Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept.

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

Validation study of genetic biomarkers of response to TNF inhibitors in rheumatoid arthritis.

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.

Comparative effectiveness of treatment with the first TNF antagonist in monotherapy, the first TNF antagonist plus one conventional synthetic disease-modifying antirheumatic drug, and the first TNF antagonist plus two or more conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) patients are treated with a mean of 3-4 conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) with or without glucocorticoids (GCs), before the first biologic prescription. The main reasons for change are inefficacy in 30-40 % of patients, and toxicity ≈ 10 %. Thus, they are treated with the first TNF antagonists in monotherapy. The aim of this study was to analyse the csDMARD and GC prescription patterns before and during treatment with the first TNF antagonist, and compare their effectiveness in three groups of patients. METHODS: An observational, prospective, multicentre study in common clinical practice was designed. Treating rheumatologists recorded patient variables, including previous and concomitant csDMARDs and GCs in a database. The data were analysed using descriptive, inferential and multivariate statistics. RESULTS: There were 1136 patients included; 21 % received the first TNF antagonist in monotherapy, 67 % received the first TNF antagonist plus one csDMARD, and 12 % the first TNF antagonist plus two or more csDMARDs. Most patients were female (73 %), RF+, and ACPA+, and had erosions; mean age was 53.2 (±13.0) years, and duration of disease was 9.1 (±7.6) years. They had high activity with DAS28 of 5.8 ± 1.1, and poor physical function with HAQ of 1.43 ± 0.63, and significant differences between groups in clinical variables and comorbidities; 94 % had received treatment with GCs, MTX, LFN, or SSZ at any time before the first TNF antagonist, 5 % (n = 52) had been treated with CLQ or HCLQ, and 1 % (n = 13) had received neither GCs nor csDMARDs. Before the first TNF antagonist, the drugs most commonly used were GCs (78 %), MTX (50 %), LFN (44 %), and SSZ (21 %). Concomitantly with the first TNF antagonist, 977 patients (85 %) were receiving GCs, MTX, LFN, or SSZ; 15 % (n = 173) received their first TNF antagonist without any concomitant GCs or csDMARDs, true monotherapy, and 6 % received their first TNF antagonist with GCs. The drug most commonly used at the time of first TNF antagonist initiation was MTX (58 %). All treatment groups had clinically and statistically significant improvements in DAS and HAQ scores. Effectiveness analysis (controlling for confounders) showed mean drug survival of 16.7, 20.1 and 11.7 months in each group, respectively (p < 0.001). The model that best explained a good EULAR response included the baseline and 6-month DAS28. CONCLUSIONS: The three groups of patiernts, have different comorbidities and disease characteristics. Treatment with low or very low doses of GCs is common. True monotherapy with the first TNF antagonist without prednisone or csDMARDs is infrequent. After controlling for potential confounders, effectiveness was a little different.

FCGR polymorphisms in the treatment of rheumatoid arthritis with Fc-containing TNF inhibitors.

OBJECTIVES: Reproducible association of a functional polymorphism in FCGR2A with response to a TNF inhibitor (TNFi) in patients with rheumatoid arthritis (RA) led us to explore other FcγR functional polymorphisms. METHODS: Functional polymorphisms FCGR3A F158V, FCGR2B I223T and promoter VNTR in FCGRT were analyzed in up to 429 patients with RA. Response to TNFi was recorded during standard care at 3, 6 and 12 months of follow-up. Fixed effects meta-analysis of studies addressing FCGR3A F158V polymorphism, which is the most studied of these polymorphisms, was conducted with inverse variance weighting. RESULTS: None of the functional polymorphisms were associated with change in DAS28. Meta-analysis of the seven studies (899 patients) with available data addressing association of FCGR3A F158V with response to TNFi in RA showed no association (OR: 1.11, 95% CI: 0.8-1.5; p = 0.5). CONCLUSION: None of the three functional polymorphisms in FcγR genes showed association with response to TNFi in patients with RA. These negative results were obtained in spite of the larger size of this study relative to previous studies addressing the same polymorphisms. In addition, meta-analysis of FCGR3A F158V was also negative against the results provided by previous studies. Original submitted 17 September 2014; Revision submitted 9 December 2014.

Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA.

Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

OBJECTIVE: The efficacy and safety of subcutaneous tocilizumab (TCZ-SC) versus subcutaneous placebo (PBO-SC) was evaluated in patients with rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs in the BREVACTA study. METHODS: Patients (n = 656) were randomized 2:1 to receive TCZ-SC 162 mg every other week or PBO-SC every other week for 24 weeks; 20% previously received anti-tumor necrosis factor treatment. Escape therapy with TCZ-SC 162 mg weekly was offered from week 12 for inadequate response. The primary end point was the American College of Rheumatology 20% improvement (ACR20) response at week 24. The key secondary outcomes were radiographic progression and safety. RESULTS: TCZ-SC was superior to PBO-SC for ACR20 response at week 24 (60.9% versus 31.5%; P < 0.0001). All secondary end points showed TCZ-SC to be superior to PBO-SC, including ACR50 and ACR70 response (40% and 20% for TCZ-SC, respectively, and 12% and 5% for PBO-SC, respectively; P < 0.0001 for both) and Disease Activity Score in 28 joints (DAS28) remission (DAS28 <2.6; 32% versus 4% [P < 0.0001]). The mean change in modified Sharp/van der Heijde score was significantly lower in the TCZ-SC group than the PBO-SC group (0.62 versus 1.23; P = 0.0149). Adverse events (AEs) and serious AEs (SAEs) were comparable between the TCZ-SC and PBO-SC groups; 4.6% and 3.7% of patients had at least 1 SAE, respectively, and infection was the most common SAE in 2.1% and 1.8% of patients, respectively. More injection site reactions occurred with TCZ-SC than PBO-SC (7.1% versus 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were 3 deaths in the TCZ-SC group and 0 in the PBO-SC group. CONCLUSION: TCZ-SC every other week had significantly greater efficacy, including ACR end points and inhibition of joint damage, compared with PBO-SC. TCZ-SC was well tolerated and its safety profile was comparable with that of previous intravenous TCZ studies.

Association of FCGR2A with the response to infliximab treatment of patients with rheumatoid arthritis.

OBJECTIVES: We aimed to assess a functional polymorphism in FCGR2A H131R, for association with the treatment response to Fc-containing inhibitors of tumor necrosis factor (TNF). METHODS: A total of 429 biologic-naive patients with rheumatoid arthritis collected in two sets (299 and 130) were treated during standard care with infliximab (INX), etanercept, or adalimumab. Response to the treatment was evaluated at 3, 6, and 12 months of follow-up as the change in the Disease Activity Score (DAS) 28 from baseline and as the response by the European League Against Rheumatism (EULAR) criteria. These variables were analyzed for association with linear and logistic regression models that included sex, inhibitors of TNF, and baseline DAS28 as covariates. RESULTS: Significant association was found between the FCGR2A H131R polymorphism and the response to treatment with INX, but not with the other two TNF inhibitors. The 131R allele was associated with a lower change in DAS28 (P=0.04-0.008 at different times) in the first set of patients and confirmed in the second group of patients (P=0.026 at 3 months of follow-up). Association was also found in the comparison between nonresponders and responders to INX by the EULAR criteria. CONCLUSION: We found an association of the FCGR2A 131R allele with poor response to INX. This finding could be of utility to understand the mechanisms behind treatment failure and contribute to biomarker panels for INX response prediction.

Interaction between oxidative stress and smoking is associated with an increased risk of rheumatoid arthritis: a case-control study.

OBJECTIVE: To investigate the relationship between oxidative stress and smoking and development of RA. METHODS: A case-control study was conducted in treatment-naïve early-onset RA patients and healthy controls, matched by age, gender and current smoking habit. Plasma lipid hydroperoxides (LOOH), carbonyl protein (CP) and malonyldialdehyde (MDA) levels were measured to estimate oxidative stress. Smoking exposure was quantified in pack-years. The presence of an interaction between oxidative stress and smoking exposure was investigated using three measures of additive interaction: relative excess risk due to the interaction (RERI), attributable proportion due to the interaction (AP) and the synergy index (S). RESULTS: A total of 65 RA patients and 65 healthy controls were included. Statistically significant differences were observed in RA-related variables, age, BMI and smoking dose between cases and controls. Plasma LOOH and CP levels were associated with RA risk, which was more prominent for LOOH levels >27.9 µM [odds ratio (OR) 18.8] and CP levels >64.3 µM (OR 24.9). A reverse association was observed between MDA levels and RA risk, OR 6.4 for MDA levels <8.5 µM. Having >20 pack-years increased risk for RA with an OR of 19.7. The interaction between smoking and oxidative stress increased RA risk significantly, and RERI between LOOH, CP or MDA and smoke exposure were 8.2, 5.0 and 51.5, respectively. CONCLUSION: These data suggest that the interaction between oxidative stress and smoking increases RA risk.

