.7	22 (15.6)	112 (79.4)	7 (5)
Koo 2016²⁷	Ointment	135	52 ± 11.7	118 (87.4)	87 (64.4)	6.7 ± 3.3	16.3 ± 8.5	7.4 ± 4.7	22 (16.3)	106 (78.5)	7 (5.2)
Ma 2016³⁶	-	120	39.9 ± 13.1	-	73 (60.8)	-	7.4 ± 7.3	-	-	83 (69.2)	37 (30.9)
Queille-Roussel 2015⁴¹	-	24	50.25 ± 13.5	-	16 (66.7)	-	22.75 ± 11.5	-	-	-	-
Reich 2015⁴²	-	1795	50.9 ± 15.22	173 (94.5)	1034 (57.6)	4.5 ± 2.19	17.7 ± 14.7		600 (33.4)	1117 (62.2)	78 (4.3)
Langley 2011³²	-	183	50.9 ± 14.3	75 (55.6)	117 (63.9)	8.93 ± 5.75	21.2 ± 13.2	9 ± 7.7	-	130 (71)	53 (28.9)
Tyring 2010⁴⁵	-	135	44.4 ± 9.5	158 (97.5)	84 (62.2)	-	10.5 ± 7.3	-	-	110 (81.5)	25 (18.5)
Fleming 2010²²	-	162	50.1 ± 14.9	205 (99)	93 (57.4)	7.7 ± 4.6	18.5 ± 13.8	-	31 (19.1)	95 (58.6)	36 (22.2)
Kragballe 2009³⁰	-	207	50.8 ± 15.3	559 (98.4)	90 (43.5)	-	18.4 ± 13.8	-		113 (54.6)	94 (45.4)
Vandekerkhof 2009⁴⁶	-	568	48.5 ± 16.4	404 (96.4)	238 (41.9)	-	15.7 ± 13.3	-	56 (9.9)	311 (54.8)	201 (35.4)
Luger 2008³⁵	-	419	48.5 ± 15.3	518 (95.7)	185 (44.2)	-	17.7 ± 13.6	-		233 (55.6)	186 (44.4)
Jemec 2008²⁵	-	541	47.9 ± 15.4	105 (97.2)	259 (47.9)	-	15.4 ± 13.5	-	47 (8.7)	304 (56.2)	190 (35.1)
Buckley 2008²⁰	-	108	48.4 ± 16.5	-	47 (43.5)	-	16 ± 15.5	-	-	-	-
Saraceno 2007⁴³	-	75	49.1 ± 15.9	-	45 (60)	9.44 ± 5.37	11.9 ± 12.5	19 ± 8	-	-	-
White 2006⁴⁷	Calcipotriol	383	49.7 ± 11.13	369 (97.9)	223 (58.2)	8.5 ± 3.5	15 ± 12	11.9 ± 4.5	-	299 (78.1)	84 (21.9)
	Alternating	377	51.4 ± 11.16	358 (95.2)	232 (61.5)	9.1 ± 3.9	15 ± 12.3	12.3 ± 4.7	-	288 (76.4)	89 (23.6)
	Vehicle	376	51.1 ± 11.83	204 (96.2)	235 (62.5)	9 ± 3.9	17.5 ± 11.17	12.2 ± 4.7	-	276 (73.4)	100 (26.6)
Kragballe 2006^28,29	Cal/BD	212	48	210 (98.6)	128 (60.4)	-	19.6	-	-	149 (70.3)	56 (26.4)
	Alternating	213	49.8	203 (97.1)	125 (58.7)	-	19.3	-	-	151 (70.9)	58 (27.2)
	Cal/BD then Cal	209	48.4	236 (94.8)	134 (64.1)	-	20.1	-	-	138 (66)	63 (30.1)
Ortonne 2004³⁸	-	249	50.8 ± 14.9	311 (96.6)	134 (53.8)	9.7 ± 6.2	20.2 ± 15.2	-	-	-	-
Kragballe 2004³¹	Group 1	322	47.8 ± 13.2	309 (95.7)	201 (62.4)	10.3 ± 7.83	18.3 ± 11.7	-	-	-	-
Kragballe 2004³¹	Group 2	323	47.8 ± 11.7		206(63.8)	10.4 ± 6.67	19 ± 10	-	-	-	-
Papp 2003³⁹	-	304	47.5	473 (96.5)	173 (56.9)		19.2	-	-	-	-
Kaufmann 2002²⁶	-	490	47.6 ± 10.7	-	308(62.9)	9.9 ± 6.93	18.3 ± 11	-	-	-	-
Guenther 2002²⁴	Once/d	152	47.9	369 (99.2)	90 (59.2)	9.9	18.3	-	-	-	-
Guenther 2002²⁴	Twice/d	237	49.3	369 (99.2)	165 (69.6)	10.6	18.3	-	-	-	-
Douglas 2002¹⁶	-	372	47.6 ± 11.8	28 (90)	216 (58.1)	10.8 ± 5.98	19 ± 10.3	-	-	-	-
Eichenfield 2015²¹	-	31	15 ± 1.25	707 (90)	12 (39)	-	4.7 ± 2.5	5.2 ± 3	-	21 (68)	10 (33)
Gooderham 2014²³	-	78	14.6 ± 0.83	-	35 (45)	-	5.9 ± 2.83	5 ± 8.17	-	58 (74)	20 (26)
Lee 2016³⁴	-	193	48.74 ± 13.61	-	104 (53.89)	-	-	4.32 ± 2.6	93 (48.19)	91 (47.15)	9 (4.66)
Ortonne 2014³⁷	-	159	46.7 ± 13.6	30 (81)	99 (62.3)	-	-	72.5 ± 45	-	-	-
Taraska 2016⁴⁴	-	37	48 ± 14	-	20 (54)	-	16 ± 12	21 ± 5	-	28 (76)	9 (24)

