Japanese Systemic Lupus Erythematosus Patients Research Articles

Unveiling the dynamics of B lymphocytes in systemic lupus erythematosus patients treated with belimumab through longitudinal single-cell RNA sequencing.

Unraveling the mechanisms underlying treatment response for targeted therapeutics in systemic lupus erythematosus (SLE) patients is challenging due to the limited understanding of diverse responses of circulating immune cells, particularly B cells. We investigated B lymphocyte dynamics during anti-BAFF treatment, utilizing longitudinal single-cell transcriptome data. We conducted single-cell RNA sequencing on PBMCs in four Korean SLE patients before and after belimumab treatment at the following time points: 2 weeks, 1, 3, 6, and 12 months. Analyzing over 73 000 PBMCs, we identified 8 distinct subsets of B cells and plasmablasts and analyzed dynamic changes within these cell subsets: initial declines in naive and transitional B cells followed by an increase at three months, contrasted by an initial increase and subsequent decrease in memory B cells by the third month. Meanwhile, plasmablasts exhibited a consistent decline throughout treatment. B cell activation pathways, specifically in naive and memory B cells, were downregulated during the third and sixth months. These findings were validated at the protein level throughout the first four weeks of treatment using flow cytometry. Comparative analysis with bulk transcriptome data from 22 Japanese SLE patients showed increased NR4A1 expression six months post-belimumab treatment, indicating its role in restricting self-reactive B cells, thereby contributing to the biological responses of anti-BAFF treatment. The observed B cell dynamics provided insights into the immunological mechanisms underlying the therapeutic effects of anti-BAFF in SLE patients. Furthermore, it underscores the need for research in predicting drug responses based on immune profiling.

Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01

ObjectiveMajor histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for...

Trust in the attending rheumatologist, health-related hope and medication adherence among Japanese systemic lupus erythematosus patients.

Poor medication adherence among patients with SLE is a critical problem associated with adverse outcomes. This study examined the relationship between trust in one's physician and goal-oriented thinking, hope and medication adherence among Japanese patients with SLE who were ethnically matched to their physicians. This cross-sectional study was conducted in the rheumatology outpatient clinics at five academic centres. Patients with SLE who were prescribed oral medications were included. The main exposures were trust in one's physician measured via the 5-item Japanese version of the Wake Forest Physician Trust Scale and the 18-item Health-related Hope Scale, with each score ranging from 0 to 100 points. Medication adherence was measured using the 12-item Medication Adherence Scale with scores ranging from 5 to 60 points. A general linear model was created after adjusting for demographics, socioeconomic status, disease activity, disease duration, basic health literacy, depression, medication variables, experiencing adverse effects and concerns regarding lupus medications. Altogether, 373 patients with SLE were included. The mean age of the patients was 46.4 years; among them, 329 (88.2%) were women. Both trust in one's physician (per 10-point increase: 0.86, 95% CI 0.49, 1.22) and the Health-related Hope score (per 10-point increase: 0.66, 95% CI 0.35, 0.97) were associated with better medication adherence. This study demonstrated that patients' health-related hope and trust in their rheumatologist were both associated with better medication adherence in SLE.

Pharmacokinetics of hydroxychloroquine in Japanese systemic lupus erythematosus patients with renal impairment.

Reduction of the hydroxychloroquine (HCQ) dosage is recommended in systemic lupus erythematosus (SLE) patients with renal impairment, but a pharmacokinetics (PK) study of patients with renal impairment has not yet been performed. We investigated the PK of both single and multiple doses of HCQ and its metabolites in SLE patients with renal impairment who newly started HCQ at a daily dose of 300 mg based on an ideal body weight dosage of 6.5 mg/kg. Population PK analysis was performed using a non-linear mixed-effects model. In total, 219 samples from 21 patients were analysed. The PK of HCQ in blood after single and multiple oral administrations followed the two-compartment model. At steady state, the concentration ratio of HCQ to each metabolite was HCQ:desethylhydroxychloroquine:desethylchloroquine:bisdesethylchloroquine = 1:0.28:0.1:0.06. The HCQ concentration correlated positively with that of each metabolite. The estimated values (relative standard error) of the population PK parameters were the total clearance at 110 l/h (31%) and a central volume of distribution of 398 l (19%). Co-administration of prednisolone and age, but not renal impairment, were factors affecting the total clearance of HCQ. From the PK perspective, a dosage reduction is unnecessary in SLE patients with impaired renal function.

