Non-adherence to subcutaneous biological medication in patients with rheumatoid arthritis: a multicentre, non-interventional study.

OBJECTIVES: To evaluate non-adherence to prescribed subcutaneous biologicals in rheumatoid arthritis (RA) patients in Spain. METHODS: ARCO (Study on Adherence of Rheumatoid Arthritis patients to SubCutaneous and Oral Drugs) was a multicentre, non-interventional retrospective study involving 42 rheumatology clinics from representative hospitals throughout Spain. The primary objective was to assess the percentage of patients (aged ≥18 years with an established RA diagnosis) with non-adherence to prescribed subcutaneous biologicals using clinical records and hospital pharmacy dispensing logs as the primary information sources. Adherence was assessed using the Medication Possession Ratio (MPR). Additionally, patients completed the Morisky-Green Medication Adherence Questionnaire. RESULTS: A total of 364 patients (77.5% females, mean age 54.9 years, median RA duration since diagnosis 7.8 years) were enrolled in ARCO. Non-adherence (MPR ≤80%) was reported in 52/363 evaluable patients (14.3%), and was lower in patients receiving initial monthly drug administration (6.4%) than with weekly (17.4%; p=0.034) or every two weeks (14.4%; p=0.102) administration. By multivariate analysis, non-adherence was positively associated with RA duration above the median and with using induction doses. Monthly administration, compared to weekly administration, was inversely associated with non-adherence. Age, gender, order of administration, and changes in the interval of administration, showed no association with non-adherence. Compared with the MPR, the Morisky-Green questionnaire performed poorly in detecting non-adherence. CONCLUSIONS: Non-adherence to the prescribed subcutaneous biological drug occurred in 14.3% of patients with RA. Patients using the most convenient administration period (i.e. monthly) had better adherence than those using more frequent dosing schedules.

Anti-TNF-alpha-adalimumab therapy is associated with persistent improvement of endothelial function without progression of carotid intima-media wall thickness in patients with rheumatoid arthritis refractory to conventional therapy.

To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1 ± 3.9%; median: 5.7% at day 14, and mean ± SD: 7.4 ± 2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5 ± 4.0%; median: 3.6%; P = 0.03 and P < 0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69 ± 0.21 mm) were compared with those found at day 0 (0.65 ± 0.16 mm) (P = 0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA.

Lack of association between RETN rs1862513 polymorphism and cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVES: To assess the influence of the RETN rs1862513 polymorphism in the risk of cardiovascular (CV) disease and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Six hundred and sixty-eight patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo, and Hospital San Carlos, Madrid, Spain, were studied. Patients were genotyped for the RETN rs1862513 polymorphism using predesigned TaqMan single nucleotide polymorphism genotyping assay. Also, HLA-DRB1 genotyping was performed using molecular based methods. Carotid intima-media thickness (IMT), flow-mediated endothelium-dependent and endothelium independent vasodilatation, used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients. RESULTS: No significant differences in the genotypic or in the allelic distribution between RA patients with or without CV disease were found. In this regard, we only observed a slight increased frequency of homozygous and heterozygous for the minor allele G (CG+GG genotypes) among patients who experienced CV events compared to those without CV events (53.04% vs. 52.62%, p=0.94). A higher frequency of classic CV risk factors was observed among the carriers of the minor allele G. However, in the adjusted logistic regression model no association between the RETN variant and CV disease was found (p=0.50). Also, when surrogate markers of subclinical atherosclerosis were assessed, in the adjusted ANCOVA model only a trend towards a higher carotid IMT was found among allele G carriers (p=0.06). CONCLUSIONS: RETN rs1862513 polymorphism does not seem to be a genetic risk factor for both clinically evident CV disease and subclinical atherosclerosis in patients with RA.

Role of the rs6822844 gene polymorphism at the IL2-IL21 region in biopsy-proven giant cell arteritis.

