Asian countries account for almost three quarter of hepatocellular carcinoma (HCC) reported globally and chronic hepatitis B infection is one of the main contributors. Clinical observations show that Malay patients with chronic hepatitis B and HCC tend to have a worse outcome, when compared to other two major races in Malaysia. The objectives of this study was to determine the frequency of human leukocyte antigen (HLA) class II alleles in chronic hepatitis B patients with HCC among Malays compared to the general population to identify potential associations of HLA alleles with this disease. HLA class II typing was performed in chronic hepatitis B patients with hepatocellular carcinoma (n=12) by -polymerase chain reaction, sequence specific primer (PCR-SSP) method. There were higher allelic frequencies of certain HLA-DQB1 and HLA-DRB1 alleles; HLA-DQB1*03 (07) (41.7%), and HLA-DRB1*12 (41.7% vs 28.6%) and compared to controls (41.7% vs 29.7%). However, there was no significant statistical correlation found when compared with the normal healthy general population. This study provides an insight into the HLA Class II association with chronic hepatitis B and hepatocellular carcinoma in Malays. However, findings from this study should be validated with a larger number of samples using a high resolution HLA typing.
This is the first report of high-resolution human leukocyte antigen (HLA) typing in four indigenous groups in Malaysia. A total of 99 normal, healthy participants representing the Negrito (Jehai and Kensiu), Proto-Malay (Temuan) and a native group of Borneo (Bidayuh) were typed for HLA-A, -B, -DRB1 and -DQB1 genes using sequence-based typing. Eleven HLA-A, 26 HLA-B, 16 HLA-DRB1 and 14 HLA-DQB1 alleles were detected, including a new allele, HLA-B*3589 in the Jehai. Highly frequent alleles were A*2407, B*1513, B*1801, DRB1*0901, DRB1*1202, DRB1*1502, DQB1*0303 and DQB1*0502. Principal component analysis based on high-resolution HLA-A, -B and -DRB1 allele frequencies showed close affinities among all four groups, including the Negritos, with other Southeast Asian populations. These results showed the scope of HLA diversity in these indigenous minority groups and may prove beneficial for future disease association, anthropological and forensic studies.
One hundred and fifty-eight Kadazan, Iban and Bidayuh individuals registered with the Malaysian Marrow Donor Registry were typed for human leukocyte antigen (HLA)-A, HLA-B and HLA-DR. Six, seven and eight HLA-A alleles as well as 13, 15 and 16 HLA-B alleles were detected in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-A allele in all three groups was HLA-A*24 with a frequency of 0.456, 0.490 and 0.422 in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-B allele detected in the Kadazan was HLA-B*40 with a frequency of 0.333; for the Bidayuh and the Iban it was HLA-B*15 with a frequency of 0.460 and 0.275, respectively. The HLA-DR allele with the highest frequency in the Kadazan was HLA-DR*1502 with a frequency of 0.500. In the Iban and the Bidayuh, HLA-DRB1*1202 was the most common DR allele with frequencies of 0.235 and 0.310, respectively. The two most common haplotypes for the Kadazan are A*34-B*38-DR*1502 and A*24-B*40-DR*0405, whereas for the Bidayuh they are A*24-B*15-DR*1602 and A*24-B*35-DR*1202 and for the Iban they are A*34-*B15-DR*1502 and A*24-B*15-DR*1202.
