Risk of Psoriasis in Postgastrectomy Gastric Cancer Survivors: A Nationwide Population-Based Cohort Study.

Background: Although patients with psoriasis have an increased risk of cancers, little is known about the risk of psoriasis in cancer patients. Objective: We aimed to comparatively analyze the incidence and risk factors of psoriasis in gastric cancer patients who underwent gastrectomy and in the general population.
Methods: A nationwide retrospective cohort of 52,608 gastric cancer survivors (2007~2015) was compared to 123,438 matched controls from the general population to estimate the incidence and hazard ratio (HR) of new-onset psoriasis. We also calculated the HRs for psoriasis according to adjuvant cancer treatment, obesity, and vitamin B12 supplementation in gastric cancer survivors.
Results: During a mean follow-up of 6.85 years, 645 of the 52,608 gastric cancer patients developed psoriasis, while 1,806 in the 123,438 matched control group developed psoriasis. Gastric cancer patients had a decreased risk of psoriasis (HR, 0.86; 95% confidence interval, 0.79~0.94), especially those who underwent subtotal gastrectomy. We found that vitamin B12 supplementation for more than 3 years had an additive effect on decreasing the risk of psoriasis in gastric cancer patients who underwent subtotal gastrectomy. Total gastrectomy, radio/chemotherapy, and obesity did not affect the risk of psoriasis in gastric cancer survivors.
Conclusion: The incidence of psoriasis is slightly lower in gastric cancer survivors than in the general population. Our results suggest that the development of psoriasis may be reduced by removing the source of systemic inflammation caused by Helicobacter pylori infection through subtotal gastrectomy in gastric cancer survivors.

INTRODUCTION

Cancer is a major disease, with 18.1 million new cases and 9.6 million cancer deaths reported worldwide in 20181. The number of cancer survivors continues to increase due to improvements in early detection and treatment, and in 2018, there were 43.8 million people who were alive within 5 years of their cancer diagnosis12. In Korea, gastric cancer is the most frequently diagnosed cancer, and the 5-year survival rate of gastric cancer in 2010~2014 (68.9%) was the highest in Korea among 71 countries34. The increased survival of patients with gastric cancer in Korea is the result of early diagnosis and treatment through its nationwide screening program; consequently, the 5-year survival rate of patients with gastric cancer who had undergone curative gastrectomy exceeded 80%56. As the number of gastric cancer survivors increases, the interest in their long-term outcomes and management is increasing substantially78910.

Psoriasis is a common chronic inflammatory disease affecting 1%~3% of the general population11. Although psoriasis primarily affects the skin, it is considered a systemic disease characterized by immune system dysfunction and the production of pro-inflammatory cytokines12131415. Psoriasis is associated with multiple comorbidities related to systemic inflammation, including cardiovascular disease, obesity, metabolic syndrome, and diabetes16. Furthermore, the risk of malignancy is of special concern among patients with psoriasis because the chronic systemic inflammation of psoriasis itself and immunosuppressive treatments may be associated with an increased risk of cancer. Recent meta-analyses and large cohort studies have reported increased risk of overall malignancy in patients with psoriasis1718192021, and a study in Korea highlighted the increased risk of gastric cancer in such cases22. However, on the contrary, estimates of the incidence and relative risk of psoriasis for patients with cancer as compared to those for the general population are extremely limited. Although a Swedish population-based cohort study reported a 17% higher risk of psoriasis in patients with breast cancer than in the general population23, no study has focused on the risk of psoriasis in other cancer patients. The risk of psoriasis in cancer survivors may be different from that in the general population because cancer cells and immunosuppressive cancer treatments such as chemotherapy can affect the immune system of cancer patients and change the immunopathogenesis of psoriasis.

In this study, we aimed to investigate the relative risk and incidence rates of psoriasis among gastric cancer patients who underwent gastrectomy and among the general population using a nationally representative sample. In addition, we evaluated the risk factors of psoriasis in gastric cancer survivors.

