Comparison of mean platelet volume (MPV) and red blood cell distribution width (RDW) between psoriasis patients and controls: A systematic review and meta-analysis.

BACKGROUND: The predictive role of hematological indexes of mean platelet volume (MPV) and red cell distribution width (RDW) has been demonstrated in cardiovascular disease concomitant with psoriasis. This meta-analysis is intended to assess whether MPV and RDW can also serve as biomarkers for the early diagnosis and disease severity assessment of psoriasis.
MATERIAL AND METHODS: 13 studies which enrolled 1331 psoriasis patients and 919 healthy volunteers were included after screening the search results from PubMed, Embase and the Cochrane Library since inception to Mar 14, 2020. MPV of psoriasis participants and their counterparts was assessed in 10 studies, and RDW was evaluated in 4 studies, while the disease severity was measured by the Psoriasis Area and Severity Index (PASI) in 11 studies. Random-effect model analysis was applied to calculate pooled standard mean difference (SMD) with 95% confidence interval (95% CI).
RESULTS: Associations of MPV and RDW with the presence of psoriasis were demonstrated (MPV: SMD = 0.503, 95% CI: 0.242-0.765; RDW: SMD = 0.522, 95% CI: 0.228-0.817), but no statistically significant correlation of MPV and disease severity of psoriasis was found in meta-regression analysis (p = 0.208). Subgroup analysis revealed that the diagnosis value of MPV and RDW was consistent regardless of PASI and study type. Heterogeneity analysis between studies was implemented by chi-squared test and I2 statistics. Begg's and Egger's test were utilized for the evaluation of publication bias. The sensitivity analysis revealed no significant alteration no matter which study was excluded.
CONCLUSION: MPV and RDW could serve as promising predictive diagnostic biomarkers of psoriasis.

Introduction

Psoriasis, a common chronic and systemic autoimmune inflammatory disease, is manifested with high individual heterogeneity symptoms, including recurrent scaly and burning skin patches, thick and dented nails, as well as swollen and stiff joints, complicated with a variety of other symptoms from cardiovascular, endocrine, digestive system and mental health [1]. The diagnosis of psoriasis primarily depends on three key items—the clinical characteristics of involving skin, nails and joints that are different from differential diagnosis; frequency of disease development; the skin biopsy [2]. Given the limitation of invasiveness and hysteresis in existing diagnostic methods [3], diagnostic biomarkers can benefit patients greatly. Up to now, promising biomarker profiles of candidate gene expression (IL36G, CCL27, NOS2, C10orf99, and S100A9) [4, 5], plasma proteins (desmoplakin, cytokeratin 17, polymeric immunoglobulin receptor, and complement C3, PI3, CCL22, IL-12B) [6, 7], inflammatory cytokines (adiponectin) [8], circulating microRNAs [9], GlycA [10] have been reported to assist the clinical diagnosis and reflect disease severity and inflammation state of psoriasis. However, examinations of these diagnostic biomarkers are time-consuming and costly compared with blood routine. Gaining more insight into the diagnostic information of hematological parameters is therefore considerable.

The hematological parameters used most frequently are red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), red cell distribution width (RDW), white blood cell (WBC), mean platelet volume (MPV), etc. To date, several studies have confirmed the role of some hematological parameters in certain diseases. As an example, the potential value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) has been verified in the clinical diagnosis of ankylosing spongdylitis (AS), Behçet’s disease, rheumatoid arthritis (RA) and psoriasis [11, 12]. Interestingly, MPV and RDW have been associated with the incident of primary adverse cardiac events in psoriasis vulgaris (PsV) and psoriatic arthritis (PsA) [13], and linked to inflammatory status and clinical progression in psoriasis patients. However, conflicting results have been described in an Egyptian case-control study that reported no significant difference in MPV value of psoriasis patients (n = 25) versus healthy controls (n = 25) [14]. To integrate these controversies, we screened all the published case-control studies, cohort studies and randomized control tests (RCTs) relating to this topic and conducted a meta-analysis, with the aim to uncover the association of MPV and RDW with diagnosis and disease severity of psoriasis.

