The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at?

To date, numerous genetic and epigenetic studies have been performed and provided a crucial step forward in our understanding of the pathogenesis of rheumatic diseases. However, most of the recent advances in the treatment of rheumatic diseases including biological therapies are not based on or even discrepant from these genetic and epigenetic findings. For example, tumor necrosis factor inhibitors are quite successful in the treatment of rheumatoid arthritis (RA), Behçet's disease (BD), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) but not in that of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren's syndrome (SS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV), conversely, RA shares genetic backgrounds more with SLE, SSc, SS and AAV than BD, AS and PsA. In this review, we briefly highlight the findings from recent genetic and epigenetic studies and discuss what needs to be studied to provide a novel, more efficacious management of rheumatic diseases.

Sustained remission with etanercept tapering in early rheumatoid arthritis.

BACKGROUND: We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy. METHODS: Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks (open-label phase). We then randomly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate (combination-therapy group), methotrexate alone, or placebo for 39 weeks (double-blind phase). Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 (treatment-withdrawal phase). The primary end point was the proportion of patients with sustained remission in the double-blind phase. RESULTS: Of 306 patients enrolled, 193 underwent randomization in the double-blind phase; 131 qualified for the treatment-withdrawal phase. More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P=0.009 for combination therapy vs. methotrexate alone; P<0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received methotrexate alone, and 15 (23%) who had received placebo were in remission (P=0.10 for combination therapy vs. methotrexate alone; P=0.02 for combination therapy vs. placebo; P=0.55 for methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the methotrexate-alone group, and 2 (3%) in the placebo group. CONCLUSIONS: In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy, continuing combination therapy at a reduced dose resulted in better disease control than switching to methotrexate alone or placebo, but no significant difference was observed in radiographic progression. (Funded by Pfizer; ClinicalTrials.gov number, NCT00913458.).

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

Pattern of response in patients with moderate-to-severe psoriasis treated with etanercept.

BACKGROUND: Etanercept (ETN) 50 mg once weekly (QW) or 50 mg twice weekly (BIW) for 12 weeks, followed by 50 mg QW in all subjects to Week 24 improved psoriasis in patients with concomitant psoriatic arthritis in the PRESTA trial. OBJECTIVES: To use data from PRESTA to evaluate the effect of ETN in the treatment of psoriasis by Psoriasis Area Severity Index (PASI) body-region and component, and determine if PASI responses correlate with the Dermatology Life Quality Index (DLQI). METHODS: Median time to 75% improvement in PASI (PASI75), body- and component-specific subscales over 24 weeks were estimated. Pearson correlation coefficients determined the association between DLQI score and PASI total score, body- and component-specific subscales with ETN treatment at baseline and up to Week 24. RESULTS: In total, 748 patients from PRESTA were included (ETN 50 mg QW/QW, n = 371; BIW/QW, n = 377). Patients achieved PASI75 total score and 75% improvements in all body regions and components faster on ETN 50 mg BIW/QW than QW/QW (all P < 0·05). Median time to 75% improvement was faster for the head and trunk followed by upper and lower extremities, and for induration and desquamation followed by erythema and total area. Weak to moderately positive correlations between improvements in DLQI and PASI total score (r = 0·223-0·463), all PASI body-specific (r = 0·114-0·432) and component-specific (r = 0·178-0·478) subscales were observed over 24 weeks. CONCLUSIONS: Etanercept treatment-response appears to occur in a body- and component-specific manner. Changes in quality of life are not captured by PASI or its subscales.

Patient-tailored dose reduction of TNF-α blocking agents in ankylosing spondylitis patients with stable low disease activity in daily clinical practice.