OBJECTIVES: To assess the influence of the interleukin (IL)2-IL21 rs6822844 G/T polymorphism in the susceptibility to biopsy-proven giant cell arteritis (GCA) and in the clinical spectrum of manifestations of this vasculitis. METHODS: Two hundred and seventy-two biopsy-proven GCA patients were included in this study. DNA from patients and matched controls (n=791) was obtained from peripheral blood. Samples were genotyped for the rs6822844 polymorphism using a predesigned TaqMan allele discrimination assay and by polymerase chain reaction amplification. RESULTS: No significant differences in the allele and genotype frequencies between biopsy-proven GCA patients and controls were observed. However, the stratification of GCA patients disclosed some differences according to gender and ischemic manifestations of the disease. In this regard, the frequency of the minor allele T was increased in males (14.8%) compared to females (8.4%) (odds ratio-OR:1.89 (95% confidence interval-CI: 1.09-3.28); p=0.02; Bonferroni adjustment p=0.12). Also, minor allele T frequency was increased in GCA patients with severe ischemic complications (12.8%) compared to those without severe ischemic complications (7.7%) (OR:1.72 (95% CI: 0.97-3.05); p=0.05; Bonferroni adjustment p=0.30), and specifically in patients with jaw claudication (13.7% versus 8.2% in those without jaw claudication; OR:1.76 (95% CI: 1.02-3.04); p=0.04; Bonferroni adjustment p=0.24). CONCLUSIONS: IL2-IL21 rs6822844 polymorphism does not appear to be a genetic risk factor for susceptibility to biopsy-proven GCA. However, this gene polymorphism may contribute to the different phenotypic expression of this vasculitis, in particular in the development of ischemic complications of the disease.

Lack of association between hypoxia inducible factor-1 alpha gene polymorphisms and biopsy-proven giant cell arteritis.

OBJECTIVES: Since the transcription factor hypoxia-inducible factor 1 (HIF-1) is a key early mediator of the response to ischemia and giant cell arteritis (GCA) is a polygenic disease leading to severe ischemic complications, in the present study we analysed for first time the implication of two HIF-1alpha gene polymorphisms in the susceptibility to and clinical expression of GCA. METHODS: Two hundred and fifteen biopsy-proven GCA patients and 470 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for two single nucleotide polymorphisms, rs11549465 (C/T) and rs11549467 (G/A), using a pre-designed TaqMan allele discrimination assay. Post PCR, the genotype of each sample was attributed automatically by measuring the allelic specific fluorescence on the ABI PRIM 7900 sequence. RESULTS: The HIF-1alpha, rs11549465 TT genotype was extremely uncommon in both GCA patients (2.3%) and controls (2.1%). Although the frequency of individuals carrying the CT or TT genotypes was increased in GCA patients (25.1%) compared to controls (20.4%) the difference was not statistically significant (OR 1.30 [95% CI: 0.89- 1.91]; p=0.17). Also, all GCA patients and most controls (98.9%) were homozygous for the rs11549467 GG genotype. GCA patients carrying the rs11549465 CT or TT genotypes had a slight increased risk of developing visual ischemic complications (33.1%) compared to the remaining GCA patients (22.8%); OR 1.60 (95% CI: 0.81- 3.16); p=0.18. CONCLUSIONS: Our results do not confirm an implication of HIF-1alpha gene polymorphisms in the susceptibility to and clinical expression of GCA.

Long-term survival of subcutaneous anti-tumor necrosis factor biological drugs administered between 2008 and 2012 in a cohort of rheumatoid arthritis patients. / Supervivencia a largo plazo de los fármacos biológicos anti-TNF subcutáneos administrados durante los años 2008-2012 en una cohorte de pacientes con artritis reumatoide.

OBJECTIVE: To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. MATERIAL AND METHODS: Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. RESULTS: Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). CONCLUSIONS: In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy.

Investigations into audiovestibular manifestations in patients with psoriatic arthritis.