Material and methods

Search strategy and literature screening

Two investigators searched and screened literature independently in the database of PubMed, Cochrane Library and Embase with cutoff date of Mar 14, 2020. This study was carried out following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement with registration number of CRD42020178415 in the international prospective register of systematic reviews PROSPERO. Details of searching and screening were shown in S1 Table.

Inclusion and exclusion standard

The criteria of literature inclusion and exclusion were formulated and inspected by all authors and executed by two independent authors. A protocol agreement was reached by all authors. The inclusion and exclusion standards are listed as follows:

case-control studies, cohort studies and RCTs measuring the value of MPV and/or RDW in psoriasis group with or without PsA and healthy control group;

patients were not treated with systemic drugs or prescribed with any drugs affecting hematological indexes including antiplatelet drugs and nonsteroid anti-inflammatory drugs at least 2 weeks before the initiation of the project;

published in English.

the review, case report, conference abstract, letters, meta-analysis, sequencing data, bioinformatics analysis, and retracted articles;

either the object of studies were not psoriasis patients or only male/female psoriasis patients;

patients with cardiac diseases, hypertension, diabetes mellitus, obesity, dyslipidemia, pregnancy, hematological diseases and any other diseases interfering the hematological parameters;

unavailable access and misleading data.

Data extraction and quality assessment

The data were extracted from 13 studies by two investigators independently, inclusive of first-author name, publication year, country, study type (prospective/retrospective study), sample size, gender, MPV, RDW, the Psoriasis Area and Severity Index (PASI) and hematology analyzer. SMDs and 95% CIs were calculated using random-effect model. The literature quality was assessed with Newcastle-Ottawa Scale (NOS), and NOS score of more than 6 indicates the adequate quality of the research.

Statistical analysis

Review Manager (RevMan 5.3) and Stata (Version 14.0) were used to analyze all extracted data. The associations of MPV and RDW with psoriasis were measured by pooling the SMD and 95% CI of each individual study. Heterogeneity analysis between studies was implemented by chi-squared test and I statistics. Random-effect model is suitable for the case of significant heterogeneity (I>50%, p<0.05), unless this case, fixed-effect model is appropriate. Potential sources of heterogeneity should be interrogated by subgroup, sensitivity and meta-regression analysis in the condition of high heterogeneity. Begg’s and Egger’s test were used to detect publication bias.

Results

Included literature

The flowchart of screening and selecting process was shown in Fig 1. A total of 134 studies were identified initially and then 30 duplicated articles were removed. After reviewing the article title and abstract, 84 researches were further excluded by following inclusion and exclusion criteria. Further assessment of full-text excluded seven of the remaining 20 studies, of which two studies were excluded as patients were concomitant with metabolic syndrome that could interfere hematological indexes. Finally, 13 qualified studies were included for meta-analysis.

Fig 1

Flowchart of literature screening in the meta-analysis.

Characteristics of the included studies

The major characteristics of 13 studies [14-26] enrolling 1331 psoriasis patients and 919 healthy controls were shown in Table 1. Twelve studies from Asia region, and one from Egypt, Africa were included. As to the type of study design, eleven studies were prospective and two were retrospective. Nine studies reported MPV, three reported RDW and one reported both. Among them, one study by D.S. Kim, et al. [18] carried out two parallel case-control studies in psoriasis patients with high (PASI≥10, n = 52) or low PASI (PASI<10, n = 124) and healthy controls (n = 101). All included studies were scored more than 6 by NOS and defined as high quality (median,7.0 points; range, 6–8).

Table 1

General characteristic of the included studies.