OBJECTIVES: Tumour necrosis factor-alpha (TNF-α) blocking agents are very effective in controlling systemic inflammation and improving clinical assessments in ankylosing spondylitis (AS). In view of potential side effects and high costs of long-term treatment, our aim was to investigate whether dose reduction of TNF-α blocking agents is possible without loss of effectiveness in AS patients in daily clinical practice. METHODS: Patients from the prospective observational GLAS cohort, fulfilling the modified New York criteria for AS, with active disease before start of TNF-α blocking therapy and stable (≥6 months) low disease activity on the conventional dose regimen, who started with dose reduction of TNF-α blocking therapy before June 2011 were studied. Dose reduction was patient-tailored (step-by-step approach) and consisted of lowering the dose and/or extending the interval between doses. RESULTS: Between June 2005 and March 2011, 58 AS patients started dose reduction of etanercept (n=39), infliximab (n=10), or adalimumab (n=9). Of all patients, 74%, 62%, and 53% maintained their reduced dose or dosing frequency after 6, 12, and 24 months, respectively. The mean dose of TNF-α blocking therapy over time corresponded to 62% of the standard dose regimen. Disease activity remained low in the majority of patients who maintained dose reduction after 24 months (94% had BASDAI<4). If there was recurrence of disease symptoms, patients achieved good clinical response after returning to the conventional regimen (88% reached BASDAI<4). CONCLUSIONS: In this observational cohort, patient-tailored dose reduction of TNF-α blocking agents was successful preserving stable low disease activity over 24 months in approximately half of the AS patients.

Discontinuation of disease-modifying anti-rheumatic drugs and clinical outcomes in the Rheumatoid Arthritis DMARD Intervention and Utilisation Study 2 (RADIUS 2).

OBJECTIVES: The purpose of this analysis was to examine discontinuation and reasons for discontinuation from disease-modifying anti-rheumatic (DMARD) therapies in the RADIUS 2 registry, a long-term, open-label, observational study of patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patients who participated in RADIUS 2 initiated etanercept (ETN) therapy at study entry and were followed for 5 years. In this post hoc analysis, patients who had received ETN continuously from entry to month 4 were categorised by treatment at month 4: ETN monotherapy, ETN+methotrexate (MTX), ETN+MTX+other DMARDs (OTH), or ETN+OTH. Outcomes were assessed at month 4 and at the time of any subsequent treatment change, and included Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: Of 3,484 patients analysed (982 ETN; 1,356 ETN+MTX; 537 ETN+MTX+OTH; 609 ETN+OTH), baseline demographic and clinical characteristics were similar across treatments. No treatment change occurred in 62.3%, 49.9%, 33.3%, and 37.1% of ETN, ETN+MTX, ETN+MTX+OTH, and ETN+OTH patients, respectively. The mean time on therapy from month 4 was longer for patients receiving ETN (23.3 months) or ETN+MTX (23.7 months) than those receiving ETN+MTX+OTH (18.0 months) or ETN+OTH (18.3 months). The greatest improvements in CDAI and HAQ-DI were seen in patients who continued on ETN. The most common reasons for discontinuing DMARD therapy were cost and ineffective treatment. CONCLUSIONS: Most patients who had received ≥4 months of ETN continued on ETN throughout the 5-year observation period. Patients with greatest clinical and disability improvements tended to continue on ETN.

Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose.

OBJECTIVES: This prospective long-term follow-up study evaluated the effects of half-dose etanercept (25 mg weekly) on clinical remission and radiographic progression in a large cohort of patients with rheumatoid arthritis (RA) in clinical remission after etanercept 25 mg bi-weekly. METHODS: 524 biologic-naïve RA patients were treated with etanercept 25 mg bi-weekly after failure of conventional drugs. Patients achieving remission (DAS28 <2.6) for ≥12 months were randomised to receive etanercept 25 mg weekly or 25 mg bi-weekly. Patients were assessed at baseline and every 12 weeks. Remission rates, radiographic progression, incidence of infections and costs of the regimens were compared. RESULTS: After a mean follow-up of 18±11 months, 347 patients (66.2%) achieved DAS28 remission; 323 were randomised to one of two dose regimens: etanercept 25 weekly (group A, 159 patients) and etanercept 25 mg bi-weekly (group B, 164 patients). At the end of follow-up, 81.8% patients of group A maintained remission for a mean of 3.6±1.5 years. Radiographic progression occurred in a small number of patients of group A and the rate of radiographic progression (TSS >0) was not significantly different in the two groups (18.85% vs. 19.0% after the first year and 16.9% vs. 21.6% after the second year, respectively). The incidence ratio of severe infections was 2.3/1.000 patient-years in group A. Etanercept half-dose regimen resulted in a saving of €3.190.545 with a cost saving up to €827.318 per year. CONCLUSIONS: Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with RA even after reduction of standard-dose etanercept.

Treatment of moderate rheumatoid arthritis with different strategies in a health resource-limited setting: a cost-effectiveness analysis in the era of biosimilars.

