HLA-DRB1 alleles associated with rheumatoid arthritis in Northern Italy: correlation with disease severity

The aim of the study was to evaluate the relationship between the presence of the 'rheumatoid epitope', defined by a sequence motif in the HLA-DRB1 alleles, rheumatoid factor and disease severity in Northern Italian patients with rheumatoid arthritis (RA). Twenty-nine DR4-positive and 57 DR4-negative RA patients were studied. Each DR4- positive patient was matched with two DR4-negative controls of similar disease duration and sex. HLA-DRB1 alleles were determined in the 86 patients and 351 controls from the same geographical area. The patients were retrospectively evaluated for extra-articular features (EAF) and radiographic damage. The rheumatoid epitope was expressed in 45% of patients. No significant differences in the presence of rheumatoid factor, EAF and articular damage were observed between patients with no, one or two doses of epitope. However, the patients encoding the epitope by an HLA-DR4 allele had a higher number of eroded joints and a higher Larsen score compared to those without the epitope. No differences were present between patients expressing HLA-DRB1*01 alleles and those lacking the rheumatoid epitope. Even in the absence of expression of the rheumatoid epitope, seropositive patients had more EAF and more erosive disease compared to those who were seronegative. Even if most Northern Italian RA patients do not express the rheumatoid epitope, the radiological severity of disease is associated with HLA- DRB1*04 alleles.      

HLA-DRB1, DQA1, and DQB1 alleles associated with giant cell arteritis in northern Italy.

OBJECTIVE: To evaluate by molecular typing the possible associations of HLA-DRB1, DQA1, and DQB1 alleles with biopsy proven giant cell arteritis (GCA) in a Mediterranean country, and to examine possible relationships between these alleles and GCA clinical subsets. METHODS: Thirty-nine patients from the Reggio Emilia area diagnosed over a 12 year period with biopsy proven GCA were studied. The clinical findings at diagnosis and during the followup were evaluated through interviews and by reviewing the medical records. HLA-DRB1, DQA1, and DQB1 alleles were determined in the 39 patients and in 250 healthy controls from the same geographic area by polymerase chain reaction amplification using sequence-specific primers. RESULTS: No associations were found between GCA and the shared epitope, the DRYF epitope, or the DRB1*04 or DQA1 alleles. The only significant association was with DQB1*0302 allele (p = 0.03, RR = 2.2). However, the association was weak and the significance was lost when corrected for the number of antigens tested. The frequencies of DQB1*0301 and 0302 in DR4 patients were not significantly different from those observed in DR4 positive controls. Significant associations were found between DRB1*04 allele and the presence of systemic signs and/or symptoms (p = 0.04, RR = 1.5) and between DRB1*07 allele and the male patients (p = 0.04, RR = 2.6). CONCLUSION: Our data showed no associations of biopsy proven GCA with HLA-DRB1*04 and HLA-DRB1*01 alleles, rheumatoid epitope, or DRYF epitope. Discrepancies with other studies may be related to the different ethnic backgrounds of the populations studied and to differences in the referral patterns of patients with GCA.     

Myelodysplastic syndrome associated with polymyalgia rheumatica

A 69-year-old man was referred to us because of severe pain in both girdles. A diagnosis of polymyalgia rheumatica was made, and low-dose prednisolone therapy (20 mg/d) was started. The patient's muscle pain disappeared after 3 weeks. After 5 months of therapy, pancytopenia became prominent. A marrow aspirate smear showed hypercellularity, trilineage dysplasia, and 7% blasts. The clinical diagnosis was myelodysplastic syndrome, subtype refractory anemia with excess of blasts. In elderly patients presenting with polymyalgia rheumatica, an underlying hematologic malignancy should always be looked for when the disease demonstrates clinical signs inconsistent with typical polymyalgia rheumatica.     

Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant cell arteritis in northern Italy

We studied the epidemiology of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) in a Mediterranean population. Ninety-nine patients with PMR and/or GCA were identified over a 9-year period (1980-1988) in Reggio Emilia, Italy. The average annual incidence of PMR and GCA was 12.7/100,000 and 6.9/100,000, respectively, in a population aged 50 years or older. Frequencies of HLA antigens were determined in 49 patients with PMR and/or GCA who were followed by staff at our rheumatology unit during the 1980-1988 period. When compared with HLA findings in 242 healthy controls, DR4 was not found to be significantly associated with PMR (24% in PMR patients versus 14% in controls). Patients with GCA also showed an increased frequency of DR4 compared with controls (36% versus 14%), but this difference was also not statistically significant. The immunogenetic features of PMR and GCA and the relationship between the immunogenetic and epidemiologic patterns in different populations are discussed.     

Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity

OBJECTIVE: Intercellular adhesion molecule 1 (ICAM-1) is widely distributed in shoulder synovial membrane of active polymyalgia rheumatica (PMR) and strongly expressed in granulomatous inflammatory infiltrate of the temporal artery in giant cell arteritis (GCA). ICAM-1 genes may contribute to the inflammatory PMR/GCA processes. We examined potential associations of ICAM-1 gene polymorphisms with PMR/GCA susceptibility and severity. METHODS: We enrolled 121 consecutive patients with "pure" PMR and 56 patients with biopsy positive GCA residing in Reggio Emilia, Italy. Among patients with PMR, 91 had a followup duration of at least one year. Selected as control subjects were 228 healthy blood donors, 75 patients with nonarteritic central retinal artery occlusion, and 116 cataract surgery patients from the same geographic area. All PMR/GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphism at codon 241 (exon 4) and codon 469 (exon 6). RESULTS: The frequency of R241 was significantly higher in PMR/GCA patients [p = 0.00001, odds ratio (OR) 5.0 (95% confidence intervals, CI 2.6-9.6) ], in pure PMR patients [p = 0.00001, OR 5.0 (95% CI 2.5-10.0)], and in GCA patients [p = 0.00005; OR 5.0 (95% CI 2.2-11.5)] compared to the healthy controls. The frequency of R241 was significantly higher in total PMR/GCA patients compared to patients with nonarteritic central retinal artery occlusion [p = 0.0007; OR 5.3 (95% CI 1.8-15.5)] and cataract surgery patients [p = 0.0003; OR 4.1 (95% CI 1.8-9.0)]. The distribution of E/K 469 genotype was similar in PMR/GCA patients and in the 3 control groups. Cox proportional hazards modeling identified 2 variables that independently increased the risk of PMR relapse/recurrence: erythrocyte sedimentation rate at diagnosis > 72 mm/h [relative risk 1.6 (95% CI 1.1-2.3)] and the presence of R241 allele [relative risk 1.6 (95% CI 1.1-2.4)]. CONCLUSION: Our findings show that G/R 241 polymorphism of ICAM-1 is associated with PMR/GCA susceptibility and confers an increased risk of relapse/recurrence in PMR.     

Genetic markers of disease susceptibility and severity in giant cell arteritis and polymyalgia rheumatica

BACKGROUND AND OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are common and often overlapping diseases that generally occur in elderly patients. In this article, we examine the role of different genes as markers of disease susceptibility and severity in GCA and PMR. METHODS: The influence of human leukocyte antigen (HLA)-DRB1 and tumor necrosis factor alleles, as well as the different allelic polymorphisms, on the susceptibility and severity to GCA and PMR was examined. A review of the literature was conducted. RESULTS: Most studies have described an association of GCA with HLA-DRB1(*)04 alleles. However, HLA-DRB1 association in patients with PMR varies from one population to another. In Northwest Spain, patients with GCA and PMR exhibited different tumor necrosis factor microsatellite polymorphism associations. Studies of intercellular adhesion molecule-1 biallelic polymorphisms have yielded contradictory results. Interleukin 1 cluster and tumor necrosis factor alpha polymorphisms increased susceptibility to GCA and PMR slightly. In Northwest Spain, interleukin 6 promoter polymorphism at position -174 modulated the phenotypic expression of PMR in biopsy-proven GCA. In the same population, regulated upon activation, normal T cell expressed and presumably secreted gene promoter biallelic polymorphism at position -403 was a marker for PMR susceptibility but not for GCA, and corticotropin-releasing hormone polymorphism appeared to be implicated in the risk of severe ischemic complications in patients with GCA. CONCLUSIONS: The present analysis confirms that GCA and PMR are polygenic diseases. The search for additional genes is necessary to better understand the pathogenesis of these conditions.     

Bronchiolitis obliterans organizing pneumonia associated with polymyalgia rheumatica.