MATERIALS AND METHODS

Data source

Our retrospective cohort was obtained from the Korean National Health Insurance Services (NHIS) database. The NHIS is Korea’s mandatory universal single-payer national healthcare system for approximately 97% of the Korean population. People in the lowest income bracket are covered by Medicaid, which is funded by general taxes.

The NHIS database contains data on the beneficiaries, such as age, sex, place of residence, monthly insurance premium, disability, medical claims information, such as disease codes (based on the International Classification of Diseases, 10th Revision; ICD-10), procedures, prescriptions, and costs incurred. It also contains the results of health screening examinations because the NHIS provides biennial National Health Screening Program to all beneficiaries who are 40 years and older and all employees regardless of age24.

The study protocol was approved by the institutional review board (IRB number: X-2005/613-904). The requirement for informed consent was waived because we used only deidentified data.

Study population

We included 150,790 patients who underwent total or subtotal gastrectomy for gastric cancer (C16) between January 1, 2007 and December 31, 2015. Patients were excluded if they had no health check-up data or had a history of another cancer (C00 to C97 except C16) or psoriasis before their gastric cancer diagnosis. In addition, we excluded patients who died or developed psoriasis within 3 years after gastrectomy because the effect of gastrectomy would not be immediate10. Finally, we included 52,608 patients with gastric cancer in this study.

The control group consisted of 452,370 subjects without cancer were selected as a 1:3 age- and sex-matched control group for the 150,790 gastric cancer patients. Matching was performed on a year-by-year basis such that incident gastric cancer cases were matched to control cases based on information from the year of cancer diagnosis. The baseline characteristics used for matching were derived from the previous year. We applied the same exclusion criteria to the control group as we did to the gastric cancer group. Matched control subjects (n=123,438) were assigned an index date corresponding to the date of gastrectomy of their matched gastric cancer patients. The flow chart of the study participants is shown in Fig. 1.

Fig. 1

Flowchart of study participants.

Outcome measures

The primary outcome was the incidence of psoriasis. Psoriasis was defined as the presence of L40 code and antipsoriatic drug codes (including topicals, systemics, and biologics). Participants were followed from the index date until the development of psoriasis, death for censored date, or the end of the study on December 31, 2015.

Statistical analyses

The baseline characteristics of the study population are presented using descriptive statistics. A Cox regression analysis was performed to evaluate the risk of psoriasis according to gastrectomy status and was adjusted for age, sex, income, place of residence, diabetes, hypertension, dyslipidemia, smoking, alcohol, and body mass index (BMI). To study the effects of radiotherapy and chemotherapy on the risk of psoriasis, the hazard ratios (HRs) of psoriasis according to adjuvant cancer treatment in gastric cancer survivors were analyzed. In addition, we performed stratified analyses according to BMI or duration of vitamin B12 supplementation to evaluate whether obesity or vitamin B12 supplementation affected the development of psoriasis among gastric cancer patients. We used the prescribed drug claims records at 3 years after gastrectomy to classify the patients who received vitamin B12 supplementation for more than 3 years and those who received vitamin B12 supplementation for less than 3 years. Data were analyzed using the SAS software version 9.4 (SAS Institute, Cary, NC, USA). p-values less than 0.05 were considered statistically significant. The detailed codes used for analysis are described in the online supplementary content (Supplementary Table 1).

RESULTS

Characteristics of the study population

Table 1 shows the demographics and clinical characteristics of the patients with gastric cancer and matched controls. Their mean age was 58.60±11.17 years, and female accounted for 33.76% of the study population. The gastric cancer patients were more likely than the matched controls to have diabetes and hypertension, to be current smokers, to drink alcohol and to have low BMI. The matched group was more likely to have dyslipidemia than the gastric cancer group. Among the gastric cancer survivors, 1.64% and 16.62% received radiotherapy and chemotherapy, respectively.