First Author	Year	Country	Study type	NOS	Psoriasis					Control						Hematology analyzer
					N	Gender(M/F)	Age (Mean ± SD)	MPV (Mean ± SD)	RDW (Mean ± SD)	PASI (Mean ± SD)	N	Gender(M/F)	Age (Mean ± SD)	MPV (Mean ± SD)	RDW (Mean ± SD)
F. Canpolat	2010	Turkey	P	7	106	59/47	41.4±14	8.7±1.1	NA	13.6±6.4	95	44/51	40.6±8	7.3±0.8	NA	NA
H.M.A. Saleh	2013	Egypt	P	7	25	13/12	31.56±10.09	9.16±1.28	NA	22.59±18.07	25	12/13	26.52±8.73	9.96±1.85	NA	Coulter LH 750 Analyzer
S. Koça	2013	Turkey	P	6	57	NA	41.8±10.8	8.56±0.90	NA	7.8±7.4	60	NA	40.0±9.4	8.19±0.74	NA	NA
S. Koçb	2013	Turkey	P	6	51	NA	42.1±11.1	NA	14.1±1.6	7.8±7.4	55	NA	40.1±13.1	NA	13.4±1	NA
Z. Ahmad	2014	Pakistan	P	7	30	16/14	40.23±10.40	8.24±1.22	NA	≥10	30	17/13	35.20±9.73	7.29±0.77	NA	Medonic-M seires Hematology Analyzer
D.S. Kima (1)	2015	Korea	R	7	124	79/45	40±15.63	9.862±0.75	NA	<10	101	42/59	37.02±15.44	9.724±0.59	NA	Sysmex XE-2100
D.S. Kima (2)	2015	Korea	R	7	52	36/16	39.40±14.12	10.08±0.67	NA	≥10	101	42/59	37.02±15.44	9.724±0.59	NA	Sysmex XE-2100
D.S. Kimb	2015	Korea	R	7	261	160/161	39.40±15.9	NA	13.6±3.5	NA	102	47/55	36.1±13.8	NA	12.9±0.7	Advia 2120 Hematology Analyzer
M. Unal	2016	Turkey	P	6	320	154/166	37.34±13.45	8.248±1.15	NA	NA	200	111/89	35.89±8.65	7.442 ±1.626	NA	NA
V. Raghavan	2017	India	P	8	50	38/12	46.10 ±11.99	9.65 ±2.07	15.16 ±3.88	15.88 ±2.51	50	41/7	50.62 ±14.78	8.51 ±1.64	13.66 ±1.21	Coulter LH780 Hematology Analyzer
Azza G.A. Farag	2018	Turkey	P	7	70	40/30	41.47±8.16	9.65±1.12	NA	12.85± 4.97	60	40/20	40.0±10.30	8.92±0.78	NA	Sysmex XN 1000 cell counter
Selma Korkmaz	2018	Turkey	R	7	38	22/16	43±9.3	10.2 ±0.9	NA	2.78 ±2.05	35	18/17	42 ±10.4	10 ±1.7	NA	Sysmex XE-2100
S.D. Pektas	2018	Turkey	P	7	87	53/34	34.5±10.4	NA	13.625±0.837	10.2±3.7	76	42/34	32.7±9.7	NA	13.0±0.583	Advia 2120 Hematology Analyzer
G.O. Yavuz	2019	Turkey	P	6	60	30/30	40.67±15.96	8.9±0.96	NA	8.1±5.2	30	15/15	41.67±11.68	8.8 ±0.89	NA	NA

NOS: Newcastle–Ottawa quality assessment scale for case–control studies; MPV: mean platelet volume; RDW: red cell distribution width; PASI: Psoriasis Area and Severity Index; P: prospective study; R: retrospective study; NA: not available.

MPV and psoriasis

The forest plot for MPV of 932 psoriasis patients and 686 age-matched healthy controls in 10 studies was shown in Fig 2. All the participants were adults except for one study by M. Unal, et al. [24] that enrolled both adults and children. High variation of PASI values indicated high heterogeneity in disease severity of included patients. MPV values of psoriasis patients were elevated compared with healthy subjects in 9 studies, however, one study by H.M.A. Saleh [14] showed the opposite correlation of MPV and psoriasis with no statistical significance (P = 0.085). In this case, random-effect model analysis was used ascribing to substantial heterogeneity among studies (I = 84%, p = 0.000). Pooled SMDs revealed that MPV values were remarkably upregulated in psoriasis patients compared with healthy counterparts (SMD = 0.503, 95% CI: 0.242–0.765; p = 0.000).