OBJECTIVES: This paper aims to explore the cost-effectiveness of reduced doses or discontinuation of etanercept biosimilar (Yisaipu) in patients with moderately active rheumatoid arthritis (RA). METHODS: A discrete event simulation model was developed to project lifetime medical costs and quality-adjusted life-years (QALYs) in moderately active RA. Strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week, 25 mg/week or MTX maintenance were compared. Resource consumptions related to RA were estimated from the perspective of the Chinese health care system. An endpoint of the American College of Rheumatology (ACR) response was used to estimate the utility scores. Uncertainty in model parameters was analysed by sensitivity analyses. RESULTS: When using ACR as an endpoint for determining successful treatment, strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week or 25 mg/week maintenance showed the greatest number of QALYs gained (nearly 11.9 and 11.3 with or without rituximab after the failure of Yisaipu, respectively). If decision makers use a threshold of 3×the per capita GDP of China or Shanghai City in 2012, then the strategies most likely to be cost-effective are initial treatment with Yisaipu 50 mg/week for nine months following MTX maintenance and Yisaipu 25 mg/week maintenance, respectively. Results were sensitive to the cost of Yisaipu. CONCLUSIONS: The analysis indicates that, in China, replacing branded etanercept with Yisaipu is likely to be a cost-effective strategy in patients with moderately active RA.

Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study.

BACKGROUND: Safety profiles of biologics for treatment of psoriasis are limited to data from randomized controlled trials. There is a need for comparative safety reports of biologics based on data from clinical practice. OBJECTIVE: We sought to estimate and compare the incidence of adverse events (AEs) leading to withdrawal of biologics (etanercept, infliximab, adalimumab, and ustekinumab) in the treatment of psoriasis. METHODS: We conducted a multicenter retrospective chart review from September 2005 to September 2014. Incidence proportion and rate of AEs leading to withdrawal by biologic agent and AE were calculated. RESULTS: For 545 treatments administered in 398 patients, 22 (4.04%) AEs were associated with withdrawal, for a rate of 1.97/100 patient-years (95% confidence interval [CI] 1.32-2.94). Common AEs were injection-/infusion-site reactions (0.55%, 0.92%, 0%, and 0% for etanercept, infliximab, adalimumab, and ustekinumab, respectively); infections (0%, 0.18%, 0.55%, 0.18%); and malignancies (0.18%, 0.18%, 0%, 0.37%). LIMITATIONS: Possible incompleteness of chart details and small study population limit the conclusiveness of findings. CONCLUSION: Biologic agents for treatment of psoriasis are safe; AEs associated with withdrawal occurred in 4% of all administered biologic therapies. It does not appear that real-world patients encounter more AEs with biologics than patients in clinical trials.

Etanercept reduces symptoms and severity of psoriasis after cessation of cyclosporine therapy: results of the SCORE study.

Cyclosporine is an established therapy for psoriasis that provides rapid relief of symptoms but has long-term toxic side effects. The objective of this study was to demonstrate the efficacy of etanercept as replacement therapy for cyclosporine in patients with moderate-to-severe plaque psoriasis. Patients with plaque psoriasis were given cyclosporine 5 mg/kg/day until achievement of PASI50 at which point cyclosporine was tapered to 0 over 6 weeks. At week 6, patients were randomised (1:1) to receive etanercept (50 mg/week) or placebo for an additional 24 weeks. Patients in the etanercept group (n = 58) experienced a reduction of -1.1 in mean PASI score (p = 0.233 vs. cyclosporine) at week 30; patients in the placebo group (n = 62) had mean PASI increase of 3.7 (p < 0.001 vs. cyclosporine). The incidence of patients reporting any adverse events was not significant between groups (77% etanercept, 74% placebo; p = 0.675). Etanercept demonstrated higher efficacy and good tolerability as replacement therapy for cyclosporine in plaque psoriasis.

A Randomized, blinded assessor study to Evaluate the efFIcacy and safety of etanercept 50 mg once weekly plus as Needed topical agent vs. Etanercept 50 mg twice weekly in patients with moderate to severe plaque psoriasis (REFINE).