The association of bronchiolitis obliterans organizing pneumonia (BOOP) with polymyalgia rheumatica is rare, and only one case has previously been described. This study reports on the case of an 80 yr-old male who presented with malaise, nonproductive cough and exertional dyspnoea for several weeks, along with a history of bilateral shoulder and pelvic girdle pain of several months' duration. The chest radiograph revealed a pneumonic infiltrate in the right lower lobe, which was unresponsive to antibiotics. Bronchoscopy, bronchoalveolar lavage and a transbronchial lung biopsy established the diagnosis of BOOP. The patient improved consistently on steroids. As in other connective diseases, organizing pneumonia may be one of the early manifestations of polymyalgia rheumatica.     

HLA-DRB1 allele distribution in polymyalgia rheumatica and giant cell arteritis: influence on clinical subgroups and prognosis

OBJECTIVE: To evaluate HLA-DRB1 associations in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in the Spanish population, especially those alleles that include the disease-linked sequence motif DRYF (positions 28 to 31 of the HVR2). METHODS: We performed a PCR based HLA-DRB1 genotyping in 89 PMR patients, 44 GCA patients, and 99 unrelated healthy controls from the same geographic area. RESULTS: We did not find any significant difference between the whole group of PMR/GCA patients (n = 133) compared with the healthy controls with the exception of a lower frequency of HLA-DRB1*0405 in the patient group (odds ratio [OR], 0.1 [CI0.02 to 1.2]; P =.04). The distribution of DRB1 alleles was very similar between PMR patients and controls. However, DRB1*0401 (OR, 3.1 [1.1 to 8.6]; P =.02) and DRB1*0404 (OR, 3.5 [0.97 to 12.9]; P =.04) were overrepresented in patients with GCA compared with the control group. DRB1*04 (OR, 1.9 [0.96 to 3.8]; P =.06), especially *0401 (OR, 2.8 [1 to 7.7]; P =.04), and DRB1*07 (OR, 2.3 [1.2 to 4.6]; P =.01) were more frequent in GCA than in PMR. Frequency of the DRYF 28-31 motif was similar among GCA (79.5%), PMR (89.9%), and controls (87.9%) and did not confer any significant risk of the development of systemic vasculitis. We also compared the DRB1 allele distribution in patients with classic PMR (n = 58) and those with an erythrocyte sedimentation rate (ESR) <40 mm/hour (n = 31). Patients with classic PMR expressed DRB1*07 less frequently (OR, 0.4 [0.1 to 1]; P =.04) and had a higher frequency of the DRYF 28-31 motif (94.8% vs 80.6%; P =.03) than patients with ESR < 40. Within the GCA group, DRB1 alleles were not predictive for the development of severe ischemic complications. However, the development of relapses in patients with PMR was associated with a higher frequency of DRB1*09 (5.6% vs 0%; P =.04). CONCLUSIONS: Our data suggest that the HLA-DRB1 alleles associated with susceptibility for developing PMR and GCA are different. Whether PMR with low ESR represents a different clinical subset of the disease should be clarified in a larger sample of patients. HLA-DRB1 genes might predict the presence of relapses in PMR, but they do not seem to be indicators of severe disease in GCA patients.     

Secondary amyloidosis associated with giant cell arteritis/polymyalgia rheumatica

Although giant cell arteritis (GCA) is characterized by chronic inflammation, secondary (AA) amyloidosis appears to be an exceptionally rare complication of this disorder. We describe an 84-year-old man with biopsy proven GCA and polymyalgia rheumatica (PMR) who was found at autopsy to have AA amyloid deposition in numerous organs, 9 years after his diagnosis of GCA. Persistent musculoskeletal symptoms, attributed to refractory PMR during the patient's life, were likely due to AA amyloidosis. This unrecognized complication of GCA/PMR confounded his therapy, leading to excessive treatment with corticosteroids and methotrexate. This case shows that the occurrence of AA amyloidosis should be considered in patients with "refractory PMR" developing after a period of treatment, and that autopsies play a vital role in enigmatic cases.     