Fig 2

Forest plot of MPV values and the presence of psoriasis.

The results of this analysis were credible because of the fixed pooled SMDs after removal of any individual study in sensitivity analysis, with the effect size ranging from 0.412 to 0.585 (Fig 3A). There was no significant publication bias manifested by Egger’s test (P = 0.511) (Fig 4A) and Begg’s test (P = 0.350) (Fig 4B).

Fig 3

Sensitivity analysis of the association of MPV (A), RDW (B) and the presence of psoriasis.

Fig 4

Publication bias of studies assessing MPV and RDW: Egger’s and Begg’s test of MPV (A and B) and RDW (C and D).

We applied subgroup analysis to investigate the potential variances affecting the pooled SMDs, containing PASI (PASI < 10 or PASI≥10, equal to mild psoriasis or moderate to severe psoriasis) and study type (retrospective or prospective study) (Figs 5 and 6, Table 2). SMD of MPV in patients with moderate to severe psoriasis (SMD = 0.659, 95% CI 0.199–1.118, p = 0.005; I2 = 87.4%, p = 0.283) was higher than that of patients with mild psoriasis (SMD = 0.236, 95% CI 0.059–0.414, p = 0.009; I2 = 0.0%, p = 0.605), while MPV was lower in retrospective studies (SMD = 0.315, 95% CI 0.054–0.576, p = 0.018; I2 = 42.1%, p = 0.178) compared with prospective ones (SMD = 0.573, 95% CI 0.237–0.909, p = 0.001; I2 = 86.0%, p = 0.000). However, the statistical differences were not identified in meta-regression analysis, with P value of 0.208 and 0.459, respectively.

Fig 5

Stratified analyses of disease severity assessed by PASI for the association between MPV and psoriasis.

Fig 6

Stratified analyses of study type for the association between MPV and psoriasis.

Table 2

Subgroup analysis of MPV in psoriasis.

Stratification group	N	SMD (95%CI)	Heterogeneity test
			P	I2(%)
Total	11	0.503(0.242,0.765)	0	84%
PASI
< 10	4	0.236(0.059,0.414)	0.605	0
≥10	6	0.659(0.199,1.118)	0.283	87.4
study type
prospective study	8	0.573(0.237,0.909)	0	86
retrospective study	3	0.315(0.054,0.576)	0.178	42.1

RDW and psoriasis

The forest plot for RDW of 449 psoriasis patients and 283 age-matched healthy controls in four studies was shown in Fig 7. RDW values in psoriasis patients were uncovered higher than healthy matching in four studies, and pooled SMDs also showed elevated RDW values in psoriasis patients (SMD = 0.522, 95% CI: 0.228–0.817, p = 0.001). Likewise, random-effect model analysis was applied due to substantial heterogeneity (I = 69.3%, p = 0.021).

Fig 7

Forest plot of RDW values and the presence of psoriasis.

The pooled SMDs were fixed in sensitivity analysis, with the effect size ranging from 0.371 to 0.662, confirming the consistency of the results of this analysis (Fig 3B). No significant publication bias was evidenced by Egger’s test (P = 0.367) (Fig 4C), as well as Begg’s test (P = 1.000) (Fig 4D).

Discussion

MPV refers to the average size of circulatory platelets derived from megakaryocytes in bone marrow, functioning as the key mediators of hemostasis and thrombosis, and thus a sensitive indicator of platelet activation or reactivity [27]. Nowadays, accumulating evidence has revealed the crucial role of platelets in immune-related and inflammatory diseases [28]. Mechanically, they store multiple immune-related chemokines, cytokines, and adhesion receptors in granules and synthesize thromboxane A2, interleukin (IL)-1, and platelet-activating factor (PAF) [28]. Once activated, platelets can express or upregulate P-selectin, CD40 ligand, Toll-like receptors, and integrins on their surface and release soluble agents such as chemokines, cytokines, 5-hydroxytryptamine (5-HT) and antimicrobial peptides to interact with immune cells [28]. Psoriasis is a chronic inflammatory Th17-driven skin disease with hyperkeratosis, dilated dermal blood vessels as well as infiltration of T cells and neutrophils [29]. Interestingly, platelet activation was found in the skin lesions of psoriasis instead of normal skin tissues and correlated with the disease severity [30].

