Re:Hemoglobin, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia in Behcet's disease patients with atrophic glossitis

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BEYOND REASON

베체트병은  chronic, relapsing, multisystemic, and inflammatory disorder 이고

riboflavin, niacin, vitamin B6, vitamin B12, folic acid or iron, diabetes mellitus, protein-calorie malnutrition, xerostomia, candidiasis, and Helicobacter pylori colonization와 관련이 있음. 

Hemoglobin, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia in Behcet's disease patients with atrophic glossitis

Author links open overlay panelYu-HsuehWuabJuliaYu-Fong ChangbcdYi-PingWangbcdYang-CheWubcHsin-MingChenbcdAndySunbc

https://doi.org/10.1016/j.jfma.2018.03.005Get rights and content

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Keywords

Atrophic glossitis

Behcet's disease

Hemoglobin

Iron

Vitamin B12

Hyperhomocysteinemia

Introduction

Behcet's disease (BD) is a chronic, relapsing, multisystemic, and inflammatory disorder. It is defined as having recurrent aphthous stomatitis (RAS) plus two of the following conditions including recurrent genital ulcerations, eye lesions, skin lesions, and positive pathergy reaction according to the criteria for diagnosis of BD proposed by the International Study Group for BD.1, 2 The minor-typed RAS (minor RAS, 57%) is the most common type of RAS in BD patients, followed by the major-typed RAS (major RAS, 40%) and herpetiform-typed RAS (3%).2

BD appears to represent an abnormal immune process triggered by an infectious or environmental antigen in a genetically predisposed individual. The human leukocyte antigen B-51 (HLA-B51) has been discovered to be associated with BD.2 Atrophic glossitic (AG) is a disease with multiple etiologies including deficiencies of riboflavin, niacin, vitamin B6, vitamin B12, folic acid or iron, diabetes mellitus, protein-calorie malnutrition, xerostomia, candidiasis, and Helicobacter pylori colonization.3 

BD patients are reported to have a relatively lower serum vitamin B12 or folate level and a higher frequency of vitamin B12 or folate deficiency than healthy control subjects.4 Moreover, active, thrombotic or ocular BD patients have been found to have a significantly higher serum homocysteine level and a significantly higher frequency of hyperhomocysteinemia than healthy control subjects and than inactive, non-thrombotic or non-ocular BD patients, respectively.5, 6, 7, 8, 9, 10, 11, 12

Our previous study found that a portion of AG and RAS patients do have hemoglobin (Hb), iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia as well as significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than healthy control subjects.3, 13 Hyperhomocysteinemia can be attributed to deficiencies of vitamin B6, vitamin B12, and/or folic acid.14, 15, 16 Therefore, the concomitant presence of AG and RAS diseases in BD patients may influence the anemia status, hematinic deficiency, and hyperhomocysteinemia in BD patients.

In our oral mucosal disease clinic, patients with RAS, AG, burning mouth syndrome, oral lichen planus, or oral submucous fibrosis are frequently encountered.3, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 For patients with these five specific diseases, complete blood count, serum iron, vitamin B12, folic acid, homocysteine, gastric parietal cell antibody (GPCA), thyroglobulin antibody (TGA), and thyroid microsomal antibody (TMA, also known as thyroid peroxidase antibody, TPO) levels are frequently examined to assess whether these patients have anemia, hematinic deficiencies, and serum GPCA, TGA, and TMA positivities.3, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37

BD patients should have RAS (so-called RAS/BD patients in this study) but they may or may not have AG.1, 2 In this study, 63 RAS/BD patients including 30 AG-positive RAS/BD (AG+RAS/BD) patients and 33 AG-negative RAS/BD (AG־RAS/BD) patients were collected. We tried to assess whether 30 AG+RAS/BD patients had significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than 33 AG־RAS/BD patients or 126 age- and sex-matched healthy control subjects. In addition, we also analyzed the anemia types in 13 anemic AG+RAS/BD patients and 6 anemic AG־RAS/BD patients.

