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Objectives: Previous reports have shown that HLA-DR4 may be a severity marker for rheumatoid arthritis (RA) in patients of northern European origin. The aim of the present study was to investigate this relation in Greek patients with RA, as RA in Greece differs from the RA described previously on clinical, serological, and immunological grounds.Methods: Eighty four patients were studied in whom HLA-DR typing was performed by restriction fragment length polymorphism and the subtypes of HLA-DR4 were determined by the polymerase chain reaction. The absence or presence of HLA-DR4 and its subtypes was correlated with the clinical and serological characteristics of the patients and with the side effects due to disease modifying drugs.Results: Twenty one of the 84 (25%) patients with RA were DR4+. There was no difference between the DR4+ and DR4-patients with respect to duration of disease, severity of arthritis, functional grade, and joint erosion score. The DR4+ group were more likely to have side effects due to disease modifying drugs (43%) than DR4- patients (36%), but this difference was not statistically significant. DR4-patients had more extra-articular manifestations, including Sjögren's syndrome (47 v 19%). Analysis of the DR4 subtypes showed that Dw15 was the most common variant (9/21 patients; 43%). There was no statistical difference in the clinical manifestations among patients with different DR4 subtypes. The same was also true when the clinical picture was correlated with the 'shared RA epitope' (QKRAA/QRRAA/RRRAA), which is common to all HLA-DRB1 alleles positively associated with RA.Conclusions: These results suggest that HLA-DR4 is not a severity marker in Greek patients with RA and further indicate differences in the clinical expression of RA in Greece. [ABSTRACT FROM AUTHOR]

Objectives: Evidence on comorbidity prevalence in antiphospholipid syndrome (APS) and its difference from high comorbidity burden rheumatic diseases is limited. Herein, we compare multiple comorbidities between APS and RA., Methods: A total of 326 patients from the Greek APS registry [237 women, mean age 48.7 (13.4) years, 161 primary APS (PAPS), 165 SLE-APS] were age/sex matched (1:2 ratio) with 652 patients from a Greek multicentre RA cohort of 3115 patients. Prevalence of cardiovascular (CV) risk factors, stroke, coronary artery disease (CAD), osteoporosis, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), depression and neoplasms were compared between APS and RA patients using multivariate regression analysis., Results: Ηyperlipidemia and obesity (ΒΜΙ ≥ 30 kg/m2) were comparable while hypertension, smoking, stroke and CAD were more prevalent in APS compared with RA patients. Osteoporosis and depression were more frequent in APS, while DM, COPD and neoplasms did not differ between the two groups. Comparison of APS subgroups to 1:2 matched RA patients revealed that smoking and stroke were more prevalent in both PAPS and SLE-APS vs RA. Hypertension, CAD and osteoporosis were more frequent only in SLE-APS vs RA, whereas DM was less prevalent in PAPS vs RA. Hyperlipidaemia was independently associated with CV events (combined stroke and CAD) in PAPS and SLE-APS, while CS duration was associated with osteoporosis in SLE-APS., Conclusion: Comorbidity burden in APS (PAPS and SLE-APS) is comparable or higher than that in RA, entailing a high level of diligence for CV risk prevention, awareness for depression and CS exposure minimization., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The 3E (Evidence, Experts and Exchange) Initiative is a multi-national effort that involves a large number of experts and practicing rheumatologists addressing specific questions relevant to everyday clinical practice, concerning the management of Ankylosing Spondylitis. Within this multinational group, the Hellenic working group, addressed specific issues complementary to the international ones, and formulated evidence-based recommendations, in order to improve everyday clinical practice for patients with Ankylosing Spondylitis., Methods: A scientific committee of rheumatologists specializing in AS formulated a set of 7 questions in three domains: diagnosis, monitoring and treatment. Literature search in MedLine for papers published up to August 2006 was conducted. The evidence to support each proposition was evaluated and scored. To avoid any conflict of interest with the sponsor issues related to the use of biologics were not discussed. After extensive discussion among 50 rheumatologists and one Delphi round of votes, the final recommendations were formulated., Results: A literature search resulted in a total of 320 relevant papers of which 29 were evaluated. A total of seven recommendations were formulated: two concerning diagnosis (role of HLA-B27 and MRI) and prognosis, one concerning monitoring for extra-articular manifestations and four concerning treatment (analgesics, disease modifying agents and physical therapy) were made. The level of evidence and the strength of recommendation were reported. The compiled agreement among experts ranged from 90% up to 100%., Conclusion: Recommendations for the management of AS were developed using an evidence-based approach followed by physicians' consensus with high level of agreement. These are complementary to existing ones, and address specific domains of everyday clinical practice.