Comparisons between US norm-based two-component and Japanese norm-based three-component SF-36 summary scores in systemic lupus erythematosus patients.

We compared the US norm-based two-component vs. Japanese norm-based three-component summary scores of the Medical Outcomes Study Short Form-36 (SF-36) in patients with systemic lupus erythematosus (SLE). One hundred fourteen Japanese SLE patients were studied. SF-36 physical component summary (PCS) and mental component summary (MCS) scores were computed by the US norm-based two-component (US2) and Japanese norm-based three-component (JP3) models, respectively, and compared. Their association with demographics and disease characteristics was also analysed. The US2-PCS scores were significantly higher than the JP3-PCS scores (p < .001); however, the US2-MCS and JP3-MCS scores were not significantly different (p = .16). Bland-Altman analyses demonstrated that the US2-PCS scores were generally higher than the JP3-PCS scores, and their difference was larger in the subjects with lower PCS scores. However, the multiple linear regression analyses for the PCS and MCS scores computed by the different models demonstrated mostly equivalent standardized regression coefficients with the variables. Although the agreement between the US norm-based two-component and Japanese norm-based three-component models of the SF-36 was insufficient, their scores demonstrated similar associations with other variables. The application of the US original version could be acceptable in certain studies depending on the research question.

Risk of adverse pregnancy outcomes in Japanese systemic lupus erythematosus patients with prior severe organ manifestations: A single-center retrospective analysis.

Systemic lupus erythematosus (SLE) increases the incidence of adverse pregnancy outcomes (APOs). Nevertheless, most of the data on SLE pregnancies were derived from database studies in which details of the pregnancies were unavailable, and no consensus exists on the risk of APO in patients with prior severe organ manifestations. SLE patients followed by rheumatologists and gynecologists throughout pregnancy at our institute were retrospectively identified, and their data between April 2003 and December 2020 were reviewed from electronic records. We assigned patients based on the presence of prior severe organ manifestation (renal/neurological manifestation, prior treatment with methylprednisolone pulse therapy/prednisolone 1 mg/kg/day/biological or cytotoxic therapy) and compared the incidence of overall and serious APO (maternal death, pregnancy loss, preterm birth <32 weeks, birthweight <1500 g, Apgar score <7 at 5 min and birth defect). This study included 34 pregnancies in 32 patients; 23 pregnancies in 22 patients were classified as SLE with prior severe organ manifestation. There was no statistical difference in the incidence of overall APO between the two groups (52.2% vs 45.5%, P = 1). Among patients with prior severe organ manifestation, 17.4% had serious APO. A detailed electronic health record search revealed specific causes of APO in all pregnancies with serious APO, except the presence of prior severe organ manifestation. The incidence of overall APO in SLE patients was not affected by prior severe organ manifestation. Although the incidence of serious APOs increased in patients with previous severe organ manifestation, there were other risk factors for poor pregnancy outcomes besides prior lupus severity. Therefore, proper management by rheumatologists and gynecologists may enable patients with prior severe organ manifestation to safely deliver healthy babies.

Efficacy and Safety of Hydroxychloroquine Therapy for Systemic Lupus Erythematosus Patients Depend on Administration Dose.