To date, platelets were found largely involved in the pathogenesis of psoriasis. Firstly, enhanced polymorphonuclear neutrophils (PMNs) infiltrations in the psoriatic lesion and blood were in relation to the platelet surface antigens as well as the recruitment and inflammatory response caused by the soluble mediators [31]. Treatment depleting circulating platelets in imiquimod (IMQ)-induced psoriasis-like mouse model could significantly ameliorate disease severity and reduce the PMNs or platelet infiltration [31]. Moreover, many chemokines, cytokines and specific markers released or upregulated by platelets might trigger immune process. P-selectin was highly expressed on the surface of platelet in psoriasis, and could increase the aggregation of platelets and leukocytes as well as leukocyte rolling in murine skin [32]. Platelet factor 4 (PF4) and β-thromboglobulin (β-TG), the most abundant CXC chemokines of platelet α-granules, were found increased in human psoriasis and associated with PASI scores [33]. They were related to the adhesion and migration of neutrophil granulocytes and monocytes [34]. Besides, PF4 could increase IL‐17 producing cells in CD4+ T cells [35]. 5-HT was another molecule expressed in psoriatic lesions, leading to the immune infiltration by increasing vascular permeability, and inhibition therapy of 5-HT was effective in patients with psoriasis [36-38]. The cytokine IL-1β was also involved in the skin inflammation of psoriasis via IL-1β-IL-1R Signaling Pathway [39].

Despite the close relation between platelets and psoriasis, controversies on diagnostic value of MPV in current studies are unignorable. For instance, opposite correlation between MPV and the presence of psoriasis has been identified in an Egyptian study by H.M.A. Saleh, et al. [14], while others indicated a positive association. A meta-analysis is therefore indispensable to address this controversy. In general, our meta-analysis has verified the positive correlation by pooling results from all included studies. Meanwhile, the meta-regression analysis of PASI showed the upward trend of MPV with disease severity, though the conclusion was not statistically significant. The moderate to severe psoriasis subgroup showed significant heterogeneity due to a large span of PASI of different participants with high clinical heterogeneity. Overall, our findings integrated scattered studies and further revealed the association of MPV and the presence of psoriasis rather than disease severity. Interestingly, one published meta-analysis assessing the MPV value and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of SLE patients observed no relationship between MPV and disease activity of SLE, although the platelet activation plays a certain role in the pathogenesis of SLE [40].

Notably, it has been reported that MPV decreased with the variation degree associated with PASI after two-year systematic treatment in a small-sample retrospective study (n = 12) [17], but increased after 12-month infliximab or adalimumab treatment in a Japanese retrospective study enrolling patients with PsV (n = 186) and PsA (n = 50) [41]. The change of MPV value before and after treatment involves with a large spectrum of factors such as therapy type and duration, treatment respond and inflammation status of individuals, and more related clinical prospective researches are needed to reveal the correlation of MPV value in pre-/post-treatment and disease status.

RDW measures the variation of volume and size of RBCs that take part in inflammatory processes and coagulation. Inflammation disturbs erythroid maturation via membrane-bound β-receptor glycoprotein 130 (gp130) to elevate the value of RDW [42]. Inflammation-induced hydroxyl radicals and cytokines influence erythropoiesis [43]. It was reported to be positively associated with serum inflammatory indexs—high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR) in many diseases [44]. Higher RDW was found in patients with Alzheimer’s disease (AD), and it was considered as a marker of inflammation, AD presence and AD severity reflected by cognition status [45]. RDW also serves as a biomarker of cardiovascular disease susceptibility and inflammation levels in RA and AS [46]. The positive correlation of RDW with pro-inflammatory cytokines TNF-α and IL-6, as well as the negative association with anti-inflammatory cytokine IL-10 have proven the function as an auxiliary inflammatory biomarker in RA [47]. Upregulated inflammatory cytokines in the skin and peripheral blood of psoriasis patients, such as interferons, TNF-a, IL-1, IL-6 and IL-10, had an effect on erythropoiesis, leading to the enhanced RDW [48]. Thus, it is generally accepted that RDW is a potential inflammatory biomarker for psoriasis, but the specific roles of RBCs in psoriasis remain unclear. One large-scale retrospective study argued that RDW was higher in psoriasis patients with no significant association with PASI and CRP [49]. Three-month standard treatment caused a temporary reduction of RDW value in moderate to severe psoriasis patients [50], suggesting the predictive role of RDW in short-term treatment respond, however, more hematological parameters like NLR and PLR should be integrated into consideration in the long-term observation [41].