Table 1

Baseline characteristics of study participants

Characteristic		Matched control (n=123,438)	Gastric cancer survivors (n=52,608)
Age (yr)		58.27±11.11	58.92±11.23
Sex
	Male	82,312 (66.68)	34,621 (65.81)
	Female	41,126 (33.32)	17,987 (34.19)
Income
	Highest quartile	30,265 (24.52)	12,301 (23.38)
	2nd quartile	27,459 (22.25)	12,058 (22.92)
	3rd quartile	30,445 (24.66)	13,451 (25.57)
	Lowest quartile and medicaid	35,269 (28.57)	14,798 (28.13)
Place of residence
	Metropolitan	74,152 (60.07)	31,065 (59.05)
	City	34,402 (27.87)	14,996 (28.51)
	Rural	14,884 (12.06)	6,547 (12.44)
Diabetes		18,584 (15.06)	9,452 (17.97)
Hypertension		51,808 (41.97)	22,716 (43.18)
Dyslipidemia		31,803 (25.76)	12,282 (23.35)
Smoking
	Non	72,008 (58.34)	27,832 (52.9)
	Ex	22,778 (18.45)	9,458 (17.98)
	Current	28,652 (23.21)	15,318 (29.12)
Alcohol
	Non	67,148 (54.76)	28,048 (53.62)
	Moderate (<30 g/day)	34,561 (28.19)	14,922 (28.53)
	Heavy (≥30 g/day)	20,904 (17.05)	9,336 (17.85)
BMI (kg/m2)		24.03±3.00	23.84±3.06
Radiotherapy		0 (0)	865 (1.64)
Chemotherapy		0 (0)	8,743 (16.62)

Values are presented as mean±standard deviation or number (%). BMI: body mass index.

Psoriasis incidence in gastric cancer survivors

For the total study population, the mean follow-up period after the 3-year time lag was 3.85 years (3.78 years for the gastric cancer survivors and 3.87 years for the matched controls). During the follow-up period, 645 of the 52,608 gastric cancer patients developed psoriasis (incidence rate, 3.24 per 1,000 person-years), while 1,806 in the 123,438 matched controls developed psoriasis (incidence rate, 3.78 per 1,000 person-years) (Table 2). The crude and multivariable-adjusted hazard ratios (aHRs) for the incidence of psoriasis in those with and without gastric cancer were 0.86 (95% confidence interval [CI], 0.79~0.94) and 0.85 (95% CI, 0.78~0.94), respectively. When psoriasis risk was evaluated by type of surgery, only gastric cancer patients who underwent subtotal gastrectomy showed a decreased risk of psoriasis as compared with the matched non-cancer control group (aHR, 0.85; 95% CI, 0.77~0.94). Analyses by adjuvant cancer treatment showed no effect of radiotherapy and chemotherapy on psoriasis risk (Table 3).

Table 2

Event count and incidence rates of psoriasis in gastric cancer survivors and matched controls

Group		Number	Event*	Person-years (p-y)	Incidence rate (per 1,000 p-y)	HR (95% CI)	aHR (95% CI)
Matched controls		123,438	1,806	477,943.4	3.77869	1 (Reference)	1 (Reference)
Gastric cancer survivors		52,608	645	199,012.5	3.241	0.86 (0.79~0.94)	0.85 (0.78~0.94)
Surgery type
	Subtotal gastrectomy	42,624	524	162,693.51	3.22078	0.85 (0.77~0.94)	0.85 (0.77~0.94)
	Total gastrectomy	9,984	121	36,318.99	3.33159	0.88 (0.74~1.06)	0.88 (0.73~1.05)

The multivariate model was adjusted for age, sex, income, place of residence, diabetes, hypertension, dyslipidemia, smoking, alcohol, and body mass index. HR: hazard ratio, CI: confidence interval, aHR: adjusted hazard ratio. *Participants who developed psoriasis.

Table 3

Hazard ratios (HRs) (95% CIs) for psoriasis in gastric cancer survivors stratified by adjuvant cancer treatment

Group		Number	Event*	Person-years (p-y)	Rate (per 1,000 p-y)	HR (95% CI)	aHR (95% CI)
Radiotherapy
	No	51,743	636	195,484.98	3.25345	1 (Reference)	1 (Reference)
	Yes	865	9	3,527.52	2.55137	0.781 (0.40~1.51)	0.86 (0.45~1.66)
Chemotherapy
	No	43,865	540	169,976.72	3.17691	1 (Reference)	1 (Reference)
	Yes	8,743	105	29,035.78	3.61623	1.142 (0.93~1.41)	1.125 (0.91~1.39)

The multivariate model was adjusted for age, sex, income, place of residence, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, and body mass index. CI: confidence interval, aHR: adjusted hazard ratio. *Participants who developed psoriasis.