Objective Hydroxychloroquine (HCQ) has been prescribed in Japan only relatively recently and is recommended for the treatment of skin lesions, arthritis and renal lesions according to the Japanese Guideline for the Management of systemic lupus erythematosus (SLE) (2019). However, the associations between the efficacy and safety and the HCQ dose in Japanese SLE patients remain unclear. We investigated the efficacy and safety of different HCQ doses in Japanese SLE patients with a low disease activity who were not receiving immunosuppressants. Methods The disease activity was evaluated using the SELENA-SLEDAI 2011 criteria, the Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) and serum biomarkers. Safety was evaluated via the frequency of adverse events over a period of three months. Results We enrolled 61 SLE patients treated with HCQ and no additional immunosuppressive therapy for more than 3 months. HCQ was administered to 46 patients at the usual dose and to 15 cases at a lower than usual dose. Although the CLASI activity scores decreased significantly in both groups, the magnitude of this decrease was larger in the usual-dose HCQ group than in the low-dose HCQ group. SLEDAI scores and immunological activity were significantly improved only in the usual-dose HCQ group. In addition, changes in the serum complement levels in the usual-dose HCQ group were more dramatic than in the low-dose HCQ group six months after the initiation of HCQ administration. Adverse events were more frequent in the usual-dose HCQ group than in the low-dose HCQ group (30.4% and 13.3%, respectively). Conclusion HCQ therapy is effective for maintenance therapy of SLE patients. The usual dose of HCQ may have some advantage in ameliorating low complement levels.

Low additive effect of hydroxychloroquine on Japanese patients with systemic lupus erythematosus taking calcineurin inhibitor.

To assess for any additive value of hydroxychloroquine (HCQ) in Japanese patients with systemic lupus erythematosus (SLE) depending on calcineurin inhibitors (CNIs). We retrospectively evaluated patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20mg/d and one immunosuppressant (IS). Patients were divided into two groups depending on HCQ use and the groups were compared for changes in SLE Disease Activity Index (SLEDAI), prednisolone (PSL) dose, and cumulative flare rate between patients who were treated and not treated with CNI. Among the 103 patients evaluated, 19 (18.4%) were treated with HCQ. On analysis of all patients, SLEDAI, PSL doses, and cumulative flare rate were significantly reduced in patients who received HCQ compared to those who did not (P=0.04, P=0.01, and P=0.03, respectively). Regarding IS use, we found less additive therapeutic effect in CNI users than in users of other ISs in terms of reduction in SLEDAI and PSL dose (P=0.05 and P<0.01, respectively). The addition of HCQ reduced disease activity, PSL dose, and flares in Japanese SLE patients but conferred less additive clinical efficacy when added to CNIs.

Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment.

Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT*3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT*3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85±0.30 mg/kg/day vs. 1.2±0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA.

Efficacy and safety of tabalumab plus standard of care in Japanese patients with active systemic lupus erythematosus: Subgroup analyses of the ILLUMINATE-1 study

Objective: To assess the efficacy and safety of tabalumab, an anti-B cell activating factor (BAFF) antibody, in combination with standard of care (SoC) therapy in Japanese patients with active systemic lupus erythematosus (SLE).Methods: A subgroup analysis was conducted in Japanese patients (n = 45) enrolled in ILLUMINATE-1, a phase III global trial in SLE patients (N = 1164). Patients received SoC plus tabalumab or placebo, starting with a loading dose (240 mg) at week 0, followed by 120 mg every 4 weeks (120 Q4W, n = 15), 120 mg every 2 weeks (120 Q2W, n = 15), or placebo Q2W (n = 15). The primary endpoint was proportion achieving SLE Responder Index-5 (SRI-5) improvement at week 52.Results: A numerically greater SRI-5 response rate was achieved with 120 Q2W (46.7%; p = 0.059 vs. placebo) compared with 120 Q4W (20.0%) and placebo Q2W (13.3%). The proportion of patients with severe SLE flare was lower for 120 Q2W (0%) and 120 Q4W (6.7%) than for placebo (26.7%). The rates of serious adverse events (AEs) and treatment-emergent AEs were similar across treatments.Conclusion: In Japanese SLE patients, tabalumab 120 Q2W improved SRI-5 response rate and reduced the frequency of severe flares compared with placebo. Safety profiles were similar with tabalumab and placebo.

