Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate long-term safety and efficacy of etanercept (ETN) in patients with rheumatoid arthritis (RA) without concomitant disease-modifying antirheumatic drug therapy. METHODS: A total of 549 patients enrolled in this 5-year, open-label extension after completing 1 of 2 randomised controlled studies; all patients received ETN 25 mg twice weekly during the extension. Safety assessments included physical exams, adverse events (AEs), vital signs, laboratory tests, and autoantibody evaluations. Key efficacy endpoints included numbers of responders achieving the American College of Rheumatology (ACR) criteria, low disease activity scores, and disease remission. RESULTS: Three hundred and eight (56%) patients completed the 5-year extension study. Total ETN exposure, including that received during the double-blind studies was 2212 patient-years. Withdrawals for efficacy- and safety-related reasons were 12% and 19%, respectively. The most common AE was upper respiratory infection (44%). Rates of serious infections decreased over the 5-year period; one case of suspected tuberculosis was reported. Rates of malignancies remained generally consistent during the 5-year period. There were no reports of demyelinating disease, serious blood dyscrasias, or opportunistic infections. The relationship between autoantibody titres and clinical events was not statistically significant. Less than 5% of patients tested positive for anti-etanercept antibodies and all antibodies were non-neutralising. After 5 years, ACR 20, 50, and 70 response rates were 78%, 51%, and 32%, respectively; the mean percentage of patients achieving low disease activity score (DAS ≤ 2.4) and remission (DAS ≤ 1.6) were 44% and 20%, respectively. CONCLUSIONS: ETN maintained a favourable safety profile and consistent efficacy throughout the 5-year study duration.

Interleukin-12 gene polymorphisim in patients with giant cell arteritis, polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

OBJECTIVE: The cytokine profile suggests that giant cell arteritis (GCA) is a Th1-driven disease, in which local IFN-gamma plays a critical role in the development of a systemic arteritis. IL-12 is a potent inducer of IFN-gamma and is critically involved in biasing an immune response towards a Th1 pathway. The purpose of this study was to investigate whether there was an association between an IL-12 gene polymorphism (-1188 A/C 3UTR) and disease susceptibility for GCA and two other age-related inflammatory conditions, such as polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we attempted to correlate such polymorphism with in vitro IL-12 production. MATERIALS AND METHODS: We analyzed genotypes at -1188 in the 3UTR of the IL-12 promoter by PCR-RFLP in 68 GCA, 138 PMR, and 72 EORA patients as well as in 465 healthy controls (HC). IL-12p70 levels in culture supernatants after stimulation with PMA+Ionomycin was assessed by ELISA. RESULTS: All groups were in Hardy-Weinberg equilibrium. Allelic and gen-omic distribution was not significantly different among the study groups. None of the genetic variants was associated with disease severity. Although the differences were not statistically significant, HC genotypes were associated with distinct IL-12 p70 production. CONCLUSIONS: The IL-12 (-1188 A/C 3UTR) gene polymorphism is not associated with disease susceptibility or severity in three age-related chronic inflammatory syndromes. The production of IL-12 p70 is dependent on the genetic background in HC, although in patients such association may be biased by other unknown factors.

The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial.

OBJECTIVE: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. METHODS: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose. RESULTS: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). CONCLUSION: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. TRIAL REGISTRATION NUMBER: NCT00124982.

A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects.

OBJECTIVE: Open label studies have suggested that tumour necrosis factor (TNF) antagonists led to sustained improvement and corticosteroid sparing effect in patients with giant cell arteritis (GCA). To confirm these observations, we conducted a randomised, double-blind, placebo controlled trial with etanercept in patients with biopsy-proven GCA with side effects secondary to corticosteroids. METHODS: We randomly assigned patients with GCA to receive etanercept (n = 8) or placebo (n = 9) over 1 year together with corticosteroids that were reduced according to a predefined schedule. The primary outcome was the ability to withdraw the corticosteroid therapy and control the disease activity at 12 months. RESULTS: Baseline characteristics were similar in the two groups, although patients in the etanercept group showed higher levels of basal glycaemia (p = 0.02) and a higher erythrocyte sedimentation rate (ESR) (p = 0.01). After 12 months, 50% of the patients in the etanercept group and 22.2% in the placebo group were able to control the disease without corticosteroid therapy (p value not significant). Patients in the etanercept group had a significant lower dose of accumulated prednisone during the first year of treatment (p = 0.03). There were no differences in the number and type of adverse events. CONCLUSION: The limited number of patients included in this study does not allow us to draw definitive conclusions. Etanercept therapy was well tolerated in this aged population. The therapeutic role of etanercept in patients with GCA should be evaluated in studies with a larger number of patients.