[Vaccines and chemo-prophylaxis in rhemautoid arthritis: is a vaccine calendar necessary?]. / Vacunas y quimioprofilaxis en artritis reumatoide: ¿podría plantearse un calendario de vacunación?

Patients with rheumatoid arthritis (RA) are at increased risk of infection compared to healthy individuals. The increased risk may be associated with the underlying disease, comorbidities and immunosuppressive therapy required to control RA activity. In several recent studies, influenza, pneumococcal and hepatitis B vaccines administered to RA patients were reported to be safe and serologically effective. However, several lines of evidence suggest a possible aberrant immunologic response following vaccination due to the compromised immunity of these patients. Therefore, vaccination of RA patients prior to immunosuppressive treatment may serve as an alternative prophylactic approach and should be considered for future investigation. Besides, prophylactic health measures should be taken to avoid latent chronic infections as tuberculosis and hepatitis B, during therapy with biological agents.

High-dose etanercept in ankylosing spondylitis: results of a 12-week randomized, double blind, controlled multicentre study (LOADET study).

OBJECTIVES: Etanercept 50 mg a week is approved in the treatment of AS. Increasing the etanercept dose to 100 mg/week improves efficacy in cutaneous psoriasis, a clinical manifestation related to the spondylarthritis family, while maintaining its safety profile. The purpose of this study was to evaluate the efficacy and safety of etanercept 100 vs 50 mg/week in patients with AS. METHODS: Adult patients with AS were randomized to receive etanercept 50 mg twice a week (biw), or etanercept 50 mg once a week (qw) for 12 weeks. The primary efficacy endpoint was Ankylosing Spondylitis Assessment Study (ASAS20) response at Week 12; secondary endpoints included ASAS40, ASAS50, ASAS70 and ASAS5/6 responses, partial remission and quality of life. Safety was assessed until 15 days after the last visit. RESULTS: A total of 108 patients were randomly selected and treated, 54 in each arm. At 12 weeks, ASAS20 response was achieved by 34 (71%) out of 48 patients of the etanercept 50 mg biw group and by 37 (76%) out of 49 patients of the etanercept 50 mg qw group (not statistically significant differences). Other efficacy variables improved significantly over time, but not between treatment groups. Fifty-six patients experienced at least one adverse event (generally, infections and infestations, gastrointestinal disorders and injection site reactions), most of them mild or moderate. CONCLUSIONS: High-dose (100 mg/week) etanercept in the treatment of AS for 12 weeks is as safe as the standard dose (50 mg/week). However, it does not significantly increase its efficacy. Trial Registration. Clinicaltrials.gov, http://clinicaltrials.gov/, NCT00873730.

Low doses of etanercept can be effective in ankylosing spondylitis patients who achieve remission of the disease.

This study aims to explore the effectiveness of low dose of etanercept (ETN) in patients with ankylosing spondylitis (AS) who achieve a good control of their disease in daily clinical practice. This is a case series of AS patients treated with ETN. According to the judgment of the treating rheumatologist and patient's preferences, a dose reduction was done in those patients who achieved a good control of their disease defined by Bath ankylosing spondylitis disease activity index (BASDAI) <4 and C-reactive protein normal values. Fifty-one AS patients treated with ETN were identified and 16 of them (32%) were on dose reduction regimen. Several regimens of dose reduction were used. These patterns were fixed and they did not change along the time. Mean time receiving ETN before adjusting the dose was 17 ± 12 months. Mean follow-up after dose change was 21 ± 21 months. At this point, all the patients in whom dose reduction was done remained in the low-dose regimen. Median BASDAI (range) at starting the low-dose regimen and 6 months later were 1.6 (0.9-2.4) and 1.4 (0.3-3.2), respectively. Median CRP values (range) at starting the low dose regimen and 6 months later were 1 mg/l (0.1-2.8), and 1.3 mg/l (0.3-4.1), respectively. Other disease-related variables also remained unchanged. Patients with follow up at 12 and 24 months and longer remained in clinical remission with BASDAI values <2 and normal CRP values. Our data suggest that AS patients in clinical remission can use low doses of ETN without increasing disease activity. So, it can be a promising strategy but additional studies are needed to prove it.

DAS-28-based EULAR response and HAQ improvement in rheumatoid arthritis patients switching between TNF antagonists.