Table 3

Safety outcomes. Abbreviations: AEs, adverse events; ER, event rate; CI, confidence interval.
Adverse event	Psoriasis type	Timepoint	ER [95% CI]	P value	ER significance	Heterogeneity	Chi² P value	Figure
Any AEs	Body psoriasis	4 weeks	0.194 [0.147, 0.252]	P < 0.0001	Low rate	Heterogenous	P < 0.0001	Figure 4
		8 weeks	0.346 [0.238, 0.473]	P = 0.018	Low rate	Heterogenous	P < 0.0001
		After excluding Lee et al. 2016	0.409 [0.358, 0.462]	P = 0.001	Low rate	Homogenous	P = 0.581
		12 weeks	0.306 [0.169, 0.489]	P = 0.039	Low rate	Heterogenous	P < 0.0001
		After excluding Saraceno et al. 2007	0.434 [0.385, 0.485]	P = 0.012	Low rate	Homogenous	P = 0.484
	Scalp psoriasis	8 weeks	0.365 [0.341, 0.390]	P < 0.0001	Low rate	Homogenous	P = 0.35	Figure 5
AEs leading to discontinuation	Body psoriasis	4 weeks	0.008 [0.004, 0.018]	P < 0.0001	Low rate	Homogenous	P = 0.369	Figure S.12
Diarrhea	Body psoriasis	4 weeks	0.013 [0.004, 0.043]	P < 0.0001	Low rate	Homogenous	P = 0.281
Diarrhea	Body psoriasis	12 weeks	0.017 [0.008, 0.037]	P < 0.0001	Low rate	Homogenous	P = 0.409
Dry skin	Body psoriasis	8 weeks	0.014 [0.005, 0.036]	P < 0.0001	Low rate	Homogenous	P = 0.285
Dry skin	Scalp psoriasis	8 weeks	0.004 [0.001, 0.013]	P < 0.0001	Low rate	Homogenous	P = 0.56
Erythema	Body psoriasis	8 weeks	0.005 [0.001, 0.023]	P < 0.0001	Low rate	Homogenous	P = 0.632
Erythema	Scalp psoriasis	8 weeks	0.001 [0.000, 0.006]	P < 0.0001	Low rate	Homogenous	P = 0.98
Headache	Body psoriasis	4 weeks	0.092 [0.011, 0.473]	P = 0.040	Low rate	Heterogenous	P = 0.047
Headache	Scalp psoriasis	8 weeks	0.024 [0.004, 0.137]	P < 0.0001	Low rate	Heterogenous	P = 0.088
Lesional or perilesional AEs	Body psoriasis	4 weeks	0.078 [0.058, 0.103]	P < 0.0001	Low rate	Heterogenous	P = 0.013
	Body psoriasis	After excluding Ortonne et al. 2004	0.086 [0.070, 0.106]	P < 0.0001	Low rate	Homogenous	P = 0.191
	Scalp psoriasis	8 weeks	0.031 [0.016, 0.057]	P < 0.0001	Low rate	Homogenous	P = 0.829
Pharyngitis	Body psoriasis	4 weeks	0.018 [0.009, 0.035]	P < 0.0001	Low rate	Homogenous	P = 0.576
	Body psoriasis	12 weeks	0.031 [0.017, 0.055]	P < 0.0001	Low rate	Homogenous	P = 0.351
	Scalp psoriasis	8 weeks	0.055 [0.025, 0.118]	P < 0.0001	Low rate	Homogenous	P = 0.785
Pruritis	Body psoriasis	4 weeks	0.041 [0.030, 0.058]	P < 0.0001	Low rate	Homogenous	P = 0.128
		8 weeks	0.021 [0.011, 0.040]	P < 0.0001	Low rate	Homogenous	P = 153
		12 weeks	0.021 [0.010, 0.043]	P < 0.0001	Low rate	Homogenous	P = 0.26
	Scalp psoriasis	8 weeks	0.023 [0.017, 0.033]	P < 0.0001	Low rate	Homogenous	P = 0.455
Psoriasis flaring	Body psoriasis	4 weeks	0.004 [0.001, 0.015]	P < 0.0001	Low rate	Homogenous	P = 0.764
		8 weeks	0.006 [0.001, 0.023]	P < 0.0001	Low rate	Homogenous	P = 0.927
		12 weeks	0.031 [0.017, 0.054]	P < 0.0001	Low rate	Homogenous	P = 0.379
	Scalp psoriasis	8 weeks	0.002 [0.001, 0.008]	P < 0.0001	Low rate	Homogenous	P = 0.599
Serious AEs	Body psoriasis	8 weeks	0.019 [0.009, 0.039]	P < 0.0001	Low rate	Homogenous	P = 0.767	Figure S.13
	Body psoriasis	12 weeks	0.004 [0.001, 0.021]	P < 0.0001	Low rate	Homogenous	P = 0.688	Figure S.13
	Scalp psoriasis	8 weeks	0.005 [0.001, 0.037]	P < 0.0001	Low rate	Homogenous	P = 0.875
Alopecia	Scalp psoriasis	8 weeks	0.004 [0.001, 0.012]	P < 0.0001	Low rate	Homogenous	P = 0.297
Skin burning sensation	Scalp psoriasis	8 weeks	0.002 [0.001, 0.007]	P < 0.0001	Low rate	Homogenous	P = 0.984
Skin inflammation	Scalp psoriasis	8 weeks	0.004 [0.001, 0.019]	P < 0.0001	Low rate	Homogenous	P = 0.208
Skin irritation	Scalp psoriasis	8 weeks	0.004 [0.002, 0.011]	P < 0.0001	Low rate	Homogenous	P = 0.612