Recall injection-site reactions associated with etanercept therapy: report of two new cases with immunohistochemical analysis.

Injection site reactions (ISRs) are the most common adverse effect reported with etanercept therapy. It has been observed that some patients treated with etanercept develop ''recall ISRs'', that are reactions at sites where etanercept was previously injected after the last injection. Etanercept-associated recall ISRs have been scarcely published. We report two patients with rheumatoid arthritis who developed recall ISRs during etanercept therapy. Biopsy specimens from ISRs demonstrated a superficial perivascular lymphocytic infiltrated with a few eosinophils. Immunohistochemical study in both cases revealed that T cells bearing a CD4+ phenotype mostly composed the inflammatory infiltrate. Our observations suggest that ISRs may be mediated by classic cellular-hypersensitivity reactions directed by CD4+ T lymphocytes.

Plasma adrenomedullin levels in patients with polymyalgia rheumatica and giant cell arteritis.

OBJECTIVE: Plasma adrenomedullin (AM) levels are elevated in several inflammatory rheumatic diseases. The aims of the present study were: a) to assess whether plasma AM levels are abnormal in patients with polymyalgia rheumatica and giant cell arteritis (PMR and GCA) and b) to investigate if this parameter is related to clinical and biochemical indicators of disease activity in these patients. MATERIALS AND METHODS: AM plasma levels were analyzed in 17 patients with PMR and GCA and in 14 healthy subjects. Twelve patients (9 PMR and 3 GCA) were studied when they had active disease before any steroid therapy and the remaining 5 patients (2 PMR and 3 GCA) were in complete clinical remission and no longer receiving steroid treatment. AM was measured by a specific radioimmunoassay. RESULTS: Plasma AM concentration was significantly higher in patients with active GCA compared to the control group (p < 0.05) and with patients with isolated PMR (p < 0.05). However, there were no significant differences between patients with active PMR and the control group. Within the PMR/GCA group with active disease, AM plasma levels were positively correlated with ESR (r = 0.6, p = 0.02), and negatively with hematocrit (r = -0.57, p = 0.03) and hemoglobin (r = -0.55, p = 0.04). No correlations were found between AM and CRP. CONCLUSION: Plasma levels of AM are elevated in patients with active GCA and correlate with parameters that reflect the acute phase response. The differences in the secretion of AM between patients with PMR and GCA might reflect the severity of the vascular endothelial cell damage in these conditions. The role of AM in the pathogenesis of PMR and GCA needs to be assessed in a larger series of patients.

A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs.

OBJECTIVE: To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. METHODS: 549 patients entered this 5-year, open-label extension study and received etanercept 25 mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs before entry into the double-blind studies. Safety assessments were carried out at regular intervals. Primary efficacy end points were the numbers of painful and swollen joints; secondary variables included American College of Rheumatology (ACR) response rate, Disease Activity Score and acute-phase reactants. Efficacy was analysed using the last-observation-carried-forward approach. RESULTS: Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%) completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis. A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the open-label trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively. Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site reactions. Rates of serious infections and malignancies remained unchanged over the course of the study; there were no reports of patients with central demyelinating disease or serious blood dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%, respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from 5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the 3-year time period. CONCLUSION: After 3 years of treatment, etanercept showed sustained efficacy and a favourable safety profile.

Clinical disease activity and titers of anti-dsDNA antibodies measured by an automated immunofluorescence assay in patients with systemic lupus erythematosus.

Autoantibodies specific for double stranded DNA (anti-dsDNA Abs) are a serological biomarker of systemic lupus erythematosus (SLE) and constitute useful tools for monitoring many SLE patients. A new automated immunofluorescence and quantitative assay (EliA dsDNA) has recently become available. Its performance has been demonstrated to be equivalent to the Farr and Crithidia luciliae fluorescence (CLIFT) tests. The aim of the present work was to assess the utility of this new assay to monitor clinical activity in a large cohort of SLE patients. To this end, 1020 sera from 181 SLE patients were evaluated by the two methods. Results showed a higher frequency of positive results of anti-dsDNA Abs during lupus flares measured by EliA dsDNA than by CLIFT. Likewise, titers of those Abs were significantly increased in active SLE in comparison with inactive SLE when measured by EliA dsDNA but not by CLIFT. Serum titers of anti-dsDNA Abs by both assays showed a significant negative association with concentrations of C3 and C4. In summary, this retrospective study on a large cohort of patients demonstrated that EliA dsDNA was at least as useful as CLIFT as monitoring tool in the follow-up of SLE patients, but with the advantages of being automated, quick and quantitative.