OBJECTIVE: Although psoriatic arthritis (PsA) is a common chronic inflammatory rheumatic disease, little is known about audiovestibular impairment in this condition. We aimed to establish whether audiovestibular manifestations were present in patients with PsA. METHODS: A set of 60 consecutive patients who fulfilled the Moll and Wright criteria for PsA and 60 matched controls were studied. During the period of recruitment, individuals were excluded who had a history of cardiovascular disease, cerebrovascular complications, peripheral artery disease, renal insufficiency, syphilis, Meniere disease and other vestibular syndromes, infections involving the inner ear, barotrauma, or were in treatment with ototoxic drugs. RESULTS: Most patients with PsA were men (63%). The mean age at the time of our study was 52.9 years and the mean age at the onset of symptoms was 33 years. Thirty-six (60%) of the 60 patients showed abnormal hearing loss in the audiogram compared to only 5 (8.3%) of the 60 controls (p < 0.001). Values of audiometric tests (pure-tone average and speech reception threshold) yielded significant differences between patients and controls (p < 0.001). The audiogram disclosed a bilateral and symmetrical sensorineural hearing loss (SNHL) in PsA with predominant pattern of high frequency SNHL in patients with PsA (46.7%) compared to controls (8.3%, p < 0.001). Patients with PsA exhibited abnormal vestibular tests more commonly than controls. A significantly increased frequency of abnormal computerized dynamic posturography with a predominant vestibular loss pattern was also observed in patients (23.3%) compared to controls (0%, p < 0.001). CONCLUSION: Our current study demonstrates strong evidence for inner ear damage in patients with PsA.

Benign paroxysmal positional vertigo and clinical test of sensory interaction and balance in ankylosing spondylitis.

OBJECTIVE: To assess the frequency and characteristics of benign paroxysmal positional vertigo (BPPV) and clinical test of sensory interaction and balance (CTSIB) abnormalities in patients with ankylosing spondylitis (AS). STUDY DESIGN: A series of consecutive patients that fulfilled the modified New York diagnostic criteria for AS and matched controls were studied. SETTING: The study was performed at the Otolaryngology Division of a tertiary reference center. PATIENTS: Fifty-nine patients with AS (47 men [79.6%]) attending hospital outpatient rheumatology clinics between March and October 2008, and 46 controls (34 men [73.9%]) were studied. INTERVENTION: Dix-Hallpike and cephalic rotational tests and CTSIB were performed in AS patients and age-, sex-, and ethnically frequency-matched controls. MAIN OUTCOME MEASURE: Type and frequency of BPPV and CTSIB conditions were assessed. RESULTS: BPPV was diagnosed in 6 patients (10.1%) with AS and in 2 (4.3%) of the controls (p = 0.24). Abnormal caloric test was more commonly observed in patients with AS (n = 15 [25.4%]) than the controls (n = 0) (p < 0.001). Increased frequency of abnormal CTSIB also was observed in patients (19/59 [32%]) compared with the controls (3 [6.5%]) (odds ratio, 6.81 [95% confidence interval, 1.77-38.0]; p = 0.001). Among the abnormal CTSIB patterns, the vestibular loss was the most commonly observed in patients with AS (15/59 [25.4%]). CONCLUSION: The present study shows an increased frequency of abnormal postural control in CTSIB test of vestibular origin in patients with AS.

Systemic lupus erythematosus in northwestern Spain: a 20-year epidemiologic study.

To further investigate the epidemiology of systemic lupus erythematosus (SLE) in southern Europe, we assessed the incidence, prevalence, clinical spectrum of the disease, flares, and survival of patients diagnosed with SLE in the Lugo region of northwestern Spain. Between January 1987 and December 2006, 150 Lugo residents were diagnosed as having SLE according to the 1982 American College of Rheumatology criteria for the classification of SLE. Women outnumbered men (127 [84.7%] vs. 23 [15.3%]). The mean age at the time of disease diagnosis was 46.1 ± 19.6 years. The mean follow-up from the time of disease diagnosis was 7.8 ± 4.5 years. The age- and sex-adjusted annual incidence rate over the 20-year study period was 3.6 (95% confidence interval [CI], 3.0-4.2) per 100,000 population aged 15 years and older. The overall annual incidence rate over the 20-year study period in women (5.9/100,000 population aged ≥ 15 yr; 95% CI, 4.9-7.0) was higher than in men (1.1/100,000 population aged ≥ 15 yr; 95% CI, 0.7-1.7) (p < 0.001). By December 31, 2006, the overall age-adjusted SLE prevalence in the Lugo region for patients who fulfilled at least 4 of 1982 American College of Rheumatology criteria was 17.5 per 100,000 population aged 15 years and older (95% CI, 12.6-24.1). Prevalence in women (29.2/100,000 population aged ≥ 15 yr; 95% CI, 20.0-40.7) was higher than in men (5.8/100,000 population aged ≥ 15 yr; 95% CI, 2.0-12.0). The most frequent clinical manifestation was arthritis. As reported in population-based studies on SLE patients of European descent, renal disease was observed in only 27.3% of the patients. The rate of flares was 0.084/year. A younger age and the presence of nephritis at the time of disease diagnosis were associated with the development of flares during the follow-up of Lugo patients. Compared with the general population the probability of survival in patients with SLE was significantly reduced (p = 0.04). In conclusion, the present study establishes a baseline estimate of the incidence and clinical spectrum of SLE in northwestern Spain. According to our results, the incidence of SLE in northwestern Spain is slightly higher than that reported in most European regions. Patients with SLE from northwestern Spain have a later average age onset and a lower frequency of nephritis than in the African-American population. However, our data show a reduced probability of survival in Spanish patients with SLE.