Although this meta-analysis has interrogated the significant relationship between two hematological parameters and psoriasis, there are some inevitable limitations. Firstly, hematology analyzer and reference range of MPV and RDW were not uniform between studies, which led to bias from inevitable inaccuracy of measurement. Secondly, standard treatment of psoriasis other than medicine affecting platelet function would influence the value of MPV and RDW, which might interfere the analysis results. Thirdly, the results may not be applied for all races and regions because of the majority of included studies are from Asian countries including Turkey, Korea, Pakistan and India. Finally, the sample size of retrospective study accounts for a large proportion, which reduces the evidential effectiveness of the analysis, and it’s even possible that the included studies are not sufficient to detect if there is a difference, thus well-designed clinical prospective trials and large scale RCTs are urgently needed to give potent evidence of our results.

Conclusion

It has been demonstrated that the values of MPV and RDW bear closely on the presence of psoriasis, though no relationship was found to the disease severity. These two promising indicators may benefit patients by providing auxiliary information for clinicians in the early diagnosis of psoriasis. On this setting, the association merits further verification in future study.

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5 Oct 2021

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Reviewer #1: This is a meta-analysis of RDW and MPV as biomarkers and predictors of disease severity by Jiang et al.

1. Which drugs affecting hematologic diseases were excluded? Was biotin also excluded?

2. Was there a reason why male or female only studies were excluded? While there are potential gender differences in values, you could also run a subset analysis based on gender. Please include reasoning.

3. In limitations, this reviewer suggests adding that it's possible that even aggregated the included studies are not sufficient to detect if there is a difference.

Minor comments:

1. Suggest adding a transition sentence between promising biomarkers and hematologic parameters to improve flow

2. There are spelling/grammar/word errors throughout the paper and highlighting several here:

Introduction- change "The diagnose the psoriasis" to "The diagnosis of psoriasis"

Exclusion standards- change retreated to retracted

Results-11 and 12 should be spelled out

Figure 1- psoriasis is misspelled

Reviewer #2: The present meta-analysis aimed at investigating the association of MPV and RDW with diagnosis and disease severity of psoriasis by extracting data from thirteen studies appropriately chosen according to certain criteria.

The manuscript provides robust statistical analysis on the extracted data to assess the association of MPV and RDW with psoriasis, the heterogeneity among studies and the entity of the publication bias, as well as sensitivity and meta-regression analysis. Nevertheless, more details are needed to clarify the biological aspects related to MPV and RDW involvement in the pathogenesis of psoriasis.

• In the Discussion Section about MPV, authors mention findings from other studies that demonstrate elevation of this parameter in psoriasis patients, suggesting the involvement of increased platelet activation in the pathogenesis of psoriasis. Authors should give a deeper explanation on how MPV can be affected by the clinical-molecular alterations underlying the disease onset and progression, outlining possible mechanisms, pathways or molecular factors related (for instance, recent articles/reviews concerning the role of angiogenesis, cell proliferation, inflammation could be employed for a better introduction of the topic).

• Previous literature suggest RDW as a biomarker of cardiovascular disease susceptibility and inflammation levels in rheumatoid arthritis (RA) and ankylosing spongdylitis (AS). In the Discussion section, authors do not explore the connection between the variation of volume and size of red blood cells (measured by RDW) and the pathological processes underlying the development of psoriasis. Therefore, authors should explain how this parameter could be involved in the pathogenesis of the disease, justifying why clinicians should consider RDW informative in psoriasis patients especially regarding its predictive role in response to treatment.