HLA-DRB1＊14和＊15等位基因与肝癌的相关性

目的探讨HLA-DRB1＊14和＊15等位基因与肝癌发生的相关性。方法以40例原发性肝癌患者作为病例组,以135例健康人作为对照组,应用PCR-SSP方法对研究对象外周血的HLA-DRB1等位基因进行检测,分析其表达与原发性肝癌的相关性。结果 HLA-DRB1＊14在病例组中的分布频率较对照组显著增高（χ2=9.925,P=0.002,OR=3.450,95%CI：1.555～7.655）,HLA-DRB1＊15在病例组和对照组中的分布频率的差异无统计学意义（χ2=1.260,P=0.262,OR=1.538,95%CI：0.723～3.274）。结论 HLA-DRB1＊14可能是原发性肝癌的易感基因,HLA-DRB1＊15可能与原发性肝癌的发生无明显关系。     

Hla–drb1 alleles in polymyalgia rheumatica,giant cell arteritis,and rheumatoid arthritis

Objective. Immunogenetic analysis has demonstrated that giant cell arteritis (GCA) and rheumatoid arthritis (RA) are associated with 2 different domains of the HLA–DR4 molecule. The present study was undertaken to evaluate whether polymyalgia rheumatica (PMR) immunogenetically resembles GCA or RA and to determine whether expression of HLA-DRB1 alleles can be used to detect heterogeneity among PMR patients. Methods. Forty-six patients with PMR, 52 with GCA, 122 with seropositive RA, and 72 normal individuals were genotyped for HLA-DRB1 alleles by allele-specific amplification and subsequent oligonucleotide hybridization. Results. The HLA-DRB1^*04 allele was the most frequent among PMR patients (67%). While the expression of allelic variants of the HLA-DR4 family was restricted to HLA-DRB1^*0401 and ^*0404/8 in RA patients, all HLA–DRB1^*04 alleles, including B1^*0402 and B1^*0403, were represented in the PMR group. The distribution of HLA–DRB1 alleles among HLA–DRB1^*04 negative patients was similar in those with PMR and those with GCA, and could be distinguished from that in RA patients. In particular, HLA–DRB1^*01 alleles, which were found in most HLA–DRB1^*04 negative RA patients, were underrepresented in patients with PMR and GCA. Conclusion. The distribution of HLA–DRB1 alleles in PMR resembles that found in GCA. PMR and GCA share the associated sequence polymorphism encoded by the second hypervariable region (HVR) of the HLA–DRB1 gene. The HLA–DRB1 association of PMR and GCA can be distinguished from that of RA, which is linked to a sequence motif in the third HVR of DRB1 alleles. The differential role of distinct domains on HLA-DR molecules suggests that multiple biologic functions are regulated by these molecules and that they contribute differently to disease mechanisms. The similarities in the distribution of HLA–DRB1 alleles in PMR and GCA indicates that HLA–DRB1 alleles are not predictive for progression of PMR to the vasculitic lesions that are pathognomonic for GCA.     

HLA-DRB1 alleles in Egyptian rheumatoid arthritis patients: Relations to anti-cyclic citrullinated peptide antibodies,disease activity and severity

BackgroundHuman leukocyte antigen HLA-DRB1 alleles encoding a common amino acid sequence called shared epitope in the third hypervariable region of DRB1 molecule have been identified as risk alleles for rheumatoid arthritis (RA).Aim of the workThe aim was to study HLA-DRB1 01, 04 and 10 alleles in Egyptian RA patients and determine their relation with anticyclic citrullinated peptide (anti-CCP) antibody level, disease activity, clinical and radiological severity.Patients and methodsThe study involved 40 RA patients and 20 control. Simplified disease activity index (SDAI) was calculated, clinical severity was assessed using the mechanical joint score (MJS) and radiological severity evaluated using the simple erosion narrowing score (SENS). HLA-DRB1 genotyping and anti-CCP antibodies were detected.ResultsThe mean patients’ age was 41.6 ± 12.7 years and disease duration 8.9 ± 7.7 years. The frequency of HLA DRB1 01, 04 and 10 in patients was 42.5%, 60% and 25% respectively. Of them 04 was significantly higher than in controls (p = 0.013) and was associated with anti-CCP positive cases (p = 0.0008) while the absence of HLA-DRB1 alleles was significantly associated with negative anti-CCP negative RA (p = 0.0008). There were significant associations between HLA-DRB1 01 and 04 with SDAI (p = 0.0002 and p = 0.005, respectively); between HLA-DRB1 04 and 10 with SENS (p = 0.002 and p = 0.001 respectively) and between HLA-DRB1 01, 04 and 10 with MJS (p = 0.02, p = 0.03 and p = 0.02, respectively).ConclusionHLA-DRB1 04 is associated with RA in Egyptian patients and is strongly associated in the production of elevated titers of anti-CCP antibodies which contribute to the development, severity and activity of the disease.     