- Publication bias

Publication bias assessment was applicable for PASI score change, PGA/IGA treatment success, and any adverse events; each in body psoriasis patients. No significant publication bias were detected for PASI score change (P = 0.17986) (figure S.9) and any adverse events (P = 0.11314) (figure S.10) as shown by the symmetry of the funnel plot and Egger's test. While publication bias was significant for PGA/IGA treatment success (P = 0.04876) (figure S.11) as shown by the asymmetry of the funnel plot and Egger's test.

This systematic review and meta-analysis included 28 trials assessing the safety and efficacy of Cal/BD fixed combination in the treatment of psoriasis vulgaris. For patients with body lesions; Cal/BD reduced PASI score and PaGA. For patients with scalp lesions; Cal/BD reduced TSS, and achieved treatment success according to PGA/IGA and PaGA. Cal/BD combination therapy AEs were tolerable, thus can be administered safely.

PASI score is the best-evaluated method for assessing the severity of plaque-psoriasis, developed in 1978 by Fredriksson and Pettersson.^48,49 This score assesses both; the intensity of the disease (erythema, induration, and desquamation) and the involved body surface area in the head, trunk, and limbs. PASI score ranges from 0 to 72, with higher scores indicating more severe cases.⁵⁰ A previous review, Yan et al. 2016,⁵¹ showed a greater PASI score reduction with Cal/BD at weeks one, two, and four compared with calcipotriol or betamethasone each alone. The results at eight weeks were inconsistent in betamethasone comparison. Our review provides more reliable data through the performed meta-analysis, the greater number of trials involved, and the focus on Cal/BD arms. The meta-analysis showed a marked improvement of PASI score at all time points (week one, two, four, and eight). In Yan et al. 2016,⁵¹ the trials showed high variation in PASI 75. However, our analysis showed a low improvement rate with Cal/BD at one and eight weeks.

TSS assesses the degree of redness, thickness and scaliness and summates them. It ranges from 0 to 12, with higher scores indicating more severe conditions. Bottomley et al. 2011⁵² compared Cal/BD combination gel to a number of topical treatments, and showed Cal/BD's superiority in TSS response at four weeks. Our results are consistent with these findings; we found significant TSS reduction at four weeks. Furthermore, our analysis added a TSS response at eight weeks.