Materials and methods

Subjects

The study group consisted of 63 BD patients (18 men and 45 women, age range 18–82 years, mean age 46 ± 16 years). For each BD patient, two age- (±2 years of each patient's age) and sex-matched healthy control subjects were selected. Thus, the normal control group consisted of 126 healthy control subjects (36 men and 90 women, age range 20–82 years, mean age 46 ± 13 years). All the patients and control subjects were seen consecutively, diagnosed, and treated in the Department of Dentistry, National Taiwan University Hospital from July 2007 to July 2017. Patients were diagnosed as having BD when they had RAS plus two of the following conditions including recurrent genital ulcers (on the scrotum and penile shaft of male patients or on the labia majora or labia minora of female patients), skin lesions (including erythema nodosum–like lesions, pseudofolliculitis, or papulopustular or acneiform lesions), and ocular lesions (including anterior or posterior uveitis, hypopyon, or retinal vasculitis) according to the criteria for diagnosis of BD proposed by the International Study Group for BD.1, 2 In this study, all the 63 BD patients had RAS that was characterized by the presence of at least one episode of oral ulcerations on the movable oral mucosa per month since childhood.13, 17, 18, 19, 20 Moreover, partial or complete AG, which was defined as having partial or complete absence or flattering of filiform papillae on the dorsal surface of the tongue, respectively, was present in 30 RAS/BD patients (so-called AG+RAS/BD patients).3, 15 The remaining 33 RAS/BD patients did not have concomitant partial or complete AG (so-called AG־RAS/BD patients). Of the 63 BD patients, 57 also had skin lesions, 53 also had genital ulcers, 21 also had ocular lesions, and 9 also had arthritis or arthralgia affecting the knees, ankles, wrists, and elbows. BD patients with betel quid chewing habit, autoimmune diseases, or traumatic or aphthous-like ulcers associated with systemic disorders were excluded.13, 17, 18, 19, 20, 38 Moreover, BD patients with a history of stroke, heavy alcohol use, or liver, kidney or coronary artery disease were also excluded13, 17, 18, 19, 20, 39 Healthy control subjects had dental caries, pulpal disease, malocclusion, or missing of teeth but did not have any oral mucosal or systemic diseases. More than 95% of our 63 BD patients were diagnosed as having inactive BD when included in this study. In addition, none of the BD patients had taken any prescription medication for BD, RAS, and AG at least 3 months before entering the study.

The blood samples were drawn from 63 BD patients and 126 healthy control subjects for the measurement of blood Hb, iron, vitamin B12, folic acid, and homocysteine concentrations. This study was reviewed and approved by the Institutional Review Board at the National Taiwan University Hospital.

Determination of blood hemoglobin, iron, vitamin B12, folic acid, and homocysteine concentrations

The blood Hb, iron, vitamin B12, folic acid, and homocysteine concentrations were determined by the routine tests performed in the Department of Laboratory Medicine, National Taiwan University Hospital.18, 19, 20

Statistical analysis

Comparisons of the mean blood levels of Hb, iron, vitamin B12, folic acid, and homocysteine between 30 AG+RAS/BD or 33 AG־RAS/BD patients and 126 healthy control subjects as well as between 30 AG+RAS/BD and 33 AG־RAS/BD patients were performed by Student's t-test. The differences in frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia between 30 AG+RAS/BD or 33 AG־RAS/BD patients and 126 healthy control subjects as well as between 30 AG+RAS/BD and 33 AG־RAS/BD patients were compared by chi-square test or Fisher exact test, where appropriate. The result was considered to be significant if the P-value was less than 0.05.