INTRODUCTION: No definitive data are available regarding the value of switching to an alternative TNF antagonist in rheumatoid arthritis patients who fail to respond to the first one. The aim of this study was to evaluate treatment response in a clinical setting based on HAQ improvement and EULAR response criteria in RA patients who were switched to a second or a third TNF antagonist due to failure with the first one. METHODS: This was an observational, prospective study of a cohort of 417 RA patients treated with TNF antagonists in three university hospitals in Spain between January 1999 and December 2005. A database was created at the participating centres, with well-defined operational instructions. The main outcome variables were analyzed using parametric or non-parametric tests depending on the level of measurement and distribution of each variable. RESULTS: Mean (+/- SD) DAS-28 on starting the first, second and third TNF antagonist was 5.9 (+/- 2.0), 5.1 (+/- 1.5) and 6.1 (+/- 1.1). At the end of follow-up, it decreased to 3.3 (+/- 1.6; Delta = -2.6; p > 0.0001), 4.2 (+/- 1.5; Delta = -1.1; p = 0.0001) and 5.4 (+/- 1.7; Delta = -0.7; p = 0.06). For the first TNF antagonist, DAS-28-based EULAR response level was good in 42% and moderate in 33% of patients. The second TNF antagonist yielded a good response in 20% and no response in 53% of patients, while the third one yielded a good response in 28% and no response in 72%. Mean baseline HAQ on starting the first, second and third TNF antagonist was 1.61, 1.52 and 1.87, respectively. At the end of follow-up, it decreased to 1.12 (Delta = -0.49; p < 0.0001), 1.31 (Delta = -0.21, p = 0.004) and 1.75 (Delta = -0.12; p = 0.1), respectively. Sixty four percent of patients had a clinically important improvement in HAQ (defined as > or = -0.22) with the first TNF antagonist and 46% with the second. CONCLUSION: A clinically significant effect size was seen in less than half of RA patients cycling to a second TNF antagonist.

[A bibliometric approach to research into fibromyalgia]. / Un acercamiento bibliométrico a la investigación en fibromialgia.

OBJECTIVES: To obtain a general and updated vision of research into fibromyalgia for its better understanding. A productivity analysis (by year and author) and a content analysis (by journal and topic) was carried out. METHODOLOGY: The computer databases of the Web of Knowledge: Science Citation Index Expanded (SCIEXPANDED) and Social Sciences Citation Index (SSCI) of the Web of Science were used. For the exploration of the topics a content analysis was done on a sample of 356 articles, obtained using a simple randomized procedure based on a random number table (risk α=0.05; z(α)=1.96≈2; p=q=0.5) with a sample error of 5%, with the purpose of reaching some general conclusions in the study of this topic area. RESULTS AND CONCLUSIONS: Overall, 3,201 article references have been obtained. In the years 1998 to 2003 the production of scientific articles increased considerably (43.5%) in comparison to the previous period, from 1992 to 1997 (27.4%). In the past decade (1996-2005) the production of articles tripled with respect to the first fifteen years (1980-1995). There is an overall 306 different journals that publish on this subject. The topic area that received most attention has been the study of the physiopathologic mechanisms (31.01%). There is an increment in the articles of psychiatry and psycology in the last few years.

Adalimumab for treating rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and safety of adalimumab in the treatment of rheumatoid arthritis (RA). METHODS: A Cochrane systematic review was performed. The literature search, selection and assessment of the methodological quality of the studies, and the data extraction were performed according to the standard methodology of the Cochrane reviews. Outcome measures included American College of Rheumatology (ACR) and European League Against Rheumatism responses, Disease Activity Score 28 and components of the ACR response, and radiographic and safety data. Weighted mean difference and relative risk were used for reporting continuous and dichotomous data, respectively. Number needed to treat (NNT) or to harm (NNH) were estimated when appropriate. When significant heterogeneity was not found, data were pooled. RESULTS: Six studies with 2,390 patients were included in this review. With adalimumab 40 mg every other week (eow) + methotrexate versus placebo + methotrexate, the absolute risk differences to achieve an ACR20, ACR50, and ACR70 response at 52 weeks were 35%, 32%, and 19% with NNT of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg eow and 20 mg every week (ew) significantly slowed the radiological progression. With adalimumab 40 mg eow versus placebo, the absolute risk differences to achieve an ACR20, ACR50, and ACR70 response at 24/26 weeks were 23.64%, 15.31%, and 12.22% with NNT of 5.0, 7.0, and 9.0, respectively. In most of the analyzed studies and comparisons, there were no significant differences in safety outcomes between adalimumab and control groups. CONCLUSION: On the basis of studies reviewed here, adalimumab is efficacious in the treatment of RA. No serious adverse effects occurred.