BACKGROUND: Topical corticosteroids are used with systemic therapies for treatment of plaque psoriasis, but data from randomized clinical trials to document efficacy of combination therapy are lacking. OBJECTIVE: To evaluate efficacy and safety of adding topical corticosteroid therapy from the time that etanercept dosage is reduced from initial label dose [50 mg twice weekly (BIW)] to maintenance dose [50 mg once weekly (QW)]. METHODS: In this phase 3b, multicentre, randomized, open-label study, patients with moderate-to-severe plaque psoriasis received etanercept 50 mg BIW for 12 weeks, and then were randomized to etanercept 50 mg BIW or 50 mg QW plus topical agent as needed to achieve static physician global assessment (sPGA) status of clear for 12 weeks. Endpoints included percentage change in Psoriasis Area and Severity Index (PASI) score from week 12 to week 24 (primary endpoint); proportion of patients achieving 50% improvement in (PASI 50), PASI 75 and PASI 90; patients achieving sPGA of clear/almost clear; and change in affected body surface area (BSA). RESULTS: Mean difference [95% confidence interval (CI)] between etanercept arm (n = 140) and etanercept plus topical arm (n = 142) in change in PASI score from week 12 to week 24 was 16.2% (-3.5%, 35.8%). PASI response rates were similar between groups. Percentage (95% CI) of patients achieving sPGA status of clear/almost clear was 40.6% (32.5%, 48.6%) and 45.8% (37.6%, 54.0%) at week 12 for patients in etanercept and etanercept plus topical arms, respectively, and 53.5% (45.3%, 61.7%) and 45.4% (37.2%, 53.6%) at week 24. Difference (95% CI) between groups in change in affected BSA from week 12 to week 24 was 4.9% (-23.4%, 33.2%). CONCLUSION: Patients who received etanercept 50 mg QW at week 12 plus as-needed topical therapy and those who stayed on etanercept 50 mg BIW maintained clinical response through week 24 with no notable differences in PASI responses.

Major cost savings associated with biologic dose reduction in patients with inflammatory arthritis.

The purpose of this study was to explore whether patients with Inflammatory Arthritis (IA) (Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) or Ankylosing Spondylitis (AS)) would remain in remission following a reduction in biologic dosing frequency and to calculate the cost savings associated with dose reduction. This prospective non-blinded non-randomised study commenced in 2010. Patients with Inflammatory Arthritis being treated with a biologic agent were screened for disease activity. A cohort of those in remission according to standardized disease activity indices (DAS28 < 2.6, BASDAI < 4) was offered a reduction in dosing frequency of two commonly used biologic therapies (etanercept 50 mg once per fortnight instead of weekly, adalimumab 40 mg once per month instead of fortnightly). Patients were assessed for disease activity at 3, 6, 12, 18 and 24 months following reduction in dosing frequency. Cost saving was calculated. 79 patients with inflammatory arthritis in remission were recruited. 57% had rheumatoid arthritis (n = 45), 13% psoriatic arthritis (n = 10) and 30% ankylosing spondylitis (n = 24). 57% (n = 45) were taking etanercept and 43% (n = 34) adalimumab. The percentage of patients in remission at 24 months was 56% (n = 44). This resulted in an actual saving to the state of approximately 600,000 euro over two years. This study demonstrates the reduction in biologic dosing frequency is feasible in Inflammatory Arthritis. There was a considerable cost saving at two years. The potential for major cost savings in biologic usage should be pursued further.

Effects of sildenafil citrate and etanercept treatment on TNF-α levels in peripheral blood of women with recurrent miscarriage.

OBJECTIVES: The aim of the study was to determine serum concentrations of a proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), in patients with recurrent abortions undergoing treatment with sildenafil or etanercept. MATERIAL AND METHODS: Serum TNF-α concentrations were determined for 24 patients with recurrent miscarriages (aged 32.7 ± 4.64 years) deemed eligible for sildenafil therapy and 7 patients treated with etanercept (aged 37.65 ± 5.45 years). Measurements were performed before and after therapy. The control group included 10 healthy women (aged 33.3 ± 5.49 years), who gave birth at least once without pregnancy-related complications. The levels of serum TNF-α were measured by Elisa. RESULTS: Patients treated with etanercept had significantly elevated levels of TNF-α before therapy as compared to the control group (41.4 ± 28.4 vs. 16.6 ± 7.2 pg/ml). Moreover we found a tendency for the concentration of TNF-α to increase in sera of patients treated with sildenafil after therapy completion (19 ± 29 vs. 15.4 ± 26.7 pg/ml). Treatment with etanercept resulted in a significant reduction of serum TNF-α levels (41.4 ± 28.4 vs. 25.4 ± 3.2 pg/ml). CONCLUSIONS: Therapy of recurrent abortions with anti-TNF-α drugs appears to be encouraging. Administration of blockers of phosphodiesterase type 5 or TNF-α blockers before conception seems to be a promising future therapy of immune-dependent recurrent miscarriages, limiting the teratogenic influence of the drugs on the fetus.