Respuesta del panel de expertos / Experts board's reply

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Segunda actualización del consenso de la Sociedad Española de Reumatología sobre la terapia biológica en la artritis reumatoide / II Update of the Consensus of the Spanish Society of Rheumatology on Biological Therapy in Rheumatoid Arthritis

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Clinical utility of anti-CCP antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica.

BACKGROUND: In a significant number of patients the differential diagnosis between elderly-onset rheumatoid arthritis (EORA) and polymyalgia rheumatica (PMR) is very difficult because of the lack of specific serum markers. Anti-cyclic citrullinated peptide antibodies (anti-CCP Abs) have recently been shown to be highly specific for rheumatoid arthritis (RA). This is the first study addressing the utility of these antibodies in the differential diagnosis between EORA and PMR. METHODS: Serum samples from 57 EORA patients and 49 PMR patients were studied for the presence of anti-CCP Abs and rheumatoid factor (RF). As controls, samples from 41 RA patients (age at onset <60 yr) and 24 aged healthy subjects were analysed. RESULTS: Sixty-five per cent of EORA patients had anti-CCP Abs, whereas none of the PMR patients or the aged healthy subjects was positive for those antibodies. Ten of the EORA patients started with polymyalgic symptoms and two of them were positive for anti-CCP Abs. Interestingly, there was a significant correlation between anti-CCP Abs and RF in EORA but not in young RA patients. CONCLUSIONS: The presence of anti-CCP Abs in a patient with clinical symptoms of PMR must be interpreted as highly suggestive of EORA.

Selective T cell receptor decrease in peripheral blood T lymphocytes of patients with polymyalgia rheumatica and giant cell arteritis.

OBJECTIVES: To investigate the phenotype and T cell receptor (TCR) use in peripheral blood T cells in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: Circulating T lymphocyte phenotype and TCR repertoire were studied by flow cytometry using specific monoclonal antibodies in 23 healthy controls and 37 patients with PMR/GCA. RESULTS: Patients with active PMR/GCA showed an inverse relation between naive and memory CD4+ T cells and unchanged expression of activation surface markers compared with controls. CD4+ TCR BV expansions were seen in 12 (52%) controls and in 8 (22%) patients with active disease (p = 0.03). Within the CD8+ subset, the frequency of expansions was similar between groups. Most T cell expansions remained stable over time. Seventeen of the 23 patients with active PMR/GCA disclosed a simultaneous CD4+ and CD8+ T cell depletion for at least one particular BV family with a clear predominance of BV5S2/S3. CONCLUSIONS: The phenotype of circulating T cells in patients with PMR/GCA is similar to that found in aged healthy subjects, except for the surface markers of naive and memory cells and a striking non-activated phenotype. Specific BV expansions in CD4+ and CD8+ T cells, which remain stable over time, are frequent in aged subjects, including patients with PMR/GCA. TCR BV changes in patients with active disease seem to be also age related, except for the significant decrease in certain BV families in both CD4+ and CD8+ T cell subsets, which may favour the participation of a superantigen stimulation in PMR/GCA.

Clinical, immunogenetic and outcome features of Hispanic systemic lupus erythematosus patients of different ethnic ancestry.