HLA-DQA1, -DQB1, and -DRB1 gene polymorphism were analyzed to study type 1 DM susceptibility in Malay patients from Southeast Asia (Malaysia and Singapore). Patients showed significant increases in the occurrence of DQA1*0501 (50.7% vs. 20.4%; RR = 3.97; Pc < 0.01), DQB1*0201 (48% vs. 19.1%; RR = 3.86; Pc < 0.05), and DRB1*0301 (38.7 vs. 6.8%; RR = 8.36; 95% Pc < 0.05). Conversely, significant decreases were noted in the occurrence of DQA1*0601 (14.7% vs. 35.2%; RR = 0.33; Pc = 0.008) and DQB1*0601 (4% vs. 23.5%; RR = 0.16; Pc < 0.05) in type 1 DM patients. Using a logistic regression model, we derived a risk prediction model for type 1 DM in our indigenous Malay population based on the identified HLA genotypes. The RR for type 1 DM increases by a factor of 5.68 for every unit increase in the number of DRB1*0301 allele (P < 0.001), and decreases by a factor of 0.18 per unit increase in the number of DQB1*0601 allele (P < 0.001). After adjusting for these two HLA genotypes, DQA1*0501, DQB1*0201 and DQA1*0601 were not statistically significant as risk predictors. The lower incidence of type 1 DM in the Malay population may be contributed by the genotypic combinations of DR and DQ genes as well as the linkage disequilibria between susceptible and protective alleles.
Soluble HLA (sHLA) are potential tumour markers released in order to counter immune surveillance. sHLA-class II is less known especially in acute lymphoblastic leukaemia (ALL). This study aimed to investigate soluble, surface and allelic expression of HLA Class II (sHLA-DR) in B-cell ALL patients and compare with soluble expression in normal individuals. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to measure soluble HLA-DRB1 in plasma. Flow cytometric analysis was performed to determine median fluorescence intensity in HLA-DR surface expression. HLA-DNA typing by polymerase chain reaction, sequence specific oligonucleotides, PCRSSO was performed to determine HLA-DRB1 type in ALL samples. Results showed sHLA-DRB1 (mean±SEM) was significantly increased (p=0.001) in plasma of ALL patients (0.260 ±0.057 μg/mL; n=30) compared to healthy controls (0.051 ± 0.007µg/mL; n=31) of Malay ethnicity. However, these levels did not correlate with percentage or median fluorescence intensity of HLA-DR expressed on leukemia blasts (CD19+CD34 ± CD45(lo)HLA-DR+) or in the normal B cell population (CD19+CD34- CD45(hi)HLA-DR+) of patients. No significant difference was observed in gender (male/female) or age (paediatric/adult). Only a trend in reduced sHLA was observed in patients carrying HLA-DR04. These results have to be validated with a larger number of samples.
BACKGROUND: To investigate the associations between HLA-DRB1 shared epitope (SE) alleles and rheumatoid arthritis in subsets of rheumatoid arthritis defined by autoantibodies in three Asian populations from Malaysia.
METHODS: 1,079 rheumatoid arthritis patients and 1,470 healthy controls were included in the study. Levels of antibodies to citrullinated proteins (ACPA) and rheumatoid factors were assessed and the PCR-SSO method was used for HLA-DRB1 genotyping.
RESULTS: The proportion of ACPA positivity among Malay, Chinese and Indian rheumatoid arthritis patients were 62.9%, 65.2% and 68.6%, respectively. An increased frequency of SE alleles was observed in ACPA-positive rheumatoid arthritis among the three Asian ethnic groups. HLA-DRB1*10 was highly associated with rheumatoid arthritis susceptibility in these Asian populations. HLA-DRB1*0405 was significantly associated with susceptibility to rheumatoid arthritis in Malays and Chinese, but not in Indians. HLA-DRB1*01 did not show any independent effect as a risk factor for rheumatoid arthritis in this study and HLA-DRB1*1202 was protective in Malays and Chinese. There was no association between SE alleles and ACPA- negative rheumatoid arthritis in any of the three Asian ethnic groups.
CONCLUSION: The HLA-DRB1 SE alleles increase the risk of ACPA-positive rheumatoid arthritis in all three Asian populations from Malaysia.