Effect of BMI on the development of psoriasis

To investigate the effect of BMI on psoriasis development, the incidence of psoriasis was compared by categorizing the study participants according their status as obese (BMI ≥25 kg/m2) or not obese (BMI <25 kg/m2). Regardless of the obesity status, the risk of psoriasis in gastric cancer patients, especially those who underwent subtotal gastrectomy, was significantly lower than that in the controls (Table 4).

Table 4

Incidence of psoriasis in gastric cancer patients and matched controls according to obesity

Group		Number	Event*	Person-years (p-y)	Rate (per 1,000 p-y)	HR (95% CI)	aHR (95% CI)
BMI <25 kg/m2
	Matched controls	79,703	1,118	308,458.44	3.62448	1 (Reference)	1 (Reference)
	Gastric cancer survivors	34,978	418	132,252.81	3.16061	0.87 (0.78~0.98)	0.86 (0.77~0.97)
	Subtotal gastrectomy	28,120	339	107,407.78	3.1562	0.87 (0.77~0.98)	0.86 (0.76~0.97)
	Total gastrectomy	6,858	79	24,845.03	3.17971	0.88 (0.70~1.10)	0.87 (0.69~1.10)
BMI ≥25 kg/m2
	Matched controls	43,735	688	169,484.96	4.05936	1 (Reference)	1 (Reference)
	Gastric cancer survivors	17,630	227	66,759.69	3.40026	0.84 (0.72~0.98)	0.84 (0.72~0.98)
	Subtotal gastrectomy	14,504	185	55,285.73	3.34625	0.83 (0.70~0.97)	0.83 (0.71~0.98)
	Total gastrectomy	3,126	42	11,473.96	3.66046	0.90 (0.66~1.24)	0.88 (0.64~1.21)

The multivariate model was adjusted for age, sex, income, place of residence, diabetes, hypertension, dyslipidemia, smoking, and alcohol consumption. BMI: body mass index, HR: hazard ratio, CI: confidence interval, aHR: adjusted hazard ratio. *Participants who developed psoriasis.

Effect of vitamin B12 supplementation on the development of psoriasis

In order to investigate the effect of vitamin B12 supplementation on the development of psoriasis, we further dividing the groups according to the duration of vitamin B12 supplementation (Table 5). The risk of psoriasis was significantly low (aHR, 0.85; 95% CI, 0.75~0.96) in gastric cancer patients who did not receive vitamin B12 supplementation and in those who were supplemented with vitamin B12 for more than 3 years after surgery (aHR, 0.76; 95% CI, 0.60~0.96). However, the reduction in psoriasis risk in gastric cancer patients who underwent total gastrectomy was not associated with vitamin B12 supplementation.

Table 5

Incidence of psoriasis in gastric cancer patients and matched controls according to vitamin B12 supplementation