[Biological treatment in severe Still's disease--a case report]. / Leczenie biologiczne w ciqikiej postaci choroby Stilla--opis przypadku.

Still's disease and systemic juvenile idiopathic arthritis (JIA) are multisystem inflammatory diseases of unknown etiology, different disease course and prognosis. Still's disease is characterized by hectic fever, arthritis, skin rash, organomegaly, elevated serum ferritin and inflammatory factors. Early diagnosis and intensive treatment can prevent disease progression and reduce complications such as amyloidosis, physical disability. The first choice of treatment are high doses of corticosteroids and synthetic disease-modifying drugs (DMARDs), including methotrexate (MTX), cyclosporine (CsA). Biologic agents are second line therapy when DMARDs aren't effective, e.g. monoclonal antibodies blocking the action of TNF-alpha (anti-TNF-α), interleukin-1 (ANK--anakinra) and interleukin-6 (TCZ--tocilizumab). We describe in details treatment strategies applied in a young woman with severe Still's disease treated with combination therapy of DMARDs and anti-TNF-α, including etanercept (ETA) or certolizumab (CER). TCZ was applied for the treatment of Still's disease following treatment failure with anti-TNF-α. We've achieved a complete remission of the Still's disease during treatment TCZ.

Clinical research for curing ankylosing spondylitis through combining etanercept, thalidomide and sulfasalazine.

This article is to explore the curative effect of treating ankylosing spondylitis (AS) through combining etanercept, thalidomide and sulfasalazine. Sixty-two patients with AS were divided into 3 groups: experimental group Ais treated by etanercept+ thalidomide + sulfasalazine for 1 year (n=22); control group B was treated with etanercept; control group C was treated with thalidomide + sulfasalazine for 1 year (n=20). In 1st, 3rd, 6th, 12th month after the treatment, ASAS20 and ASAS50 were obtained through Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), erythrocyte sedimentation rate (ESR), C react protein (CRP) and then curative effect was analyzed. In 1 and 3 months after the treatment, each indicator had downtrend, and ASAS20 of experimental group and etanercept control group reached 100%; ASAS50 increased compared with the first months' treatment; although ASAS20 and ASAS50 in thalidomide control group was smaller, they increased; in 6 and 12 months after the treatment, ASAS20 improvement ratio in group A still remained on 100%, ASA50 improvement ratio increased; recurrence rate of group B increased; ASA20 and ASA50 had a continuous and significant increase, but its their was less than group A. This study proved that, the effect of curing AS combiningetanercept, thalidomide and sulfasalazine is better, therefore, it is a high-feasible treatment approach.

Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375.

Confirmation of -174G/C interleukin-6 gene promoter polymorphism as a genetic marker predicting antitumor necrosis factor treatment outcome.

BACKGROUND: The IL-6 -174G/C genetic variant has recently been associated with the clinical response to etanercept therapy in rheumatoid arthritis (RA) patients. Considering previous results, the aim of our study was to validate the role of this polymorphism as a predictor of the antitumor necrosis factor (anti-TNF) treatment outcome in RA. MATERIALS AND METHODS: Our study population was composed of 199 Spanish patients with RA receiving anti-TNF therapy. The IL-6 -174G/C (rs1800795) genetic variant was genotyped using the TaqMan allelic discrimination technology. Patients were classified, according to the European League Against Rheumatism (EULAR) criteria, as responders (good and moderate response) and nonresponders at 6, 12, 18, and 24 months after the first infusion. RESULTS: The -174*G allele was significantly associated with a good or moderate EULAR response at 12 [P=0.015, odds ratio (OR)=2.93, 95% confidence interval (CI) 1.29-6.70], 18 (P=4.54E-03, OR=5.17, 95% CI 1.80-14.85), and 24 months (P=4.54E-03, OR=14.86, 95% CI 2.91-75.91). A meta-analysis combining these data with the results from a previous study confirmed this association (P=1.89E-02, OR=1.80, 95% CI 1.13-2.87, at 12 months). CONCLUSION: Our results support the role of the -174G/C IL-6 polymorphism as a genetic marker of responsiveness to anti-TNF therapy.

Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.

BACKGROUND: Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. METHODS: In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3.2 and ≤5.1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15-25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. FINDINGS: 604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5-49.1%; p<0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0-44.8%; p<0.0001). INTERPRETATION: Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. FUNDING: Pfizer.

The role of methotrexate co-medication in TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR-DMARD study.

BACKGROUND: The role of co-medication with tumour necrosis factor inhibitors (TNFi) is well established in rheumatoid arthritis and ankylosing spondylitis. In psoriatic arthritis (PsA) there is little evidence available on this issue. MATERIAL AND METHODS: The analyses were based on data from the Norwegian longitudinal observational study on disease-modifying antirheumatic drugs (NOR-DMARD). Patients with PsA starting their first TNFi, either as monotherapy or with concomitant methotrexate (MTX), were selected. Baseline characteristics, responses after 3, 6 and 12 months, and drug survival were compared between those with and without MTX co-medication. A secondary analysis was performed on patients who had confirmed swollen joints at baseline. Cox regression was used to identify predictors of discontinuation. RESULTS: We included 440 patients, 170 receiving TNFi as monotherapy and 270 receiving concomitant MTX. The groups had similar baseline characteristics, except for number of swollen joints, which was higher in the concomitant MTX group. Responses were similar in the two groups in both analyses. Drug survival analyses revealed a borderline significant difference in favour of patients receiving co-medication (p=0.07), and this was most prominent for patients receiving infliximab (IFX) (p=0.01). In the Cox regression analysis lack of concomitant MTX and current smoking were independent predictors of discontinuation of TNFi. CONCLUSIONS: We found similar responses to TNFi in patients with and without concomitant MTX, but drug survival was superior in patients receiving co-medication. The effect of MTX on drug survival was most prominent in patients receiving IFX. Smoking at baseline and use of TNFi as monotherapy were identified as independent predictors of drug discontinuation.

Short-term efficacy of etanercept plus methotrexate vs combinations of disease-modifying anti-rheumatic drugs with methotrexate in established rheumatoid arthritis.

OBJECTIVES: The aims of this study were to investigate the short-term benefit of etanercept (ETN) + MTX vs conventional synthetic DMARDs (csDMARDs; HCQ, LEF or SSZ) + MTX in subjects with established RA. The effect of disease duration (≤2 years vs >2 years) and severity (moderate vs severe) on treatment outcomes was also assessed. Methods. Data from Asian and Latin American subjects with inadequate response to MTX were pooled from the APPEAL (ETN 25 mg biweekly + MTX or csDMARD + MTX; NCT00422227) and Latin RA (ETN 50 mg/week + MTX or csDMARD + MTX; NCT00848354) studies. Endpoints included the 28-joint DAS with ESR (DAS28-ESR) low disease activity (LDA; ≤3.2), DAS28 remission (<2.6) and HAQ score ≤0.5. RESULTS: Four hundred seventy-eight subjects received ETN + MTX, 245 subjects received csDMARD + MTX [HCQ + MTX (n = 81), LEF + MTX (n = 69), SSZ + MTX (n = 95)]. At week 16, significantly more subjects receiving ETN + MTX vs subjects on csDMARDs + MTX achieved DAS28-ESR LDA (39% vs 18%, P < 0.001), remission (18% vs 7%, P < 0.001) and HAQ ≤0.5 (48% vs 34%, P < 0.001). For both treatment arms, these endpoints were achieved by a greater proportion of subjects with ≤2 years vs >2 years disease duration and with moderate vs severe disease activity. CONCLUSION: Overall, ETN + MTX was more effective in treating subjects with established RA than csDMARDs + MTX at 16 weeks. More subjects with shorter disease duration and moderate disease activity achieved optimal response regardless of treatment regimen. TRIAL REGISTRATION: clinicaltrials.gov, NCT00422227 and NCT00848354.