TNFA -308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis.

OBJECTIVE: To assess the influence of the TNFA rs1800629 (G > A) polymorphism in the risk of cardiovascular (CV) disease and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: 587 patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were studied. Patients were genotyped for the TNFA rs1800629 polymorphism using predesigned TaqMan single nucleotide polymorphism genotyping assay. Also, HLA-DRB1 genotyping was performed using molecular based methods. Carotid artery intima-media thickness, flow-mediated endothelium-dependent and endothelium independent vasodilatation, used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients. RESULTS: We observed a higher frequency of carriers of the minor allele A among the patients with CV disease (with 37.6% vs. without 27.9%, p = 0.06, OR 1.56 [95% confidence interval-CI 0.95-2.54]). Carriers of the minor allele A exhibited a higher risk of CV events after adjustment for demographic and traditional CV risk factors (p = 0.023, HR 1.72 [95% CI 1.076-2.74]). Also, a significant interaction between this polymorphism and the presence of the rheumatoid shared epitope (SE) was observed (p = 0.024). Due to this, the association between carriers of the minor allele A and CV disease was only present in carriers of the SE, even after adjustment (p = 0.001, HR 2.43 [95% CI 1.41-4.19]). No significant association between the TNFA variant and the surrogate markers of subclinical atherosclerosis was observed. CONCLUSION: Our results show that TNFA rs1800629 gene polymorphism is associated with predisposition to CV complications in patients with RA. This predisposition is restricted to individuals carrying the rheumatoid SE.

CCR5Δ32 variant and cardiovascular disease in patients with rheumatoid arthritis: a cohort study.

INTRODUCTION: The aim of our study was to analyze the influence of the CCR5Δ32 polymorphism in the risk of cardiovascular (CV) events and subclinical atherosclerosis among patients with rheumatoid arthritis (RA). METHODS: A total of 645 patients fulfilling the American Rheumatism Association 1987 revised classification criteria for RA were studied. Patients were genotyped for the CCR5 rs333 polymorphism using predesigned TaqMan assays. Also, HLA DRB1 genotyping was performed using molecular-based methods. Carotid intima-media thickness, flow-mediated endothelium-dependent dilatation (FMD) and endothelium-independent vasodilatation, which were used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients with no clinical CV disease. RESULTS: A lower frequency of carriers of the CCR5Δ32 allele among patients with CV events (3.4% versus 11.3%, P = 0.025, odds ratio 0.28, 95% confidence interval (95% CI) 0.06 to 0.89) was observed. However, after adjusting for gender, age at time of RA diagnosis, and the presence of shared epitope, rheumatoid factor and classic CV risk factors in the Cox regression analysis, this reduction of CV events in CCR5Δ32 allele carriers was slightly outside the range of significance (P = 0.097; hazard ratio 0.37 (95% CI 0.12 to 1.19)). Carriers of the CCR5Δ32 deletion also showed higher FMD values than the remaining patients (CCR5/CCR5Δ32 patients: 7.03% ± 6.61% versus CCR5/CCR5 patients: 5.51% ± 4.66%). This difference was statistically significant when analysis of covariance was performed (P = 0.024). CONCLUSIONS: Our results show a potential influence of the CCR5Δ32 deletion on the risk of CV disease among patients with RA. This may be due to a protective effect of this allelic variant against the development of vascular endothelial dysfunction.