Survivin is a biomarker of cancer known for its anti-apoptotic and cell-cycle regulating properties. In the context of non-cancer pathology, high levels of survivin may be measured in blood and synovial fluid of patients with rheumatoid arthritis (RA) and associate with early joint damage and poor therapy response. The aim of the study was to investigate the value of survivin measurements in blood for diagnosis of RA in the frame of the Malaysian epidemiological investigation of rheumatoid arthritis (MyEIRA) study. The study enrolled RA patients from eight rheumatology centres in Peninsular Malaysia. The healthy controls matched by age, gender and ethnicity were recruited on the community basis from the residential area of the patients. Levels of survivin were measured in blood of RA patients (n = 1233) and controls (n = 1566) by an enzyme-linked immuno-sorbent assay (ELISA). The risk for RA was calculated as odds ratio (OR) and 95% confidence intervals in the individuals with high levels of survivin. The risk was calculated in relation to antibodies against cyclic citrullinated peptides (ACPA), detected by ELISA and HLA-DRB1 shared epitope (SE) alleles, identified by the polymerase chain reaction using sequence specific oligonucleotide method. High levels of survivin were detected in 625 of 1233 (50.7%) RA cases and in 85 of 1566 (5.4%) controls, indicating its high specificity for RA. Survivin was association with an increase in RA risk in the patients having neither SE-alleles nor ACPA (OR = 5.40, 95% CI 3.81-7.66). For the patients combining survivin, SE, and ACPA, the estimated risk for RA was 16-folds higher compared to the survivin negative patients with SE and ACPA(OR = 16.21, 95% CI 5.70-46.18). To conclude, detection of survivin in blood provides a simple test to improve diagnostic and to increase predictability for RA.
Introduction: Human leukocyte antigens (HLA) are a group of unique transmembrane glycoproteins that are ex-pressed on the surface of virtually all types of cells within the human body. These molecules are encoded by a set of highly polymorphic gene sequences known also as the major histocompatibility complex (MHC) and play an essential role in the presentation of antigenic peptides to immune cells for recognition and response. In recent years, various HLA alleles have been found to be associated with different autoimmune and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and allergic rhinitis. Identification of these alleles via HLA typing is necessary for initial screening and diagnosis purposes. Besides that, HLA typing is also used to determine compatibility matching between a donor and a recipient for tissue/organ transplantations in order to prevent graft rejection. Therefore, good quality and quantity of genomic DNA is required. In most scenarios, peripheral blood is chosen as the most reliable source of DNA for analysis, however this approach is seen as invasive and may cause pain and anxiety among the patients, particularly young children and weak subjects. Hence, derivation of genomic DNA from buccal cells as an alternative source material is becoming increasingly popular, especially in PCR-based genetic assays. Some of the most commonly described methods to collect buccal cells include using oral swabs, cytological brushes, mouthwashes and treated cards. Each technique yields varying quantities of DNA with diverse purity levels. In this study, we aim to evaluate the amount and purity of genomic DNA extracted from buccal swabs and brushes as well as blood for screening of selected HLA class II alleles. Methods: Cheek cell samples were col-lected using sterile foam tipped buccal swabs (Whatman) and buccal collection brushes (Gentra Puregene) whereas peripheral blood samples were withdrawn following routine venipuncture techniques. All samples were subjected to DNA extraction according to modified commercial kit protocols. Screening of selected HLA-DRB1 alleles was con-ducted via PCR with sequence-specific primers as established by Bunce et al. 1995. Results: There was no significant difference (p > 0.05) in the total DNA yield obtained from blood and buccal swab samples, which were 17.57μg (± 8.66) and 13.28μg (± 4.81), respectively. All samples exhibited similar 260/280 ratios of about ~1.80 (p > 0.05). However, buccal brush samples contributed the least amount of DNA (0.29μg, ± 0.12) compared to other sources (p < 0.05). The pure genomic DNA isolated from both blood and buccal swab samples were successfully typed for low resolution HLA-DRB1 alleles. Conclusion: Buccal swabs provide good quantity and quality of DNA for screening of HLA alleles with high accuracy and thus can be utilized as a non-invasive substitute for venipuncture.
BACKGROUND: Human leukocyte antigen (HLA) antigens and genes have long been reported associated with systemic lupus erythematosus (SLE) susceptibility in many populations. With the advance in technologies such as genome-wide association studies, many newly discovered SLE-associated single-nucleotide polymorphisms (SNPs) have been reported in recent years. These include HLA-DRB1/HLA-DQA1 rs9271366 and HLA-DQB1/HLA-DQA2 rs9275328. Our aim was to investigate these SNPs in a Malaysian SLE cohort.