PGA/IGA evaluates disease improvement with respect to the baseline status. Bottomley et al. 2011⁵² demonstrated Cal/BD's superiority over the other topical medications at four weeks. Our updated analysis results showed that; in case of scalp lesions, Cal/BD was successful at four and eight weeks, while its success rate was insignificant for body lesions at most measured timepoints (four, eight, and 12 weeks). PaGA is an indicator of treatment success from the patient's perspective, our results showed improvement with Cal/BD.

AEs rates were low with Cal/BD as reported by a previous meta-analysis Bottomley et al. 2011⁵² compared to many topical medications. Gorelick et al. 2018 reported high rates of patients' satisfaction with Cal/BD treatment.⁵³ Our analysis provides an update with greater number of trials and AEs assessed. The results are consistent with the previous meta-analysis, indicating Cal/BD combination therapy's safety and tolerability.

The large number of trials and patients involved strengthens this review. In addition, performing a meta-analysis provides more reliable data. Our review is an update to the literature in this field with good to fair quality trials, which used different formulations of Cal/BD. We assessed a considerable number of outcomes and added long-term results. However, limitations came from the non-randomized design of some trials and the heterogeneity across the trials in many outcomes.

We concluded that, Cal/BD fixed combination effectively reduces psoriasis' severity, as measured according to PASI, TSS, PGA/IGA, and PaGA. In addition, it is safe and well-tolerated by the patients. Thus, Cal/BD can be applied in clinical practice to enhance treatment adherence and improve psoriasis outcomes. Further RCTs are required to compare different formulations of this combination.

Search strategy and data collection

We searched four databases: PubMed, Cochrane, Web of Science, and Scopus for all published clinical trials till April 6th, 2020 and updated the search on Febreuary 1st, 2021 using the following keywords: “Calcipotriene”, “Calcipotriol”, “Psorcutan”, “Sorilux”, “Dovonex”, “Daivonex”, “Calcitrene”, “Kalosar”, “betamethasone dipropionate”, “Diprosone”, “Diprolene”, “Beloderm”, “Maxivate”, “Eleuphrat”, “Sernivo”, “Alphatrex”, “Beta-Val”, “Luxiq”, “Del-Beta”, “Dovobet”, “Occlucort”, “Beta Derm”, “Betanate”, “Betatrex”, “Valisone”, “Enstilar”, “Calcipotriene-Betamethasone”, “Calcipotriene Betamethasone”, “Calcipotriene/Betamethasone”, Taclonex”, “Dovobet”, “corticosteroid-vitamin D combination”, “Psoriases”, “Pustulosis of Palms and Soles”, “Palmoplantaris Pustulosis”, and “Pustular Psoriasis of Palms and Soles”.

After removing the duplicates using Endnote software and screening all retrieved papers' titles and abstracts according to our selection criteria. We screened the remaining studies' full texts, and those matched our criteria were included in the analysis. Besides, references of the included studies were searched manually for additional relevant papers.

Selection criteria

We included all clinical trials that enrolled patients with plaque psoriasis—including psoriasis vulgaris of the body, and scalp psoriasis—and investigated Cal/BD fixed combination therapy's safety or efficacy at all topical pharmacological forms. Single- and multiple-arm trials with one or more arms matching our criteria were included. For arms that receive Cal/BD followed by another intervention, only Cal/BD duration results were analyzed. When Cal/BD results are not reported separately, the arm was excluded. If more than one trial reported the same population, the most complete dataset of results was used. No restrictions for age, sex, site, or publication date were applied.

We excluded animal studies, observational studies, non-English studies, non-available studies, abstracts, studies that did not report our outcomes of interest, and studies on guttate psoriasis, pustular psoriasis, erythrodermic psoriasis, nail psoriasis, or psoriatic arthritis. Studies using psoralene and ultraviolet A (PUVA) therapy, ultraviolet B (UVB), retinoids, immunosuppressives, biological therapies, or any additional therapy that may affect psoriasis were also excluded.

Data extraction

We extracted data related to the following: 1) Summary of the included trials, 2) Baseline criteria of the enrolled population, 3) Safety and efficacy outcomes, and 4) Quality assessment domains.

The extracted outcomes included: psoriasis area and severity index (PASI) score change, physician/investigator's global assessment (PGA/IGA) based treatment success, patient's global assessment (PaGA) based treatment success, total sign score (TSS) change, TSS based treatment success and adverse events to treatment with Cal/BD combination. Authors extracted data separately and disagreements were solved by discussion to prevent any misinterpretation.