Association between polymyalgia rheumatica and vascular disease: A systematic review

Objective

To systematically identify and appraise the existing literature on the association between polymyalgia rheumatica (PMR) and vascular disease.

Methods

The Medline, Embase, CINAHL, and Cochrane databases were searched from inception to September 2010. Search criteria included observational studies containing patients with isolated PMR reporting on a vascular outcome. Data were extracted and articles were assessed for quality.

Results

The database search identified 545 articles. Eight articles reporting on 7 unique studies were included in the final review. Four studies reported on vascular mortality and 3 studies reported on other vascular outcomes. Four of the studies reported statistically significant positive associations between PMR and vascular disease and 3 studies reported no statistically significant results. The heterogeneity of the results was investigated; the strongest explanatory variable was that 2 of 3 studies that reported nonsignificant results were prospective, whereas all of those studies reporting significant results were retrospective.

Conclusion

There is some evidence to suggest that, like other inflammatory rheumatic disorders, PMR may be linked to an increased risk of vascular disease. Further studies are required to quantify the level of risk to determine whether patients with PMR should be actively screened for cardiovascular disease and its risk factors.     

Inflammatory diseases in older adults: polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a common inflammatory disease in adults over age 50, and particularly in women. Teasing apart the diagnosis of PMR from other inflammatory and degenerative diseases is mandatory because there are effective treatments for this reversible condition. Onset of PMR is usually acute, with pain typically beginning in the neck and upper arms, though it can begin in the pelvic girdle. Low grade fever may occur; swelling of the joints is not typical, although swelling of the knees may be present on occasion. There are no specific laboratory or radiographic findings although some consider an elevated sedimentation rate (> 50 mmg/hr) to be essential to diagnosis. Differential diagnoses can be myriad. Treatment, typically with prednisone (occasionally methylprednisolone), requires individualized regimens, particularly during tapering.     

A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for rheumatoid arthritis structural severity

OBJECTIVE: A new classification of HLA-DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA. METHODS: The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA-DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence-specific oligonucleotide probes. HLA-DRB1 alleles were classified according to the above-mentioned new system. The association between the HLA-DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests. RESULTS: The presence of S2 alleles (HLA-DRB1*0401 and HLA-DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA-DRB1*11001, HLA-DRB1*1104, HLA-DRB1*12, and HLA-DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01). CONCLUSION: The studied classification of HLA-DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70-74 of the third hypervariable region of the HLA-DRbeta chain.     

HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis.

OBJECTIVE: To examine the effects of HLA-DRB1 alleles and amino acid sequences that carry the shared epitope (SE) upon rheumatoid arthritis (RA) susceptibility and disease severity in patients from Eastern France. METHODS: HLA-DRB1 alleles were determined in 120 patients and 104 healthy controls by polymerase chain reaction/sequence specific oligonucleotide probes. Subtyping of DRB1*01 and *04 were performed using sequence specific primers. Patients were retrospectively evaluated for disease duration, age at disease onset, presence of rheumatoid factors, subcutaneous nodules, vasculitis and other extraarticular diseases, for the need for arthroplasty and immunosuppressive/immunoregulatory agents, and for radiographic damage. RESULTS: The prevalence of HLA-DRB1*04 was significantly higher in patients (46.6%) than in controls (17.3%) (Pcorr = 0.000003). HLA-DRB1*0101 and *0401 were the most prominently associated subtypes in patients with RA (33.3%, Pcorr = 0.011, and 28.3%, Pcorr = 0.00008, respectively). A significant fraction of patients (72.5%) expressed one or 2 copies of the SE (p < 0.0000001; OR 4.77, CI 2.61-8.78). The presence of double SE was associated with a higher risk of developing RA (OR 4.83, CI 1.91-12.71; p = 0.0001). No significant differences in the clinical records among patients expressing no RA linked alleles, one and 2 copies of the SE, were observed. However, analyzing the specific effect of each amino acid sequence, we observed a significant association of the QKRAA motif with vasculitis (p = 0.03) and history of joint replacement surgery (p = 0.05), suggesting a role for lysine in position 71 of the shared sequence. CONCLUSION: These findings differ from those of previous HLA-DRB1 allele studies in patients with RA from other regions of France. Thus, the heterogeneity in both the expression of DRB1 alleles and the association of these alleles with disease severity could be relevant within a country such as France.