Potential Correlation Between Eczema and Hematological Malignancies Risk: A Systematic Review and Meta-Analysis

Background Eczema characterized by itch, sleeplessness, and adverse effects on quality of life is associated with a risk of hematological malignancies. However, there is a controversy pertaining to whether this association implies a greater or lesser risk of hematological cancers. We aimed to explore the link between eczema and hematological malignancies risk. Methods We systematically searched PubMed and Embase databases from their inception to February 17, 2022. Two reviewers independently screened articles, extracted data and assessed study quality, respectively. The odds ratios and 95% confidence intervals (CIs) were pooled by using fixed or random-effects models. Results 29 studies involving 2,521,574 participants examined the contribution of eczema to hematological malignancies. We found that eczema significantly increased the risk of Hodgkin's lymphoma (1.44; 95% CI, 1.07–1.95), myeloma (1.15; 95% CI, 1.04–1.28), and significantly decreased the risk of lymphocytic leukemia (0.91; 95% CI, 0.84–0.99); however, it is not significantly associated with Non-Hodgkin's lymphoma, and myelocytic leukemia. Conclusion Eczema has been shown to be associated with the risk of hematological cancer, this association still needs to be verified in large randomized controlled trials. Systematic Review Registration https://inplasy.com/, INPLASY202260097.


INTRODUCTION
Hematological malignancies, mainly including lymphoma, leukemia, myeloma, are a common group of highly heterogeneous disorders characterized by uncontrolled proliferation and differentiation of hematopoietic cells (1). In accordance with American Cancer Society, approximately 184,130 new cases and 57,810 deaths of hematological malignancies were estimated in the United States in 2022 (2). Although many researchers have focused on the pathogenesis of hematologic malignancies in recent years and new treatments are available, the long-term survival rate is still unsatisfactory (3)(4)(5). Therefore, there is an urgent need to find new specific and non-invasive indicators to evaluate the prognosis of the disease so as to carry out early intervention.
Eczema (atopic dermatitis), one of the most common chronic skin diseases, affecting more than 2.5% of adults and 10% of children (6), may be associated with risk of hematological malignancies (7). However, until now, the role of eczema in the incidence of hematological tumors has been controversial, so this study was designed to explore the relationship between eczema and the risk of hematological cancers.

Search Strategy
According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (8,9), we performed this study. PubMed and Embase databases were systematically searched till February 17, 2022 to find studies performed on the relationship between eczema and hematological cancers. Electronic search strategy is available in Supplementary Material 1. The bibliographies of these literatures were conducted by meticulous analysis of the references listed in the selected articles. Two reviewers (LJ and ZY) did the screening independently, and resolved the conflict through discussion. Firstly, we screened relevant articles based on the titles and abstracts. Then, all papers passing the initial screening would be reviewed the full text.

Selection Criteria
The inclusion criteria were as follows: all cohort and casecontrol studies focusing on the relationship between eczema and hematological malignancy; odds ratios (ORs) and 95% confidence intervals (CIs) were provided or calculated. Animal studies, reports with no indication of the association between eczema and cancers, and reviews were excluded. If there is duplication of data in these studies, we selected the study including the largest sample size. The quality of the studies were evaluated according to the Newcastle-Ottawa Scale (NOS) (10). Studies with NOS scores ≥ 7 were considered to be qualified.

Data Analysis
Two teams (LZH and XSY formed one team; ZY, and LJ formed the other) extracted independently all data. When one study included more than one cohort, we pooled the cohorts and considered each cohort as an independent study. For each independent study, we recorded the following information: first author's name, publication year, study region, study design, type of cancer, participants' sex and age, sample size, and adjustment factors.
The ORs and 95% CIs reported in the studies were pooled by meta-analysis. The Cochrane Q and I2 statistics were used to evaluate heterogeneity (11). When P value was <0.10 or the I2 value was >50%, the data were considered heterogeneous, and a random-effects model (12) was applied. Otherwise, a fixedeffects model (13) was used. To further explore the origin of heterogeneity, we performed subgroup analyses by region, study design, and cancer type. To assess the credibility of our results, sensitivity analyses were conducted by excluding each study in turn to estimate the influence of each individual study on the pooled results. Begg's test (14) and Egger's test (15) were used to assess the potential publication bias. STATA software v12.0 (College Station, TX, USA) was used to analyze the data.