MATERIALS AND METHODS: SNPs rs9271366 and rs9275328 were screened across 790 Malaysian citizens from three ethnic groups (360 patients and 430 healthy volunteers) by Taqman SNP genotyping assays. Allele and genotyping frequencies, Hardy-Weinberg equilibrium, Fisher's exact test and odds ratio were calculated for each SNP and ethnic group. Linkage disequilibrium and interaction between the two SNPs were also evaluated.
RESULTS: The minor allele G and its homozygous genotype GG of HLA-DRB1/HLA-DQA1 rs9271366 significantly increased the SLE susceptibility in Malaysian patients, including those of Malay and Chinese ethnicity (odds ratio (OR) > 1, p HLA-DQB1/HLA-DQA2 rs9275328, the minor allele T and the heterozygous genotype CT conferred protective effect to SLE in Malaysians, as well as in Malays and Chinese, by having OR HLA variants, rs9271366 and rs9275328 are additional polymorphisms worth considering in the Malaysian and possibly in a larger Asian SLE scenario.
The incidence of aplastic anemia is reported to be higher in Asia than elsewhere. We studied the frequency of human leukocyte antigen (HLA) DRB1 alleles in aplastic anemia patients from 2 genetically similar aboriginal groups, the Kadazan and the Dusun, and compared them with genetically matched community and hospital controls. HLA-DRB1*15 was significantly higher in the patients compared with controls (p = 0.005), confirming similar findings in Japanese and Caucasian studies. Further testing indicated a significantly higher frequency of HLA-DRB1*1501 in patients compared with controls (p = 0.0004) but no significant difference in the frequency of HLA-DRB1*1502. The high frequency of HLA-DRB1*15 in the Kadazan and Dusun population combined with the wide variety of environmental factors associated with aplastic anemia could be the reason for the elevated incidence of aplastic anemia in the Kadazan and Dusun in Sabah.
In this study, human leukocyte antigen (HLA) class I and II were examined through sequence-specific primer typing in 176 unrelated individuals from six Malay subethnic groups of Peninsular Malaysia: Kelantan (n = 25), Minangkabau (34), Jawa (30), Bugis (31), Banjar (33), and Rawa (23). The most common HLA alleles in all groups were A*24 (26-41%), Cw*07 (24-32%), B*15 (22-30%), DRB1*12 (15-36%), and DQB1*03 (25-51%). The Malay subethnic groups studied demonstrated a close relationship to each other and to other Asian populations, despite specific differences between them. Banjar, Bugis, and Jawa Malays demonstrated no significant difference from each other, which could be a result of their related origin from the islands around the Java Sea. These three Malay subethnic groups were then collapsed into one group, which also helped to increase the sample number and sharpen statistical results. Minangkabau and Rawa Malays exhibited high similarities in allele group and haplotype frequencies, which could be a consequence of their common origin from Sumatera. Kelantan Malays, in addition to their statistically significant differences compared with the other groups, also exhibited differences on the most frequent haplotypes, which are almost absent in the other subethnic groups studied.
The earliest settlers in Peninsular Malaysia are the Orang Asli population, namely Semang, Senoi and Proto Malays. In the present study, we typed the HLA-A, -B and -DRB1 loci of the Kensiu and Semai Orang Asli sub-groups. Sequence-based HLA typing was performed on 59 individuals from two Orang Asli sub-groups. A total of 11, 18 and 14 HLA-A, -B and -DRB1 alleles were identified, respectively. These data are available in the Allele Frequencies Net Database under the population name "Malaysia Kedah Kensiu" and "Malaysia Pahang Semai".
A total of 194 Southeast Asia Chinese from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, the HLA-B, HLA-DRB1 and HLA-DQB1 were in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from HWEP in HLA-A (p HLA-C (p
A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p<0.0001), -B (p<0.0001), -DRB1 (p<0.0001) and -DQB1 (p<0.01) loci. Minor deviations from HWEP were detected for HLA-C (p=0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015).