Objective: To examine TNF microsatellite allele frequencies in SLE patients in the Greek population, where disease susceptibility is less associated with HLA-DR3 haplotypes., Methods: A cohort of 46 Greek SLE patients were investigated. Allele frequencies for the TNF microsatellite markers a, b, c and d were determined using a fluorescence based DNA fragment sizing technique. HLA class II typing was performed using a molecular based technique., Results: Associations between SLE and DRB1*1501, *1601 and *0701 were observed and DRB1*0301 was only marginally increased in patients. Linkage disequilibrium was found between DRB1*1501 and TNF a11 and also for DR3 and TNF a2, b3, d2. Stratification of patients suggested that DRB*1501 and TNF a11 frequencies were higher in SLE patients with renal disease and TNF a2 and b 3 frequencies in those without, although these differences did not reach statistical significance., Conclusions: SLE in this Greek population appears to be associated with a number of HLA-DRB1 alleles. The development of renal complications in these patients may be related to the TNF polymorphism encoded on these HLA haplotypes.

The clinical spectrum and outcome of necrotizing vasculitis were evaluated in a retrospective study in order to assess: (1) the clinical expression and evolution of the disease; (2) the response to several therapeutic approaches based on major events (organ involvement causing disability or death); (3) the immunogenetic background of patients. Sixty-six Greek patients fulfilling the ACR criteria for the diagnosis of vasculitis entered the study. Thirty-seven were diagnosed with Wegener's granulomatosis (WG), 22 with polyarteritis nodosa (PAN) and seven with Churg-Strauss syndrome (CSS). The demographic characteristics of patients with WG and PAN were similar. Cutaneous manifestations, gastrointestinal and peripheral nervous system involvement occurred more often in patients with PAN, whereas pulmonary and upper respiratory tract involvement, renal, ear abnormalities and fever were more frequent in patients with WG. Muscle weakness and asthma were found exclusively in patients with PAN and CSS, respectively, while the presence of classic-antineutrophil cytoplasmic antibodies (c-ANCA) characterized WG patients. Hepatitis B surface antigen (HBsAg) was found in 22% of PAN patients. No significant differences were detected when comparing the PAN and WG groups with respect to the first major event (log-rank P = 0.50) with and without potential confounders (age, gender, therapy or c-ANCA). For WG patients, a statistically significant difference was found on different routes of administration of cyclophosphamide (oral vs pulse) (P = 0.006). Regarding the HLA antigens, an increased frequency of DR1 (26.9% vs 10.3%, P = 0.057) in WG and the absence of DR3 in patients with PAN and CSS were noted. It appears that although the immunogenetic background and the clinical expression of the diseases differ, the response to treatment as well as the evolution and the survival rate of these patients are similar in the two groups.

One hundred and seventy-one unrelated elderly healthy subjects selected according to the Senieur protocol (57 men and 114 women), aged 75-104 years, and 405 healthy individuals (238 men and 167 women), aged 18-65 years, were typed for HLA-A, HLA-B, and HLA-DR antigens. The purpose of the study was to investigate a possible association between HLA antigens and longevity. In the total group of elderly, an increased frequency of HLA-B16 (11.11 vs. 5.43%) and HLA-DR7 (38.33 vs. 15.67%) and a decreased frequency of HLA-B15 (1.75 vs. 5.18%) and HLA-DR4 (11.66 vs. 24.15%) were observed. The HLA-B15DR4 haplotype was not represented (vs. 2.1%), HLA-A1B8 was found with a low frequency (2.9 vs. 4.4%), and HLA-B8DR3 was very rarely found (1.6 vs. 10.1%), whereas the HLA-B13DR7 haplotype was observed with an increased frequency (6.6 vs. 3.3%). These results are in agreement with other published data and suggest that longevity in humans may be influenced by the genetic background.

Mixed cryoglobulinemia (MC) is a systemic disorder whose pathogenesis is based on the presence of serum cryoglobulins. The purpose of this study was to evaluate on a prospective basis patients presenting with MC with regard to the clinical manifestations and the underlying disorders. We present ten patients with MC, who were diagnosed and followed up during a one year period in the Division of autoimmune rheumatic diseases (Clinical Department of Pathophysiology). MC was associated with hepatitis C virus (HCV) infection in two cases, with hepatitis B virus (HBV) infection in six, one patient had both HCV and evidence of HBV infection, while the remaining three patients fulfilled European classification criteria for diagnosis of Sjögren's syndrome (SS). In all ten cases, the presence of an underlying factor was identified, being either viral or autoimmune. It is concluded therefore that all patients presenting with MC should be completely evaluated for a hepatitis virus infection or an autoimmune or lymphoproliferative disorder. Furthermore, since the initiation of the process of MC is triggered by many factors, research should be directed towards the identification of the underlying common denominator.