The Association of Eczema to Myeloma
Fifthly, the pooled analysis of six studies (16,19,20,22,32,42) indicated that eczema was significantly associated with

DISCUSSION
Eczema characterized by itch, sleeplessness, and adverse effects on quality of life is associated with a risk of several diseases (43).
A meta-analysis found that eczema was associated with increased risk of various cardiovascular diseases in cohort studies (44). A recent study also suggested that eczema is associated with an increased risk of developing depression and anxiety (45). But at present, the relationship between eczema and hematological tumors is still controversial, and our study aims to resolve this issue.
Our study indicated that the relationship between eczema and the risk of various types of hematological tumors was different. Firstly, our study showed no statistical relationship between eczema and an increased risk of non-Hodgkin's lymphoma, but the new results after excluding three articles with visible bias in sensitivity analysis showed that eczema was associated with an increased risk of non-Hodgkin's lymphoma, which was consistent with the findings of the cohort subgroup. In addition, eczema was significantly associated with the increased risk of Hodgkin's lymphoma and myeloma. Eczema was likely to the increased risk of myelocytic leukemia without statistical significance. On the contrary, eczema was statistically related with the decreased risk of lymphocytic leukemia. This difference is possibly due to the different risk factor spectrum of non-Hodgkin's lymphoma, Hodgkin's lymphoma and other hematological tumors (46). Of course, the existence of confounding bias and different treatment detections (especially immunomodulatory systemic therapeutics) may also be important reasons (16). What's more, T-cell NHL presenting in an indolent manner is always misdiagnosed as a nonneoplastic skin condition, and this diagnostic confusion could slightly attenuate the link between eczema and NHL risk (32).
Further subgroup analyses suggested that different study regions affect the association between eczema and hematological malignancies. Eczema was statistically associated with the increased risk of Hodgkin's lymphoma and myeloma in the American subgroup, but this link would be substantially attenuated in the European subgroup. This result was resulted from differences in race and environmental factors (47,48).
In addition, eczema was significantly associated with the decreased risk of acute lymphocytic leukemia, but it was not statistically associated with the risk of chronic lymphocytic leukemia. This may be because some treatments for eczema (Glucocorticoids, biological inhibitors, etc.) may have a certain preventive effect on acute lymphoid leukemia (49), but this effect is not obvious for chronic lymphoid leukemia. Meanwhile, patients with eczema often receive phototherapy, which may affect their risk of cancer because of its therapeutic effect on cancer (50).
Although our study addresses the shortcomings of a single study with a small sample size and a non-universal population investigated, there are still many limitations. Firstly, there is a different degree of heterogeneity in some of our results, which affects the reliability of our results, but we performed subgroup analyses to look for sources of heterogeneity; In addition, although most of the studies we included had adjusted for confounding factors, the confounding factors adjusted were different.

CONCLUSION
This study demonstrated that eczema significantly increases the risk of Hodgkin's lymphoma, myeloma, and significantly decreases the risk of lymphocytic leukemia. Although eczema has been shown to be associated with the risk of many hematological malignancies, this association still needs to be verified in large randomized controlled trials. At the same time, the mechanism of eczema leading to cancer is needed to explore.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
Material preparation, data collection, and analysis were performed by ZL, SX, JL, HJ, YT, and YZ. The first draft of the manuscript was written by ZL, JL, and HJ. All authors contributed to the study conception, design, commented on previous versions of the manuscript, and approved the final manuscript.