"Bumiputra" or "son of the soil" is a term used to represent the Malays and other indigenous populations of Malaysia. The Malays are Austronesian speaking population and originated from different parts of the Indo-Malay Archipelago. The migration of Malay population from different parts of Indo-Malay Archipelago were mainly due to trading purposes which shaped the current Malay sub-ethnic groups with unique culture and with distinctive dialects. In this study, HLA typing was carried out using Sequence-based Typing (SBT) method on 109 individuals comprising of four Malay sub-ethnic groups namely Kelantan (n = 28), Champa (n = 29), Patani (n = 25) and Mandailing (n = 27) Malays. The HLA data is available in the Allele Frequencies Net Database (AFND).
A total of 271 Southeast Asia Indians from Peninsular Malaysia were genotyped for HLA-A, -B, -C, -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, HLA-B and HLA-DQB1 was in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from the HWEP for HLA-A (p HLA-C (p HLA-DRB1 (p
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease afflicting multiple organs. Lupus nephritis (LN) is a serious complication of SLE and remains a major cause of mortality and morbidity. Curative therapy remains unavailable as etiology from genetic and environmental factors is still unclear. The present study was conducted to elucidate the link between HLA-DRB1 gene polymorphisms with SLE and LN through clinical and laboratory/biological presentations in a population of Malaysian Malay females with SLE. A total of 100 Malay female SLE patients inclusive of 70 SLE patients without LN and 30 patients with LN were included in this study. HLA-DRB1 allele examination in SLE patients was performed using PCR-SSO, and the alleles' frequencies were compared with 951 publicly available datasets representing Malay healthy controls in Malaysia. Cytokines and free radical levels were detected by ELISA and bead-based multiplexed Luminex assays. The association between HLA-DRB1 alleles with clinical and serological manifestations and immune mediators was analyzed using different statistical approaches whenever applicable. Our study showed that HLA-DRB1*0405, HLA-DRB1*1502, and HLA-DRB1*1602 were associated with the increased risk of SLE while HLA-DRB1*1201 and HLADRB1*1202 alleles were associated with a lower risk of SLE development. Furthermore, HLA-DRB1*04 showed significant association to LN and arthritis while HLA-DRB1*15 was significantly associated with oral ulcer in Malay SLE patients. Association analysis of HLA-DRB1*04 with clinical and biological factors revealed that HLA-DRB1*04 was significantly associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, anti-nuclear antibody (ANA), C-reactive protein (CRP) in the blood, and total protein in the urine. SLE carriers with the HLA-DRB1*04 allele were significantly correlated to the increased levels of cytokines (IFN-y, GM-CSF, IL-17F, IL-18, IL-21, and VEGF) and were significantly showing negative correlation to IL-5 and free radicals (LPO and catalase enzyme) levels compared to SLE carriers without HLA-DRB1*04 allele. The results suggested that disease severity in SLE may be determined by HLA-DRB1 alleles. The risk of HLA-DRB1*04 allele with LN was supported by the demonstration of an intense inflammatory response in Malay SLE patients in Malaysia. More studies inclusive of a larger and multiple SLE cohorts in the future are warranted to validate these findings.
Type 1 diabetes (T1D) is a complex autoimmune disorder that is highly prevalent globally. The interactions between genetic and environmental factors may trigger T1D in susceptible individuals. HLA genes play a significant role in T1D pathogenesis, and specific haplotypes are associated with an increased risk of developing the disease. Identifying risk haplotypes can greatly improve the genetic scoring for early diagnosis of T1D in difficult to rank subgroups. This study employed next-generation sequencing to evaluate the association between HLA class II alleles, haplotypes, and amino acids and T1D, by recruiting 95 children with T1D and 150 controls in the Kuwaiti population. Significant associations were identified for alleles at the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci, including DRB1*03:01:01, DQA1*05:01:01, and DQB1*02:01:01, which conferred high risk, and DRB1*11:04:01, DQA1*05:05:01, and DQB1*03:01:01, which were protective. The DRB1*03:01:01~DQA1*05:01:01~DQB1*02:01:01 haplotype was most strongly associated with the risk of developing T1D, while DRB1*11:04-DQA1*05:05-DQB1*03:01 was the only haplotype that rendered protection against T1D. We also identified 66 amino acid positions across the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes that were significantly associated with T1D, including novel associations. These results validate and extend our knowledge on the associations between HLA genes and T1D in Kuwaiti children. The identified risk alleles, haplotypes, and amino acid variations may influence disease development through effects on HLA structure and function and may allow early intervention via population-based screening efforts.