Validation of the Japanese version of the Systemic Lupus Activity Questionnaire that includes physician-based assessments in a large observational cohort.

The Systemic Lupus Activity Questionnaire (SLAQ) is a patient-reported outcome for systemic lupus erythematosus (SLE). We aimed to translate it into Japanese and further investigate its validity and reliability. The English version of the SLAQ was translated into Japanese and administered to Japanese SLE patients at our university clinic. Physicians assessed disease activity using the SLE Disease Activity Index 2000 (SLEDAI-2K). The patients were prospectively followed for repeat assessment a year later. Ultimately, 255 patients participated. The patients' 10-point ratings of disease activity and SLAQ scores were significantly correlated (Spearman's ρ = 0.53). The SLAQ score was weakly correlated with the SLE Disease Activity Index 2000 (SLEDAI-2K)-nolab (omitting laboratory items; ρ = 0.18) but not with the SLEDAI-2K (ρ = 0.02). These results suggested its convergent and discriminant validity. The SLAQ demonstrated acceptable internal consistency (Cronbach's α = 0.80), and good test-retest reliability (intraclass correlation coefficient = 0.85). The effect sizes and the standardized response means of the SLAQ were as follows: clinical worsening, 0.26 and 0.31, and improvement, -0.39 and -0.41, respectively, which indicated a small but significant responsiveness. The Japanese version of the SLAQ demonstrated acceptable reliability and validity; its performance was comparable to that of the original version.

Human Leukocyte Antigens and Systemic Lupus Erythematosus: A Protective Role for the HLA-DR6 Alleles DRB1*13:02 and *14:03

Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10−10, corrected P (Pc) = 1.59×10−8, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69–2.79), decreased DRB1*13:02 (P = 7.17×10−5, Pc = 0.0020, OR 0.46, 95% CI 0.34–0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18–0.63). Additionally, the “*15:01/*13:02 or *14:03” genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10−11, OR 2.39, 95% CI 1.84–3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population.

Prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus

Objective We examined the prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus (SLE).Methods We performed lateral radiographs of the thoracic and lumbar spine and bone mineral density (BMD) measurements and collected demographic, lifestyle, clinical, and treatment characteristics of 52 SLE patients. Vertebral fractures were defined as a >20 % reduction of vertebral body height. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were computed to assess the strength of associations between vertebral fractures and selected factors among SLE patients.Results At least one vertebral fracture was detected in 50 % of SLE patients. A history of previous bone fracture was significantly associated with an increased risk of vertebral fractures among SLE patients (adjusted OR = 14.8, 95 % CI = 1.62–134; P = 0.017). Daily use of tea or coffee was marginally associated with a decreased risk of vertebral fractures among SLE patients (adjusted OR = 0.11, 95 % CI = 0.01–1.01; P = 0.051).Conclusion The high prevalence of vertebral fracture in SLE patients (50 %) indicates that we need to assess the lateral spine radiograph in more female Japanese SLE patients regardless of BMD and use of corticosteroids, although additional studies are warranted to confirm the findings suggested in this study.

Association of Increased Frequencies of HLA-DPB1*05∶01 with the Presence of Anti-Ro/SS-A and Anti-La/SS-B Antibodies in Japanese Rheumatoid Arthritis and Systemic Lupus Erythematosus Patients