• This meta-analysis demonstrates a correlation of MPV and RDW with the presence of psoriasis rather than with disease severity. Authors should implement the conclusion suggesting how this finding could help clinicians with the disease management, selection of therapies and patient follow-up, since they purpose these parameters as promising predictive and diagnostic biomarkers of psoriasis.

• References must have the same format even if they come from different databases to allow users easier searching on the source of information mentioned in the manuscript. Therefore, authors should review the bibliography inserting some missing information for example the Digital Object Identifier (doi) and the source of the cited article in all references.

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21 Oct 2021

Response to Reviewers

Thanks for your thoughtful and constructive comments. We have learned a lot from these comments, and addressed all of questions accordingly. Please find the revised texts highlighted in the revised manuscript, and the point-by-point responses as follows:

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Response: We have changed data availability statement to “all relevant data are within the manuscript and its Supporting Information files”, since there is no additional data for this manuscript.

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Response: We have ensured that abstract on the online submission and the abstract in the manuscript are identical.

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Response: We have included captions for our Supporting Information files at the end of our manuscript, and updated the in-text citation to match accordingly.

Reviewers' comments:

Reviewer #1: This is a meta-analysis of RDW and MPV as biomarkers and predictors of disease severity by Jiang et al.

1. Which drugs affecting hematologic diseases were excluded? Was biotin also excluded?

Response: Thanks for your comment. We have excluded the antiplatelet drugs and nonsteroid anti-inflammatory drugs but not biotin, because the measurement of MPV and RDW is independent of biotin in blood (certain laboratory results influenced by biotin include troponin, thyroid and other hormones and vitamin D level) (https://labtestsonline.org/articles/biotin-affects-some-blood-test-results).

2. Was there a reason why male or female only studies were excluded? While there are potential gender differences in values, you could also run a subset analysis based on gender. Please include reasoning.

Response: Thanks for your important comment. Indeed, only one monosexual study was excluded based on this criterion. The reason for establishing this standard is that all enrolled studies focused on both the male and female except one study by Ozlem Karabudak in 2008. As you mentioned, subset analysis could be used to diminish the effect of gender, however, only two included studies have provided the MPV value stratified by gender. Consequently, data is insufficient to get credible results for the subset analysis of gender. In order to avoid bias caused by gender, we have excluded this study by exclusive standard.

3. In limitations, this reviewer suggests adding that it's possible that even aggregated the included studies are not sufficient to detect if there is a difference.

Response: We have added “it's possible that even aggregated the included studies are not sufficient to detect if there is a difference” in limitations.

Minor comments:

1. Suggest adding a transition sentence between promising biomarkers and hematologic parameters to improve flow

Response: Thanks for your suggestion. We have added a transition sentence between promising biomarkers and hematologic parameters in introduction section to improve flow.

2. There are spelling/grammar/word errors throughout the paper and highlighting several here:

Introduction- change "The diagnose the psoriasis" to "The diagnosis of psoriasis"

Response: We have changed "The diagnose the psoriasis" to "The diagnosis of psoriasis"

in introduction section.

Exclusion standards- change retreated to retracted

Response: We have changed “retreated” to “retracted” in exclusion standards.

Results-11 and 12 should be spelled out

Response: We have spelled out 11 and 12 in results.

Figure 1- psoriasis is misspelled

Response: We have corrected the spelling mistake in figure 1.

Meanwhile, we have our manuscript polished by a native English speaker to make it more readable.

Reviewer #2: The present meta-analysis aimed at investigating the association of MPV and RDW with diagnosis and disease severity of psoriasis by extracting data from thirteen studies appropriately chosen according to certain criteria.

The manuscript provides robust statistical analysis on the extracted data to assess the association of MPV and RDW with psoriasis, the heterogeneity among studies and the entity of the publication bias, as well as sensitivity and meta-regression analysis. Nevertheless, more details are needed to clarify the biological aspects related to MPV and RDW involvement in the pathogenesis of psoriasis.