Group		Number	Event*	Person-years (p-y)	Rate (per 1,000 p-y)	HR (95% CI)	aHR (95% CI)
No supplements
	Matched controls	49,636	651	171,279.57	3.8008	1 (Reference)	1 (Reference)
	Gastric cancer survivors	38,644	467	143,326.52	3.25829	0.85 (0.76~0.96)	0.85 (0.75~0.96)
	Subtotal gastrectomy	35,503	425	133,392.64	3.18608	0.84 (0.74~0.94)	0.83 (0.74~0.94)
	Total gastrectomy	3,141	42	9,933.88	4.22795	1.11 (0.81~1.52)	1.08 (0.79~1.47)
S tarted supplementation but quit within 3 years
	Matched controls	5,384	60	16,497.09	3.637	1 (Reference)	1 (Reference)
	Gastric cancer survivors	4,401	58	12,828.39	4.52122	1.25 (0.87~1.80)	1.26 (0.87~1.82)
	Subtotal gastrectomy	2,756	44	9,290.96	4.73579	1.31 (0.89~1.93)	1.33 (0.90~1.98)
	Total gastrectomy	1,645	14	3,537.43	3.95768	1.10 (0.62~1.98)	1.07 (0.60~1.93)
S tarted supplementation more than 3 years after surgery
	Matched controls	12,505	187	50,512.03	3.70209	1 (Reference)	1 (Reference)
	Gastric cancer survivors	9,563	120	42,857.59	2.79997	0.74 (0.59~0.94)	0.76 (0.60~0.96)
	Subtotal gastrectomy	4,365	55	20,009.91	2.74864	0.73 (0.54~0.98)	0.72 (0.53~0.98)
	Total gastrectomy	5,198	65	22,847.68	2.84493	0.76 (0.57~1.01)	0.79 (0.59~1.05)

The multivariate model was adjusted for age, sex, income, place of residence, diabetes, hypertension, dyslipidemia, smoking, alcohol, and body mass index. CI: confidence interval, HR: hazard ratio, aHR: adjusted hazard ratio. *Participants who developed psoriasis.

DISCUSSION

In this large national cohort, the incidence of psoriasis was 15% lower in gastric cancer patients than in matched reference individuals. We found that subtotal gastrectomy and vitamin B12 supplementation for more than 3 years were clinical factors associated with decreased risk of psoriasis in gastric cancer survivors, while total gastrectomy, radio/chemotherapy, and obesity did not affect the risk of psoriasis in gastric cancer survivors.

To the best of our knowledge, our study is the first to comparatively analyze the relative risk and incidence rates of psoriasis in gastric cancer patients who underwent gastrectomy and in the general population. We demonstrated that gastric cancer survivors who underwent subtotal gastrectomy had a 0.85-fold lower risk of psoriasis than the controls, whereas the risk of psoriasis was similar between those who underwent total gastrectomy and the controls. In contrast, a previous study reported a higher risk of psoriasis in patients with breast cancer than in the general population, explaining that radiotherapy or mastectomy for breast cancer treatment may lead to skin trauma and trigger the onset of psoriasis23. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, and surgical resection to treat gastric cancer is different from mastectomy, which directly causes extensive skin wounds. Additionally, we found that radiotherapy or chemotherapy, used as neoadjuvant or adjuvant treatment approaches for resectable gastric cancer, did not affect the risk of psoriasis in gastric cancer survivors.

In our study, a decreased risk of psoriasis in gastric cancer patients was also not associated with obesity. Obesity is a significant risk factor for the onset and severity of psoriasis25, and several case reports have shown that psoriasis rapidly improved after gastrectomy as a bariatric procedure for obese patients with psoriasis262728. However, our results showed that even in the non-obesity group (BMI <25 kg/m2), the risk of psoriasis significantly decreased in gastric cancer survivors, and the risk of psoriasis was consistently reduced only in gastric cancer patients who underwent subtotal gastrectomy, not total gastrectomy. Although the baseline obese group (BMI ≥25 kg/m2) tended to low incidence of psoriasis after subtotal gastrectomy more than the non-obese group (BMI <25 kg/m2), considering that the surgical procedure and metabolic beneficial changes of gastrectomy for gastric cancer patients are similar to those of bariatric surgery2930,31, the effects of gastrectomy itself or weight loss due to gastrectomy do not seem to be major factors reducing the risk of psoriasis in gastric cancer patients.