Objective: The presence of antikeratin antibodies (AKA) has been associated with rheumatoid arthritis (RA) in patients from north and central Europe. Our aim was to investigate the prevalence of AKA in Greek patients with RA., Methods: One hundred and twenty two sera of Greek patients with RA were tested for the presence of AKA by an indirect immunofluorescence technique, and HLA-DR typing was performed by restriction fragment length polymorphism., Results: Nineteen of 122 (16%) Greek patients with RA were positive for AKA. The percentage of AKA in Greek patients with RA is lower than described previously. These antibodies correlated with a male preponderance (p < 0.01) and were associated with the presence of rheumatoid factor (RF) (p < 0.05) and with HLA-DR1 antigen (p < 0.05)., Conclusion: Our results suggest that AKA are present frequently in Greek patients with RA. Their presence was found to be associated with RF and HLA-DR1 antigen. This emphasizes the different clinical expression of RA in Greece.

Fifty-two British and 29 Greek idiopathic membranous nephropathy (IMN) patients were analysed for DRB, DQA1, DQB1 and DPB1 gene polymorphism using second exon amplification and sequence-specific oligonucleotides (SSO). In addition 100 British and 92 Greek controls were analysed. A highly significant increased frequency of the DRB1*0301 allele was found in IMN patients from Britain (80%), when compared to controls (27%, OR 10.6, P = 0.000004). A lower frequency of DRB1*0301 was observed in Greek IMN patients (33%), but this was just significant before correction, when compared to Greek controls (15%, OR 3, P = 0.02). The DRB3 allele most often associated with DRB1*0301 was DRB3*0101 (OR 4.2, P = 0.00025) in British patients and DRB3*0201/2 (OR 11, P = 0.006) in Greek patients. In Greek IMN patients a decrease in DR16 was found (OR 0.08, P = 0.004), and the overall incidence of DR2 was significantly lowered when both sets of IMN patients were combined (OR 0.21, chi 2 17.6, P = 0.00013). The incidence of DQA1*0501 was raised in both Greek (96% vs. 66%, OR 9.7, chi 2 6.9, P = 0.009) and British IMN (85% vs. 45%, OR 7.4, chi 2 20, P = 0.00007) patients. This gives some support to a proposal for a major role for this allele in IMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen., Methods: We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization., Results: DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004)., Conclusion: Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.

Using the Taq1 restriction enzyme and DR beta, DQ alpha probes, the DNAs of Greek RA patients and controls were characterised for RFLP's associated with DR4. Three DR beta bands, 14.8kb, 6.1kb and 5.4kb were observed at significantly higher frequency in the patients compared with controls. By using a DQ alpha probe, the 2.6kb band (associated with DR1, DRw10, DRBR and DRw14 (Dw9)) was at a significantly raised frequency in the patients. The DQ alpha 5.3kb band associated with DR4, DR7 and DR9 was also raised in the RA patients although this increase did not reach statistical significance. In view of the previously documented lack of association between DR4 (and other DR antigens) and RA in Greeks, the results suggest that some degree of HLA class II association exists with RA in this population at the DNA level which may not be overtly reflected serologically.

It has been shown that Greek RA patients do not show an increased frequency of HLA-DR4 compared with Greek controls. As only the Dw4 and Dw14 subtypes of DR4 are implicated in RA, we have characterised DR4-positive Greek RA patients and controls using serology, MLC typing and RFLP analysis to see whether the distribution of DR4 subtypes or other HLA antigens associated with DR4 could account for these findings. In the 10 patients and 12 controls studied, Dw10 was common, being present in almost half the controls. Dw4 was not detected in the controls, but was present in three of the RA patients, indicating that there may be some relationship between Dw4 and RA in this population; Dw13 and Dw14 were also found, Dw15 was not detected. Eight of the subjects did not type as any of the HLA-D antigens mentioned. Three controls had unusual DR4-DQ associations, two having DR4-DQw2 and one possessing DR4-DQw4. Analysis of the TaqI DRB RFLP of the subjects showed that one control did not have the 6.1 kb band characteristic of DR4s. All these results indicate that DR4 is a heterogeneous antigen in this population and that several as yet undescribed variants of DR4 may be present.

Ninety-five rheumatoid arthritis patients treated with aurothiomalate and/or D-penicillamine have been studied for possible associations between HLA-A, -B, -DR antigens and various toxic reactions to the above drugs. HLA-DR3 and -DRw6 had a higher frequency in patients with toxic reactions (all types) than in patients without toxic reactions (28.5 per cent vs 13.0 per cent and 26.5 per cent vs 4.3 per cent, chi 2 = 2.6 and 7.2, respectively). HLA-B8 was found at a higher frequency in patients with proteinuria and other types of renal involvement (20.0 per cent vs 7.4 per cent in controls), whereas skin manifestations were mainly associated with the presence of HLA-DRw6. The lowest frequency of side-effects was seen in patients with HLA-DR1 and DR2 (10.2 per cent vs 28.3 per cent and 28.5 per cent vs 54.3 per cent, chi 2 = 3.9 and 5.5, respectively). In addition, seropositive patients possessing HLA-DR1, showed toxic reactions less frequently.