IntroductionAutoantibodies to ribonucleoprotein are associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA). Many studies on associations between human leukocyte antigen (HLA) alleles and RA have been reported, but few have been validated in RA subpopulations with anti-La/SS-B or anti-Ro/SS-A antibodies. Here, we investigated associations of HLA class II alleles with the presence of anti-Ro/SS-A or anti-La/SS-B antibodies in RA.MethodsAn association study was conducted for HLA-DRB1, DQB1, and DPB1 in Japanese RA and systemic lupus erythematosus (SLE) patients that were positive or negative for anti-Ro/SS-A and/or anti-La/SS-B antibodies.ResultsAn increased prevalence of certain class II alleles was associated with the presence of anti-Ro/SS-A antibodies as follows: DRB1*08∶03 (Pc = 3.79×10−5, odds ratio [OR] 3.06, 95% confidence interval [CI] 1.98–4.73), DQB1*06∶01 (Pc = 0.0106, OR 1.70, 95%CI 1.26–2.31), and DPB1*05∶01 (Pc = 0.0040, OR 1.55, 95%CI 1.23–1.96). On the other hand, DRB1*15∶01 (Pc = 0.0470, OR 3.14, 95%CI 1.63–6.05), DQB1*06∶02 (Pc = 0.0252, OR 3.14, 95%CI 1.63–6.05), and DPB1*05∶01 (Pc = 0.0069, OR 2.27, 95% CI 1.44–3.57) were associated with anti-La/SS-B antibodies. The DPB1*05∶01 allele was associated with anti-Ro/SS-A (Pc = 0.0408, OR 1.69, 95% CI 1.19–2.41) and anti-La/SS-B antibodies (Pc = 2.48×10−5, OR 3.31, 95%CI 2.02–5.43) in SLE patients.Conclusion HLA-DPB1*05∶01 was the only allele associated with the presence of both anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese RA and SLE patients.

Prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus

We examined the prevalence and risk factors of vertebral fracture in female Japanese patients with systemic lupus erythematosus (SLE). We performed lateral radiographs of the thoracic and lumbar spine and bone mineral density (BMD) measurements and collected demographic, lifestyle, clinical, and treatment characteristics of 52 SLE patients. Vertebral fractures were defined as a >20% reduction of vertebral body height. Odds ratios (ORs) and their 95% confidence intervals (CIs) were computed to assess the strength of associations between vertebral fractures and selected factors among SLE patients. At least one vertebral fracture was detected in 50% of SLE patients. A history of previous bone fracture was significantly associated with an increased risk of vertebral fractures among SLE patients (adjusted OR = 14.8, 95% CI = 1.62-134; P = 0.017). Daily use of tea or coffee was marginally associated with a decreased risk of vertebral fractures among SLE patients (adjusted OR = 0.11, 95% CI = 0.01-1.01; P = 0.051). The high prevalence of vertebral fracture in SLE patients (50%) indicates that we need to assess the lateral spine radiograph in more female Japanese SLE patients regardless of BMD and use of corticosteroids, although additional studies are warranted to confirm the findings suggested in this study.

Association ofTNFAIP3Polymorphism with Susceptibility to Systemic Lupus Erythematosus in a Japanese Population

Recent genome-wide association studies demonstrated association of single nucleotide polymorphisms (SNPs) in the TNFAIP3 region at 6q23 with systemic lupus erythematosus (SLE) in European-American populations. In this study, we investigated whether SNPs in the TNFAIP3 region are associated with SLE also in a Japanese population. A case-control association study was performed on the SNPs rs13192841, rs2230926, and rs6922466 in 318 Japanese SLE patients and 444 healthy controls. Association of rs2230926 G allele with SLE was replicated in Japanese (allelic association P = .033, odds ratio [OR] 1.47, recessive model P = .023, OR 8.52). The association was preferentially observed in the SLE patients with nephritis. When the TNFAIP3 mRNA levels of the HapMap samples were examined using GENEVAR database, the presence of TNFAIP3 rs2230926 G allele was associated with lower mRNA expression of TNFAIP3 (P = .013). These results indicated that TNFAIP3 is a susceptibility gene to SLE both in the Caucasian and Asian populations.

Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study

IntroductionTNFAIP3 interacting protein 1, TNIP1 (ABIN-1) is involved in inhibition of nuclear factor-κB (NF-κB) activation by interacting with TNF alpha-induced protein 3, A20 (TNFAIP3), an established susceptibility gene to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recent genome-wide association studies revealed association of TNIP1 with SLE in the Caucasian and Chinese populations. In this study, we investigated whether the association of TNIP1 with SLE was replicated in a Japanese population. In addition, association of TNIP1 with RA was also examined.MethodsA case-control association study was conducted on the TNIP1 single nucleotide polymorphism (SNP) rs7708392 in 364 Japanese SLE patients, 553 RA patients and 513 healthy controls.ResultsAssociation of TNIP1 rs7708392C was replicated in Japanese SLE (allele frequency in SLE: 76.5%, control: 69.9%, P = 0.0022, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.13-1.74). Notably, the risk allele frequency in the healthy controls was considerably greater in Japanese (69.9%) than in Caucasians (24.3%). A tendency of stronger association was observed in the SLE patients with renal disorder (P = 0.00065, OR 1.60 [95%CI 1.22-2.10]) than in all SLE patients (P = 0.0022, OR 1.40 [95%CI 1.13-1.74]). Significant association with RA was not observed, regardless of the carriage of human leukocyte antigen DR β1 (HLA-DRB1) shared epitope. Significant gene-gene interaction between TNIP1 and TNFAIP3 was detected neither in SLE nor RA.ConclusionsAssociation of TNIP1 with SLE was confirmed in a Japanese population. TNIP1 is a shared SLE susceptibility gene in the Caucasian and Asian populations, but the genetic contribution appeared to be greater in the Japanese and Chinese populations because of the higher risk allele frequency. Taken together with the association of TNFAIP3, these observations underscore the crucial role of NF-κB regulation in the pathogenesis of SLE.

Race Differences in Immunogenetic Features and Photosensitivity of Cutaneous Lupus Erythematosus from the Aspect of Japanese Studies

Skin lesions of collagen diseases are influenced by environmental triggers, such as UV light, and are variable in cutaneous lupus erythematosus (LE), such as systemic LE (SLE), chronic discoid LE (CDLE), subacute cutaneous LE (SCLE), and LE tumidus (LET). Although there are a few conflicting reports on photosensitivity in collagen diseases, many Japanese dermatologists feel there are photosensitivity differences in LE between Asians and Caucasians with SCLE and LET. To address this issue, we have carried out genetic studies of Japanese SLE and CDLE patients and reviewed the race differences in photosensitivity of cutaneous LE from Japanese studies. Human leukocyte antigen (HLA) studies in Japanese patients revealed that HLA-DRB1*1501 association was with CDLE and SLE. The association between HLA-Cw6 and CDLE was first reported in a Japanese population, and a HLA-A33-B44-DRB1*1302 haplotype showed a positive association in CDLE. However, these results are not compatible with those from Caucasian subjects. There are no significant associations among HLA studies, photosensitivity, and anti-Ro/SS-A antibodies in Japanese CLE patients. Photosensitivity will be a key factor to dissolve multifactorial complexes of LE etiopathogenesis. An axis of photosensitivity, anti-Ro/SS-A antibodies, and apoptosis via tumor necrosis factor-alpha is the best marker to verify the contribution of genetics in CLE patients. The incidence and degree of photosensitivity of SCLE and LET are much lower in Japanese than in Caucasians. This discrepancy may lead to investigations of CLE pathogenesis through global collaborations.

Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case–control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.

Subarachnoid hemorrhage in systemic lupus erythematosus in Japan: two case reports and a review of the literature

We report 51- and 43-year-old Japanese female patients with systemic lupus erythematosus (SLE) associated with subarachnoid hemorrhage (SAH) due to rupture of intracranial saccular aneurysms. We also review the literature of Japanese SLE patients with SAH. SAH in Japanese SLE patients is more frequent than in patients from Western countries, has different features from the general population, and can occur regardless of SLE disease activity. Clinicians must pay attention to SAH in all SLE patients.