Results

The mean blood concentrations of Hb, iron, vitamin B12, folic acid, and homocysteine in 30 AG+RAS/BD and 33 AG־RAS/BD patients and 126 healthy control subjects are shown in Table 1. Because men usually had higher blood levels of Hb and iron than women, these two mean levels were calculated separately for men and women. We found that the 30 AG+RAS/BD patients had significantly lower mean blood Hb, iron, and folic acid levels and significantly higher serum homocysteine level than healthy control subjects (all P-values < 0.05). Although 30 AG+RAS/BD patients also had a lower mean serum vitamin B12 level than healthy control subjects, the difference was not significant (Table 1). Moreover, the 30 AG+RAS/BD patients had significantly lower mean blood Hb level than 33 AG־RAS/BD patients (P-values < 0.05). However, there were no significant differences in the mean serum iron, vitamin B12, folic acid and homocysteine levels between 30 AG+RAS/BD and 33 AG־RAS/BD patients (Table 1). In addition, the 33 AG־RAS/BD patients had significantly lower mean blood Hb, iron, and folic acid levels than healthy control subjects (all P-values < 0.05). Although the 33 AG־RAS/BD patients had slightly higher mean serum vitamin B12 level and slightly lower mean serum homocysteine level than healthy control subjects, the differences were not significant (Table 1).

Table 1. Comparisons of mean blood concentrations of hemoglobin (Hb), iron, vitamin B12, folic acid, and homocysteine between 30 atrophic glossitis (AG)-positive recurrent aphthous stomatitis (RAS)/Behcet's disease (BD) (AG+RAS/BD) or 33 AG-negative RAS/BD (AG־RAS/BD) patients and 126 healthy control subjects as well as between 30 AG+RAS/BD and 33 AG־RAS/BD patients.

Group	Hb (g/dL)		Iron (μg/dL)		Vitamin B12 (pg/mL)	Folic acid (ng/mL)	Homocysteine (μM)
	Men	Women	Men	Women
AG+RAS/BD patients (n = 30)	12.6 ± 1.7 (n = 7)	12.2 ± 1.3 (n = 23)	73.4 ± 45.6 (n = 7)	66.5 ± 26.5 (n = 23)	586.7 ± 267.8	10.6 ± 6.7	10.7 ± 8.6
aP-value	<0.001	<0.001	0.014	<0.001	0.131	0.007	0.011
bP-value	0.008	0.013	0.462	0.360	0.084	0.619	0.157
AG־RAS/BD patients (n = 33)	14.6 ± 1.1 (n = 11)	13.1 ± 1.0 (n = 22)	85.6 ± 23.3 (n = 11)	74.5 ± 31.4 (n = 22)	695.3 ± 223.3	11.4 ± 6.0	8.3 ± 4.1
aP-value	0.023	0.007	0.038	0.002	0.466	0.026	0.698
Healthy control subjects (n = 126)	15.2 ± 0.6 (n = 36)	13.6 ± 0.7 (n = 90)	102.6 ± 23.1 (n = 36)	98.4 ± 30.8 (n = 90)	661.8 ± 237.2	14.1 ± 6.2	8.5 ± 2.1

a

Comparisons of means of parameters between 30 AG+RAS/BD or 33 AG־RAS/BD patients and healthy control subjects by Student's t-test.

b

Comparisons of means of parameters between 30 AG+RAS/BD and 33 AG־RAS/BD patients by Student's t-test.

According to the World Health Organization (WHO) criteria, men with Hb < 13 g/dL and women with Hb < 12 g/dL were defined as having Hb deficiency or anemia.40 Furthermore, patients with the serum iron level < 60 μg/dL,41 the serum vitamin B12 level < 200 pg/mL,39 or the folic acid level < 4 ng/mL42 were defined as having iron, vitamin B12 or folic acid deficiency, respectively. In addition, patients with the blood homocysteine level >12.7 μM (which was the mean serum homocysteine level of healthy control subjects plus two standard deviations) were defined as having hyperhomocysteinemis. By the above-mentioned definitions, 43.3%, 33.3%, 13.3%, 6.7%, and 20.0% of 30 AG+RAS/BD patients and 18.2%, 36.4%, 0%, 6.1%, and 9.1% of 33 AG־RAS/BD patients were diagnosed as having Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively (Table 2). We found that 30 AG+RAS/BD patients had significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than healthy control subjects (all P-values < 0.05) as well as a higher frequency of Hb deficiency (P = 0.058, marginal significance) and a significantly higher frequency of vitamin B12 deficiency (P = 0.046) than 33 AG־RAS/BD patients (Table 2). Moreover, the 33 AG־RAS/BD patients had significantly higher frequencies of Hb and iron deficiencies than healthy control subjects (both P-values < 0.001).