Quality assessment

We used the national institute of health (NIH) tool for non-controlled studies to assess the quality of the included studies.⁵⁴ Included trials' quality was judged as good, fair or poor. The quality of the included randomized controlled trials (RCTs) was assessed using the Cochrane risk of bias tool.⁵⁵ Any disagreement between authors was solved by discussion and consensus.

Study outcomes

We assessed the efficacy of Cal/BD compound product in patients with plaque psoriasis through the following outcomes: (1) PASI score change. In studies using modified PASI (mPASI) score, mPASI score change was used instead. (2) PASI 75: the number of patients achieving at least 75% improvement according to PASI score or mPASI score. (3) PGA/IGA treatment success: the number of patients achieving treatment success (clear or almost clear disease) according to the investigator's global assessment. (4) PaGA treatment success: the number of patients achieving treatment success (clear disease, very mild disease, satisfied or very satisfied patient with treatment) according to the patient's global assessment. (5) TSS change. (6) TSS treatment success: the number of patients achieving a TSS equal to or less than one.

Extracted safety measures included: dry skin, pruritis, skin irritation, skin burning sensation, skin inflammation, psoriasis (increase or flare-up of the disease), erythema, total lesional or perilesional adverse events, alopecia, headache, patients with any adverse event (AE) (Fig. 4,5), AEs leading to treatment discontinuation, serious AEs, upper respiratory tract infection, pharyngitis or nasopharyngitis, and diarrhea.

Statistical analysis

Measures of treatment effect

Continuous data were pooled as mean differences (MD) and 95% confidence intervals (CI) using the Inverse-Variance method, while dichotomous data were pooled as event rate (ER) and 95% CI using the Mantel-Haenszel method. We used the fixed-effect model when pooled data are homogenous; otherwise, random-effects model was used instead.

Data synthesis

We used the Comprehensive Meta-analysis (CMA) software to conduct the analysis. When the mean or standard deviation data are missing, they were calculated from standard errors, 95% CIs, or p values of the difference between study groups according to Cochrane handbook for systematic reviews of interventions (Chap. 7; 7.7).⁵⁶

Assessment of heterogeneity

We used the chi-Square test to assess the heterogeneity and the I-Square test to assess its extent. Significant heterogeneity was considered at Chi-Square P-value < 0.1.

Subgroup analysis

We analyzed data of patients with scalp psoriasis separately from patients with psoriasis vulgaris of the body. In addition, we performed a subgroup analysis according to different time points of measurement after the start of the study treatment.

Publication bias

We used the Egger's test and funnel-plot method to assess the publication bias when more than ten pooled trials are reporting an outcome.⁵⁷ In a funnel-plot, the effect measure and the standard error were plotted against each other. For less than ten pooled studies, publication bias assessment is unreliable.^57,58

Data availability:

The datasets generated and analysed during the current study are available from the corresponding author on a reasonable request.

Acknowledgment:

We would like to thank our colleagues in the International Medical Research Association (IMedRA) for their continuous efforts and support.

Author contributions:

W.A. and W.E. were responsible for data collection, screening sheet, title and abstract screening (revision), full-text screening (revision), data extraction, quality assessment (revision), analysis, writing original draft, Writing – review & editing. M.A.H., A.K.A., A.A., A.A.A., M.M.A., Y.A., and M.B. did the title and abstract screening, full-text screening, data extraction, quality assessment, writing – original draft. K.M.R., and M.S.Z. were responsible for idea validity & identifying search strategy, title and abstract screening (revision), full-text screening (revision), data extraction (revision), quality assessment (revision), writing – original Draft. A.Z.N reviewed and edited writing, and supervised the paper.

All authors revied the manuscript and approved it.

Additional information:

The authors declare no conflict of interest, and the study wasn’t funded.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

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Calcipotriol/betamethasone dipropionate fixed combination for the treatment of psoriasis vulgaris: a systematic review and meta-analysis.

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Abstract

Figures

Introduction

Results

Literature search results

Summary of the included studies

Quality assessment

Outcomes

- Efficacy outcomes

PASI score change (body psoriasis)

PASI 75 (body psoriasis)

Treatment success according to PGA/IGA

Treatment success according to PaGA

TSS change (scalp psoriasis)

Treatment success according to TSS (scalp psoriasis)

- Safety outcomes

- Publication bias

Discussion

Methods

Search strategy and data collection

Selection criteria

Data extraction

Quality assessment

Study outcomes

Statistical analysis

Measures of treatment effect

Data synthesis

Assessment of heterogeneity

Subgroup analysis

Publication bias

Declarations

References

Table

Additional Declarations

Supplementary Files

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