1. In the Discussion Section about MPV, authors mention findings from other studies that demonstrate elevation of this parameter in psoriasis patients, suggesting the involvement of increased platelet activation in the pathogenesis of psoriasis. Authors should give a deeper explanation on how MPV can be affected by the clinical-molecular alterations underlying the disease onset and progression, outlining possible mechanisms, pathways or molecular factors related (for instance, recent articles/reviews concerning the role of angiogenesis, cell proliferation, inflammation could be employed for a better introduction of the topic).

Response: Thanks for your constructive comment! We have cited more related literation to elaborate MPV-involved possible mechanisms underlying the disease onset and progression. Platelets synthesize, store, and secret inflammatory factors to induce inflammatory response. At the same time, they express P-selectin, CD40 ligand, Toll-like receptors, and integrins on their surface for the recruitment of polymorphonuclear neutrophils, cell adhesion and migration, as well as interaction with immune cells in the onset and progression of psoriasis.

2. Previous literature suggested RDW as a biomarker of cardiovascular disease susceptibility and inflammation levels in rheumatoid arthritis (RA) and ankylosing spongdylitis (AS). In the Discussion section, authors do not explore the connection between the variation of volume and size of red blood cells (measured by RDW) and the pathological processes underlying the development of psoriasis. Therefore, authors should explain how this parameter could be involved in the pathogenesis of the disease, justifying why clinicians should consider RDW informative in psoriasis patients especially regarding its predictive role in response to treatment.

Response: Thanks for your important comment. We pretty agree with your point of view. However, the erythroid disturbance in psoriasis patients has been hardly reported. A few studies reported that increased inflammatory cytokines in the skin and peripheral blood of psoriasis patients influenced erythropoiesis and elevated the value of RDW. We have cited and discussed these articles in the discussion section (page 17-18). Moreover, further studies are needed to have a more in-depth sight.

3. This meta-analysis demonstrates a correlation of MPV and RDW with the presence of psoriasis rather than with disease severity. Authors should implement the conclusion suggesting how this finding could help clinicians with the disease management, selection of therapies and patient follow-up, since they purpose these parameters as promising predictive and diagnostic biomarkers of psoriasis.

Response: Thanks for your comment. The current study could only demonstrate the correlation of MPV and RDW with the presence of psoriasis. Further analysis such as the disease severity and long-term prognosis is limited by unavailable data currently. Thus, we could only point out that MPV and RDW contribute to the early diagnosis of psoriasis for clinicians. As we know, patients could benefit a lot from early diagnosis and treatment. Besides, several studies have showed that the induction of these two indicators possibly provide reference significance for the judgement of treatment efficacy in the short term, however the comprehensive analysis of several hematological parameters are needed for efficacy evaluation in the long term. We have further elucidated the above opinion in the discussion section.

4. References must have the same format even if they come from different databases to allow users easier searching on the source of information mentioned in the manuscript. Therefore, authors should review the bibliography inserting some missing information for example the Digital Object Identifier (doi) and the source of the cited article in all references.

Response: We have reviewed the bibliography and inserted some missing information including doi and the source of the cited article in all references except for Ref. 26, 46 and 50 without available doi.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

14 Feb 2022

Comparison of mean platelet volume (MPV) and red blood cell distribution width (RDW) between psoriasis patients and controls: a systematic review and meta-analysis

PONE-D-21-08384R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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Reviewer #2: Yes

Reviewer #3: Partly

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Reviewer #3: Yes

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Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: The present version of the manuscript is considerably improved. In particular, the revised version of the manuscript provides a more detailed and clearer explanation of MPV and RDW involvement in the pathogenesis of psoriasis clarifying its related biological aspects.

Reviewer #3: The present meta-analysis aimed at investigating the association of MPV

and RDW with diagnosis and disease severity of psoriasis. The language of the manuscript is good and the structure is reasonable.

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Reviewer #2: No

Reviewer #3: No

17 Feb 2022

PONE-D-21-08384R1

Comparison of mean platelet volume (MPV) and red blood cell distribution width (RDW) between psoriasis patients and controls: a systematic review and meta-analysis

Dear Dr. Wang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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