Table 2. Comparisons of frequencies of blood hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia between 30 atrophic glossitis (AG)-positive recurrent aphthous stomatitis (RAS)/Behcet's disease (BD) (AG+RAS/BD) or 33 AG-negative RAS/BD (AG־RAS/BD) patients and 126 healthy control subjects as well as between 30 AG+RAS/BD and 33 AG־RAS/BD patients.

Group	Patient number (%)
	Hemoglobin deficiency (Men < 13 g/dL, women < 12 g/dL)	Iron deficiency (<60 μg/dL)	Vitamin B12 deficiency (<200 pg/mL)	Folic acid deficiency (<4 ng/mL)	Hyperhomocysteinemia (>12.7 μM)
AG+RAS/BD patients (n = 30)	13 (43.3)	10 (33.3)	4 (13.3)	2 (6.7)	6 (20.0)
aP-value	<0.001	<0.001	<0.001	0.044	0.007
bP-value	0.058	0.990	0.046	>0.999	0.289
AG־RAS/BD patients (n = 33)	6 (18.2)	12 (36.4)	0 (0.0)	2 (6.1)	3 (9.1)
aP-value	<0.001	<0.001	ND	0.057	0.453
Healthy control subjects (n = 126)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	5 (4.0)

ND = not done.

a

Comparisons of frequencies of parameters between 30 AG+RAS/BD or 33 AG־RAS/BD patients and 126 healthy control subjects by chi-square test.

b

Comparisons of frequencies of parameters between 30 AG+RAS/BD and 33 AG־RAS/BD patients by chi-square test or Fisher exact test, where appropriate.

Nineteen BD patients (including 13 AG+RAS/BD and 6 AG־RAS/BD patients) had anemia (defined as having an Hb concentration < 13 g/dL for men and <12 g/dL for women).40 Of 13 anemic AG+RAS/BD patients, one had pernicious anemia (define as having anemia, a mean corpuscular volume (MCV) ≧ 100 fL, a serum vitamin B12 level < 200 pg/mL, and the presence of serum GPCA positivity),21, 22 one had macrocytic anemia (define as having anemia and an MCV ≧ 100 fL),23 7 had normocytic anemia (define as having anemia and an MCV between 80 fL and 99.9 fL),18, 19, 20 3 had iron deficiency anemia (defined as having anemia, an MCV ≦ 80 fL, and a serum iron level < 60 μg/dL),43 and one had thalassemia trait-induced anemia (defined as having anemia, a RBC count > 5.0 M/μL, an MCV < 74 fL, and a Mentzer index (MCV/RBC) < 13).44 Moreover, of 6 anemic AG־RAS/BD patients, 5 had normocytic anemia and one had iron deficiency anemia (Table 3). These findings suggest that by strict WHO criteria the normocytic anemia was the most common type of anemia in both 30 AG+RAS/BD and 33 AG־RAS/BD patients.

Table 3. Anemia types of 19 anemic Behcet's disease (BD) patients including 13 atrophic glossitis (AG)-positive recurrent aphthous stomatitis (RAS)/BD (AG+RAS/BD) and 6 AG-negative RAS/BD (AG־RAS/BD) patients.

Anemia type	Patient number (%)
	Patient number (%)	Mean corpuscular volume	Vitamin B12 deficiency (<200 pg/mL)	Iron deficiency (<60 μg/dL)	Folic acid deficiency (<4 ng/mL)
AG+RAS/BD patients (n = 13)
Pernicious anemia	1 (5.3)	≧ 100 fL	1 (100.0)	1 (100.0)	0 (0.0)
Macrocytic anemia	1 (5.3)	≧ 100 fL	0 (0.0)	0 (0.0)	0 (0.0)
Normocytic anemia	7 (36.8)	80–99.9 fL	1 (14.3)	3 (42.9)	1 (14.3)
Iron deficiency anemia	3 (15.8)	<80 fL	0 (0.0)	3 (100.0)	1 (33.3)
Thalassemia trait-induced anemia	1 (5.3)	<74 fL	0 (0.0)	0 (0.0)	0 (0.0)
AG־RAS/BD patients (n = 6)
Normocytic anemia	5 (26.3)	80–99.9 fL	0 (0.0)	5 (100.0)	0 (0.0)
Iron deficiency anemia	1 (5.3)	<80 fL	0 (0.0)	1 (100.0)	0 (0.0)
Total	19 (100.0)		2 (10.5)	13 (68.4)	2 (10.5)