The polymorphism of the human leucocyte antigen HLA-DR2 and the heterogeneity of HLA-DR2 class II-related haplotypes (HLA-DRB1-DRB5-DQA1-DQB1) were investigated in four populations of east and south-east Asia (SEA) and five Melanesian populations using TaqI restriction fragment length polymorphism (RFLP) analysis, and the polymerase chain reaction (PCR) amplification-based techniques PCR-RFLP and sequence-specific oligonucleotide (SSO) typing. The haplotype DRB1*1502-DRB5*0101-DQA1*0102-DQB1*0601 was common in Malaysians, Javanese, Thursday Islanders, Madang, Goroka and the Australian Aborigines, while DRB1*16021-DRB5*0101-DQA1*0102-DQB1*0502 was common in the Thai and Thursday Islanders. DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 was present at a high frequency in Northern Chinese, Goroka, Watut and Australian Aborigines. The study describes four rare or unusual haplotypes: HLA-DRB1*1501-DRB5*0101-DQA1*0101-DQB1*0601, DRB1*1502-DRB5*0101-DQA1*0101-DQB1*0502, DRB1*1502-DRB5*0102-DQA1* 0102-DQB1*0502 and DRB1*1501-DRB5*0101-DQA1*0101/2-DQB1*0503; the latter two were confirmed by segregation in two Javanese families. A new DR2 allele, initially detected by PCR-RFLP and confirmed by DNA sequencing as DRB1*16022 (previously designated DRB1*16Madang), was seen in a Madang individual. A new HLA-DR2 TaqI RFLP subtype, locally designated as DR15U, is also described. This RFLP subtype segregated in a Javanese family and correlated with a typically SEA haplotype, DRB1*1502-DRB5*0102-DQA1*0101-DQB1*0501. The allele HLA-DR16Thai, determined by TaqI DRB RFLP, was found by PCR-RFLP and SSO typing to correlate with a unique SEA haplotype, HLA-DRB1*16021-DRB5*0101-DQA1*0102-DQB1*0502, and was observed in the Thai, Malaysian, Thursday Islander, Javanese and Northern Chinese populations.
OBJECTIVE:
To assess the relationship between the HLA-DRB1 genes with disease severity as assessed by radiological erosions in Malaysian patients with rheumatoid arthritis (RA).
METHODS:
In this cross-sectional study, we studied 61 RA patients who fulfilled the ACR criteria for the diagnosis of RA. HLA-DRB1 genotyping was performed by sequence specific primer (SSP) - PCR. Radiological grading and erosive score of the hands and wrists was calculated according to the Larsen-Dale method. Demographic data and treatment given to the patients were obtained from their case records.
RESULTS:
Fifty-six females and five males were studied from three ethnic groups. In 57 patients with erosions, rheumatoid factor was detected in 80%, HLA-DR4 in 40%, HLA-DRB1*0405 in 24% and shared epitope (SE) in 31%. The median delay in starting DMARDs was 24 months. The presence of rheumatoid factor, HLA-DR4 and HLA-DRB1*0405 were not significantly associated with a worse erosive score. Patients who possessed the SE had a higher erosive scores, compared to those who did not (p = 0.05). Concurrently, a delay in starting DMARD was associated with a high erosive score (p = 0.023, r = 0.348). However, after adjustment for the delay in starting DMARD, SE was no longer significantly associated with the erosive score.
CONCLUSIONS:
In these patients, the delay in starting DMARDs had a greater influence on the erosive score than SE alone. Whilst we cannot discount the contribution of the SE presence, we would advocate early usage of DMARDs in every RA patient to reduce joint erosions and future disability.