The decreased risk of psoriasis in gastric cancer patients who underwent subtotal gastrectomy may be related to the characteristic pathogenic mechanism of distal gastric cancer. Gastric cancer can be classified as per two topographic subsites: proximal gastric cancer, also known as cardia gastric cancer, and distal gastric cancer (noncardia cancer). The risk factors for proximal gastric cancer include Caucasian race, male sex, obesity, gastro-esophageal reflux, tobacco-alcohol abuse, high socioeconomic status, and low fruit and vegetable intake, while the risk factor for distal gastric cancer is well-known as chronic inflammation associated with Helicobacter pylori infection323334. Recently, many studies have been performed concerning the potential role of H. pylori in different extra-gastric diseases such as ischemic heart diseases, obesity, insulin resistance, non-alcoholic fatty liver diseases, Alzheimer’ disease and autoimmune diseases353637. Because H. pylori infection is persistent and stimulates both a local and a systemic immune response that could cause significant changes in the markers of inflammation like C-reactive protein, tumor necrosis factor-α, interleukin (IL)-6, IL-12, and interferon (IFN)-γ, these pro-inflammatory factors also may be involved in the development of psoriasis1238394041. From that point of view, subtotal gastrectomy, a treatment of choice for distal gastric cancer, could reduce the incidence of psoriasis by eliminating the distal part of the stomach (gastric antrum), which is a source of H. pylori colonization with inflammatory potential.

Two recent meta-analyses concluded that patients with psoriasis had increased H. pylori infection rate, and psoriasis patients with H. pylori infection were more severe4243. These meta-analyses proved a significant association between psoriasis and H. pylori infection, which suggest that H. pylori infection could play a role in the pathogenesis of psoriasis by inducing the abnormal immunological cascade. Our study also supports a significant relationship between H. pylori infection and psoriasis. In contrast, Cho et al.44 did not find a significant relationship between H. pylori infection and psoriasis, but their conclusion has a limitation in that they were based on a 1-year cross-sectional study.

Interestingly, vitamin B12 supplementation for more than 3 years further reduced the incidence of psoriasis in gastric cancer patients by about 10%. Although several studies have shown that vitamin B12 deficiency is associated with psoriasis4546, some studies have shown inconsistencies in this regard 4748, and thus there is currently insufficient evidence supporting the role of vitamin B12 in psoriasis49. However, our study suggests that vitamin B12 supplementation for at least 3 years or more had an additive effect on lowering the incidence of psoriasis in gastric cancer patients who underwent subtotal gastrectomy, and therefore, vitamin B12 deficiency could play a contributory role in the development of psoriasis. Potential mechanisms linking vitamin B12 deficiency and psoriasis include increased serum homocysteine level, which is a well-known risk factor for atherosclerosis50. Homocysteine metabolism is dependent in part on folate and vitamin B12, such that deficiency of these vitamins may lead to elevated homocysteine levels, which in turn impair endothelial function and increase the risk of cardiovascular disease51. Psoriasis and cardiovascular disease share the same inflammatory pathophysiology5253, and hyperhomocysteinemia due to vitamin B12 deficiency may also be a risk factor for psoriasis associated with metabolic syndrome and cardiovascular disease.

Our study has several limitations. First, our study is an observational study that only demonstrates associations and not causation. Although we suggested risk factors that were statistically related to psoriasis development in patients with gastric cancer, prospective cohort studies and laboratory data are needed to confirm these associations and to elucidate the biological mechanisms. Second, the study was conducted in Korea, a country with a single-payer national health insurance system. Our findings may not be generalizable to other race/ethnicity groups or to other health care settings. In particular, gastric cancer is well known for its geographic variations, indicated by its higher incidence in East Asian countries than in Western countries; hence, there may be differences in the incidence and risk factors of psoriasis when studying gastric cancer patients of other races.

In conclusion, the gastric cancer survivors who underwent gastrectomy had a lower risk of psoriasis than the matched controls. Subtotal gastrectomy and vitamin B12 supplementation for more than 3 years were associated with a decreased risk of psoriasis in the gastric cancer patients. Our results suggest that chronic systemic inflammation induced by H. pylori as a critical pathogenesis of gastric cancer may contribute to the development of psoriasis, and inflammation due to atherogenic conditions induced by vitamin B12 deficiency may have synergic effects in the development of psoriasis. Further research is needed to evaluate the effects of subtotal gastrectomy and vitamin B12 deficiency on the onset of psoriasis in gastric cancer patients and to identify the biological mechanisms underlying this process.