Audiovestibular manifestations in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin affecting up to 1% of the population. Little is known about audiovestibular impairment in patients with AS, especially the presence of cochleovestibular dysfunction in these patients. To investigate audiovestibular manifestations in AS, we studied a series of 50 consecutive patients who fulfilled the modified New York diagnostic criteria for AS and 44 matched controls. Individuals with history of cardiovascular disease, cerebrovascular complications, peripheral artery disease, renal insufficiency, syphilis, Meniere and other vestibular syndromes, infections involving the inner ear, barotrauma, or in treatment with ototoxic drugs were excluded. Most patients with AS were men (80%). The mean age at the time of study was 52.5 years, and mean age at the onset of symptoms was 34.4 years. Twenty-nine (58%) patients showed abnormal hearing loss in the audiogram compared to only 8 (18%) controls (p < 0.001). Values of audiometric tests (pure-tone average and speech reception threshold) yielded significant differences between patients and controls (p < 0.001). It is noteworthy that the audiogram shape disclosed a predominant pattern of high-frequency sensorineural hearing loss in AS patients (50%) compared to controls (18%) (p = 0.002). Also, AS patients exhibited abnormal vestibular tests more commonly than controls. AS patients had an increased frequency of head-shaking nystagmus (20%) compared to controls (0%) (p < 0.001). Moreover, patients (26%) showed a significantly increased frequency of abnormal caloric test compared to controls (0%) (p < 0.001). Finally, a significantly increased frequency of abnormal clinical test of sensory integration and balance with a predominant vestibular loss pattern was observed in patients (36%) compared to controls (5%) (p < 0.001). In conclusion, the current study demonstrates strong evidence for inner ear compromise in patients with AS.

Relapses and recurrences in giant cell arteritis: a population-based study of patients with biopsy-proven disease from northwestern Spain.

We conducted the present study to determine the incidence of disease flares (relapses and recurrences) in a series of patients with biopsy-proven giant cell arteritis (GCA). We assessed a series of 174 patients who were diagnosed with biopsy-proven GCA, uniformly treated, and followed at the rheumatology division of Hospital Xeral-Calde (Lugo, Spain), the single rheumatology division for a well-defined population. All of them were followed for at least 1 year after the disease diagnosis. Seventy-one (40.8%) experienced relapses or recurrences of the disease. Patients who had relapses or recurrences did not show clinical differences when compared with the remaining biopsy-proven GCA patients. However, the total duration of corticosteroid therapy was significantly longer in those patients who had relapses or recurrences of the disease. The median dose of prednisone and the median duration of corticosteroid treatment at the time of the first relapse were 5 mg/d and 16 months, respectively. Headache (52%) was the most common feature at the time of the first relapse. Polymyalgia rheumatica manifestations occurred in 30% of the patients at that time. However, none of them developed visual loss. Thirty-two patients experienced recurrences of the disease when prednisone dose had been discontinued. The median time from the disease diagnosis to the time of the recurrence was 23 months. The presence of anemia (hemoglobin <12 g/dL) at the time of disease diagnosis was the best predictor of relapses or recurrences of GCA (odds ratio, 2.17; 95% confidence interval, 1.02-4.62; p = 0.04). The results from the present study confirm that relapses and recurrences are frequent in homogenously treated patients with biopsy-proven GCA. A chronic inflammatory response manifested by anemia at the time of disease diagnosis may predict the development of disease flares.

Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy.

Increased prevalence of insulin resistance has been observed in patients with rheumatoid arthritis (RA). High-grade systemic inflammation is implicated in the development of insulin resistance in these patients. Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine that plays a role in the initiation and progression of inflammation and the mechanisms associated with accelerated atherosclerosis in RA. In assessing data immediately prior to and after intravenous infusion of the anti-TNF-alpha monoclonal antibody-infliximab in RA patients on period treatment with this drug attributable to disease refractory to conventional disease-modifying antirheumatic drugs, a dramatic improvement of insulin resistance and insulin sensitivity was observed. A long-term positive effect of TNF-alpha antagonists infliximab and etanercept on insulin resistance in RA patients with severe disease was also reported. These results highlight the importance of therapies that act blocking TNF-alpha function to reduce the mechanisms implicated in the development of the metabolic syndrome observed in RA.