Discussion

Our previous study found that 22.2%, 26.7%, 7.4%, 1.7%, and 21.6% of 176 AG patients had Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively. The 176 AG patients had significantly higher frequencies of Hb, iron, and vitamin B12 deficiencies and hyperhomocysteinemia than 176 healthy control subjects.3 Our previous study also discovered that 43.1%, 35.6%, 11.9%, 2.5%, and 15.0% of 160 AG+/RAS patients and 19.5%, 20.0%, 6.7%, 4.1%, and 8.2% of 195 AG־/RAS patients had Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively.18 Both 160 AG+/RAS and 195 AG־/RAS patients had significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia than 355 healthy control subjects. However, the 160 AG+/RAS had significantly higher frequencies of Hb and iron deficiencies than 195 AG־/RAS patients.18 This study showed that 43.3%, 33.3%, 13.3%, 6.7%, and 20.0% of 30 AG+RAS/BD patients and 18.2%, 36.4%, 0%, 6.1%, and 9.1% of 33 AG־RAS/BD patients had Hb, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively. Moreover, 30 AG+RAS/BD patients had significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than healthy control subjects. In addition, the 33 AG־RAS/BD patients had significantly higher frequencies of Hb and iron deficiencies than healthy control subjects. The 30 AG+RAS/BD patients had a marginally and significantly higher frequency of Hb deficiency and a significantly higher frequency of vitamin B12 deficiency than 33 AG־RAS/BD patients. The aforementioned findings indicate that AG+RAS/BD and AG־RAS/BD patients had similar anemia, hematinic deficiencies, and hyperhomocysteinemia patterns to AG+/RAS and AG־/RAS patients, respectively.18 In general, AG+RAS/BD and AG+/RAS patients tend to have higher frequencies of Hb and vitamin B12 deficiencies and of hyperhomocysteinemia than AG־RAS/BD and AG־/RAS patients, although the differences may or my not reach the significant level.18 In other words, if RAS or BD patients have concomitant AG, they are prone to have Hb and vitamin B12 deficiencies and of hyperhomocysteinemia.18 Reversely speaking, the results of our previous and present studies suggest that Hb, iron, vitamin B12 and folic acid deficiencies are at least some of the possible etiological factors for AG in our AG+/RAS and AG+RAS/BD patients.3, 18

BD is a chronic, multisystemic, and inflammatory disorder commonly complicated by vasculitis and vascular thrombosis.4, 5, 6, 7, 8, 9, 10, 11, 12 Homocysteine is an independent risk factor for venous and arterial thrombosis.6, 12 Therefore, the serum or plasma homocysteine level, the preval‎ence of hyperhomocysteinemia, and the association of hyperhomocysteinemia with thrombosis or ocular lesions have been more extensively studied in BD patients. In summary, these previous studies found that active, thrombotic, or ocular BD patients do have a significantly higher serum homocysteine level and a significantly higher frequency of hyperhomocysteinemia than healthy control subjects and than inactive, non-thrombotic, or non-ocular BD patients, respectively.4, 5, 6, 7, 8, 9, 10, 11, 12 However, RAS patients do not have a significantly higher mean serum homocysteine level than healthy control subjects.10 Our previous study also showed no significant difference in the mean serum homocysteine level between 273 RAS patients and 273 healthy control subjects.13 On the contrary, our 273 RAS patients do have a significantly higher frequency of hyperhomocysteinemia than 273 healthy control subjects.13 La Regina et al.12 did a meta-analysis study of the serum homocysteine levels in a total of 979 BD patients and found that hyperhomocysteinemia is more preval‎ent in thrombotic BD patients than in non-thrombotic BD patients. Moreover, the mean serum homocysteine levels are significantly higher in thrombotic BD patients than in non-thrombotic BD patients.12 In this study, we found that AG+RAS/BD patients rather than AG־RAS/BD patients had a significantly higher mean serum homocysteine level than healthy control subjects. Moreover, AG+RAS/BD patients rather than AG־RAS/BD patients had a significantly higher frequency of hyperhomocysteinemia than healthy control subjects. The above-mentioned findings indicate that anemia and hematinic (especially, vitamin B12 and folic acid) deficiencies may be the important factor that cause AG,3, 18 and in turn result in hyperhomocyteinemia in a portion of AG+/RAS and AG+RAS/BD patients.18 Moreover, the elevated serum homocysteine may subsequently cause active, thrombotic and/or ocular diseases in BD patients.4, 5, 6, 7, 8, 9, 10, 11, 12