The aim of this study was to compare and contrast the clinical, immunogenetic and outcome features of two subgroups of Hispanic patients with systemic lupus erythematosus (SLE), one from Northern Spain (Spaniards) and one of from the USA (Hispano-Americans: Hispanics primarily of Mexican ancestry (Amerindian and Spaniard backgrounds). Patients with SLE as per the American College of Rheumatology classification criteria, from two University-affiliated Hospitals (Universidad de Cantabria) and disease of five or less years in duration (n = 28) and with four years of follow up constituted the Spaniard subgroup. Fifty-two patients of Hispano-American ancestry from the LUMINA (Lupus in Minority populations: Nature versus Nurture) cohort constituted the Hispano-American subgroup. Patients were studied using a similar protocol. In short, sociodemographic, clinical, immunological, immunogenetic and psychosocial and behavioral features were obtained at enrollment into the study (baseline visit) and yearly thereafter. The relationship between these variables and disease activity at baseline and over time, as measured by the systemic lupus activity measure (SLAM) and disease damage, as measured by the SLICC (Systemic Lupus International Collaborating Clinics) Damage Index (SDI) were determined. Variables found to be significant at P = 0.10 were then entered into multivariable linear regression models with disease activity at baseline and over time, and damage as the outcome measures. Patients of Hispano-American and Spaniard ethnicity had comparable sociodemographic features except for home density, which was higher among the Hispano-Americans. HLA-DRB1*08 was associated with SLE among the Hispano-Americans but not among the Spaniards. Hispano-American patients had more severe disease as manifested by more frequent clinical manifestations (renal and neurological), higher SLAM scores at baseline and over time and higher SDI scores at the year 4 visit (that despite the fact that Hispano-American patients had overall shorter disease duration than the Spaniard patients). Hispano-American ethnicity, younger age at disease onset and the number of ACR criteria at baseline and over time were consistently associated with disease activity, whereas increased home density and the absence of HLA-DRB1*0301 were significant predictors only over time. Disease damage was associated with disease activity over time, the number of ACR criteria at baseline, increased home density and the presence of HLA-DRB1*08. This is the first longitudinal study of SLE in two different Hispanic subgroups. Hispanics with a strong Amerindian background have a more serious disease than that observed in Spaniards. Genetic and socio-economic differences between these two Hispanic subgroups probably account for these findings.

Functional outcome and subset identification in RA patients from meridional Europe: analysis of a Spanish cohort.

The aim of this study was to study the short-term functional and anatomical prognosis of rheumatoid arthritis (RA) in a series of Spanish patients and to identify different subsets of patients as well as possible baseline factors associated with specific outcomes. All patients seen in our division who met the ACR criteria for RA and with disease duration between 2 and 7 years were eligible for the study. Available patients were further evaluated at the clinic for disease activity using biological tests and joint indices as joint counts and Thompson's index, functional capacity using the ACR functional classification (ACR-FC) and the modified Health Assessment Questionnaire (M-HAQ) and radiologic damage by the Sharp's radiologic scoring method. Cluster analysis was used to identify different clinical subsets of patients. One hundred and sixty-three patients were eligible for the study, 13 could not be located or refused to participate and 12 had died. Mean (+/-SD) age at disease onset and mean disease duration were, respectively, 56(+/-14) years and (55+/-20) months. Median (interquartile range) of M-HAQ was 0.4 (0.1-1.1) and 41% of patients were in III or IV ACR-FC. The majority of patients (93%) showed radiologic lesions and 65% had erosions. Cluster analysis identified three subsets: cluster I (70% of patients) was characterised by a good prognosis, cluster II (13%) by a high level of disease activity, and cluster III (17%) by a greater anatomic damage and longer disease duration. No baseline predictive markers were found for these different outcomes. We concluded that RA portends an overall poor short-term prognosis in a relative large percentage of our patients with significant anatomic and functional sequelae. Aggressive management is specially indicated in this subgroup of patients, although definitive prognostic markers for its early identification are still lacking.

Homocysteine levels in polymyalgia rheumatica and giant cell arteritis: influence of corticosteroid therapy.

OBJECTIVES: It has been suggested that patients with giant cell arteritis (GCA) may share a common pathway with atherosclerosis. Furthermore, patients with GCA and polymyalgia rheumatica (PMR), in addition to advanced age, are treated for prolonged periods of time with corticosteroids, a factor that can also accelerate atherosclerosis. Hyperhomocysteinaemia is considered an independent risk factor for atherosclerosis, and might play a role in ischaemic manifestations that occur with a variable frequency during the course of GCA. The purposes of the present study were: (i). to analyse the plasma levels of homocysteine in patients with GCA and PMR, (ii). to determine the influence of corticosteroid therapy on the homocysteine levels and (iii). to analyse if the levels of homocysteine may predict the development of ischaemic complications in patients with GCA. METHODS: Plasma homocysteine concentration was measured in 56 patients with active PMR/GCA (17 GCA and 39 isolated PMR) before steroid treatment and 23 healthy age-matched volunteers were used as controls. The total plasma homocysteine level was quantified using a fluorescent polarization immunoassay. RESULTS: Homocysteine concentrations were higher in PMR and GCA patients than age-matched controls (P < 0.05). Patients with GCA had slightly higher levels of plasma homocysteine than those with isolated PMR (13.6+/-4.3 vs 12.7+/-3.1 micromol/l, P=0.6). In 30 of these patients (12 GCA and 18 PMR) a second measurement of homocysteine concentration was done when they were in clinical remission with steroid treatment. The post-treatment levels of homocysteine were significantly increased in GCA rather than in PMR patients. In 13 patients with homocysteine levels above the normal upper limit of our laboratory, therapy with folic acid and/or vitamin B12 was started. After 3 months of vitamin supplements, the homocysteine concentration significantly decreased from 19.2+/-3.1 to 13.6+/-3.2 micromol/l (P=0.001). Such decrease was less marked in the PMR than in GCA patients. Ten out of the 17 patients with GCA had ischaemic manifestations of the disease. The levels of homocysteine were slightly higher in GCA patients with ischaemia than in those without ischaemic manifestations, although the difference did not reach statistical significance (15+/-4.9 vs 11.6+/-1.9 micromol/l, P=0.46). CONCLUSIONS: Patients with active PMR and GCA had elevated plasma concentrations of homocysteine. Corticosteroid therapy significantly increased such levels, especially in GCA patients. Treatment with supplements of folic acid and/or vitamin B12 reduced the homocysteine concentrations. These data support the hypothesis that patients with GCA (and to a lesser extend PMR patients) may share a common pathway with atherosclerosis and suggest a new atherogenic mechanism of corticosteroids.

Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid.

OBJECTIVE: To investigate the pathogenic mechanism of reactive arthritis after instillation of Calmette-Guérin bacillus (BCG). Although the clinical features of reactive arthritis after BCG therapy are well described, only a few reports have studied the possible pathogenic mechanisms. METHODS: We analysed by flow cytometry the phenotype and T-cell receptor (TCR) expression of peripheral blood (PB) and synovial fluid (SF) T cells in a patient who developed reactive arthritis (ReA) following intravesical BCG immunotherapy for bladder cancer. The proliferative response of short-term T-cell lines (TCL) from PB of this patient to mycobacterial antigens was tested by bromodeoxyuridine incorporation. RESULTS: CD4(+) and CD8(+) SF T cells with activated and memory phenotype were observed at the onset of arthritis. We were able to detect BV-restricted expansion of CD8(+) T cells in PB (BV17) and in SF (BV5S1 and BV12). The percentage of PB and SF CD8(+) T cells that expanded diminished when the symptoms remitted. The strongest response of CD4(+) TCL from the patient in vitro was obtained for human hsp-60 in an inversely dose-dependent manner. Very important was the finding that CD8(+) TCL from the patient demonstrated no proliferative response to any antigenic challenge that was reversed after the addition of exogenous interleukin 2. CONCLUSION: Although the identity of the stimulating antigen that led to the expansions observed in this patient is not clarified by the present data, both CD4(+) and CD8(+) T cells might play a role in the development of ReA following intravesical administration of BCG.

Familial aggregation of polymyalgia rheumatica and giant cell arteritis: genetic and T cell repertoire analysis.

OBJECTIVE: Several reports of familial aggregation of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) have been described although detailed genetic and immunological studies are scarce. Our aims were to investigate the influence of HLA-DRB1 alleles and to analyze the phenotype and T cell receptor (TCR) usage of circulating T lymphocytes in a familial case of GCA and PMR. METHODS: HLA-DRB1 typing was carried out using polymerase chain reaction amplification with specific primers. The study of the circulating T cell repertoire was performed by staining with specific monoclonal antibodies and flow cytometry analysis. RESULTS: Patient 1 developed GCA at the age of 71, four years prior to the diagnosis of PMR in her older brother. The HLA-DRB1 typing of Patient 1 was DRB1*04 (DRB1*0401)/DRB1*12 and in Patient 2 was DRB1*07/DRB1*12. In our patient population, GCA was associated with an increased frequency of HLA-DRB1*04 compared with PMR patients. Regarding T cell phenotype, the brother with active PMR had a higher expression of surface markers indicating activation in both T cell subsets (CD25 and HLA-DR). The sister with GCA showed a pronounced decrease of CD4+/CD45RA+ T cells with respect to her brother with PMR. Both patients carried a significant depletion of CD28 in both subsets, specially within the CD8+ T cell compartment. The BV gene usage differed from one patient to the other. T cell expansions were identified in both patients but the specificities were different. CONCLUSION: We describe an association of GCA and PMR between two first degree relatives with significant genetic and immunologic differences. Our results suggest that the pathogenic mechanisms leading to the development of GCA and PMR are probably multifactorial, and both genetic and environmental factors may contribute to the development of these diseases.