Shadmanfar et al.45 found no significant differences in either the mean plasma homocysteine level or the preval‎ence of hyperhomocysteinemia between HLA-B51-positive BD patients and HLA-B51-negative BD patients or healthy control subjects. These findings indicate no significant association of plasma homocysteine level with HLA-B51 in both BD patients and healthy control subjects.45

Hematinic (iron, vitamin B12 and folic acid) deficiencies are less commonly studied in BD patients. Yesilova et al.4 showed that the plasma vitamin B12 and folate levels are significantly lower, while the plasma total homocysteine concentrations are significantly higher in BD patients with thrombosis and eye involvement than in those without thrombosis and eye involvement. They concluded that the accelerated catabolism of folate and vitamin B12 due to chronic inflammation and the moderately increased total homocysteine levels associated with deficiencies of these cofactors and administration of immunosuppressive drug may be potential risk factors for vascular diseases in BD.4

Homocysteine is formed during methionine metabolism.46 Both vitamin B12 and folic acid function as coenzymes for the conversion of homocysteine to methionine.47 The abnormally high serum homocysteine level has been shown to cause oxidative stress, endothelial cell damage, and vascular thrombosis in experimental studies. Thus, hyperhomocysteinemia is associated with increased rates of coronary heart disease and stroke.14, 46, 48 A previous study has shown that a supplementation with folic acid and vitamins B12 and B6 can reduce blood homocysteine levels.14 Our previous studies also demonstrated that supplementations with vitamin BC capsules plus corresponding deficient vitamin B12 and/or folic acid can reduce the abnormally high serum homocysteine level to significantly lower levels in patients with either atrophic glossitis or burning mouth syndrome.15, 16 Therefore, we suggest that AG+RAS/BD and AG־RAS/BD patients with hyperhomocysteinemia, supplementations of vitamin BC capsules plus deficient hematinics (especially, vitamin B12, and folic acid) may lower the serum homocysteine level to a relatively lower level and further improve or prevent the vascular thrombotic diseases in these BD patients.

The present study found that 30 AG+RAS/BD patients had significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than healthy control subjects, and had a marginally and significantly higher frequency of Hb deficiency and a significantly higher frequency of vitamin B12 deficiency than 33 AG־RAS/BD patients. The normocytic anemia is the most common types of anemia in both 30 AG+RAS/BD and 33 AG־RAS/BD patients. We conclude that AG+RAS/BD patients do have significantly higher frequencies of Hb, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than healthy control subjects and have significantly higher frequencies of Hb and vitamin B12 deficiencies than AG־RAS/BD patients. In addition, we suggest that supplementations of vitamin BC capsules plus deficient hematinics (especially, vitamin B12 and folic acid) may reduce the high serum homocysteine level to a relatively lower level in AG+RAS/BD and AG־RAS/BD patients with hyperhomocysteinemia14, 15, 16 and may be beneficial to those BD patients with active disease, thrombosis, or ocular involvement.4, 5, 6, 7, 8, 9, 10, 11, 12

Conflicts of interest

The authors have no conflicts of interest.

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