Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial.

OBJECTIVES: To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). METHODS: In an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores. RESULTS: IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments. CONCLUSIONS: Risk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer. TRIAL REGISTRATION NUMBERS: NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661.

Inmune-mediated inflammatory rheumatic diseases in transgender people: A scoping review.

BACKGROUND: In immune-mediated inflammatory rheumatic diseases (IMIRD), there are differences between cis-men and cis-women in epidemiology, clinical feature, therapeutic approach, treatment response, and prognosis. In transgender individuals, information concerning IMIRD is not substantial. The assessment of information concerning rheumatic diseases in transgenders is crucial because transgenders may undergo treatments with potential impacts on IMIRD. We aim to collect and discuss current knowledge on IMIRD in transgender individuals, determine the coverage of the literature, identify the knowledge gaps, and highlight opportunities for future research. METHODS: We did a scoping review of publications collected through a systematic search of transgender patients with any IMIRD. Data sources were Medline, Embase, and Web of Knowledge. Synthesis of results and qualitative review of data information was collected in tables. A semi-quantification of the quality of the articles reporting clinical studies was performed. RESULTS: There were 11 transwoman, and 3 transmen cases of systemic lupus erythematosus (5 cases), skin lupus erythematosus (2), systemic sclerosis (4), anti-synthetase syndrome (1), rheumatoid arthritis (1) and ankylosing spondylitis (1). Eleven were de novo cases and three had prior history of IMIRD and developed a comorbidity after starting hormone replacement therapy. The clinical expression of the disease was variable. Two transwomen and one transman developed thrombotic events. The lupus skin lesions in one transman improved following testosterone treatment. No clinical studies were identified. Quality of publications was disparate. CONCLUSION: Although the number of cases is small, most cases of IMIRD occur in transwomen. The absence of solid data warrants caution in establishing recommendations regarding hormone replacement therapy in transgenders with IMIRD. There is an essential need for the consideration of cisgender and transgender particularities in future research on IMIRD.

Factors associated with long-term retention of treatment with golimumab in rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis: an analysis of the Spanish BIOBADASER registry.

BACKGROUND: Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. Retention of golimumab was high in clinical trial extensions and real-world studies up to 5 years in patients with immune-mediated rheumatic diseases. OBJECTIVE: To assess the probability of real-world long-term retention of treatment with golimumab up to 7 years after treatment initiation. METHODS: This retrospective noninterventional study involved analysis of the Spanish biological drugs registry, BIOBADASER. Adults who had ever received golimumab for rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA), and had initiated it > 6 months before the analysis date, were included. RESULTS: Among 685 patients (28.5% RA, 42.9% SpA, 28.6% PsA), the overall probability of retention of golimumab treatment since initiation was 71.7% (95% confidence interval 68.1-74.9) at year 1, 60.5% (56.5-64.2%) at year 2, 55.6% (51.5-59.5%) at year 3, 50.6% (46.2-54.8%) at year 4, 45.1% (40.1-50.0%) at year 5, 44.2% (39.0-49.3) at year 6, and 39.5% (32.8-46.2) at year 7. Retention was greater in patients with axial SpA or PsA versus RA (p < 0.001) and when golimumab was used as first-line treatment versus third or later lines (p < 0.001). Factors associated with greater golimumab retention in Cox regression included use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy. Steroids were associated with lower retention. CONCLUSION: In this real-world study of RA, axial SpA, and PsA patients, the retention rate of golimumab was 39.5% at year 7. Key Points • Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. • This real-world study of 685 patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA) showed that golimumab treatment had a retention rate up to 39.5% at year 7. • Greater golimumab retention was associated with use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy.

Impact of baseline body mass index on the efficacy and safety of tofacitinib in patients with psoriatic arthritis.

OBJECTIVES: This post-hoc analysis explored the impact of body mass index (BMI) on tofacitinib efficacy/safety in patients with active psoriatic arthritis (PsA). METHODS: Data were pooled from two phase 3 studies (NCT01877668; NCT01882439). Analyses included patients randomised to tofacitinib 5/10 mg twio times a day or placebo, stratified by baseline BMI: <25 kg/m2, ≥25-<30 kg/m2, ≥30-<35 kg/m2 or ≥35 kg/m2. Endpoints (month 3): American College of Rheumatology (ACR20/50/70), Health Assessment Questionnaire-Disability Index (HAQ-DI) and Psoriasis Area and Severity Index (PASI) 75 response rates; dactylitis/enthesitis resolution rates; changes from baseline Short Form-36 Health Survey version 2 (SF-36v2) Physical/Mental Component Summary (PCS) scores and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score. Safety was also reported. RESULTS: Analysis included 710 patients; 43.8% were obese (BMI ≥30 kg/m2). Tofacitinib demonstrated higher efficacy response rates at month 3, compared with placebo, regardless of baseline BMI. Generally, ACR20/50/70 and HAQ-DI response rates, enthesitis resolution rates and changes from baseline in SF-36v2 PCS score and FACIT-F total score (month 3) were reduced in patients with baseline BMI ≥35 kg/m2 versus patients with lower BMIs. Elevated alanine aminotransferase/aspartate aminotransferase levels were reported in patients with baseline BMI ≥35 kg/m2 receiving tofacitinib 5 mg but not 10 mg two times a day. CONCLUSION: Tofacitinib demonstrated greater efficacy than placebo in patients with PsA, regardless of baseline BMI. For all treatment arms, reduced efficacy was observed in patients with baseline BMI ≥35 kg/m2. Safety was generally comparable across BMI categories, although the effect of tofacitinib on liver enzymes in patients with baseline BMI ≥35 kg/m2 was inconclusive.

Update of the Position Paper of the Spanish Society of Rheumatology on Biosimilar Drugs. / Actualización del Documento de posicionamiento de la Sociedad Española de Reumatología sobre fármacos biosimilares.

In 2015 the Spanish Society of Rheumatology (Sociedad Española de Reumatología [SER]) published its position paper on biosimilar drugs. In this update, the SER, continues to manifest its unequivocal commitment to the sustainability of the health system of our country and is aligned with the measures that, without reducing quality of care, are aimed at ensuring its continuity. Since the publication of the previous position paper, the European Commission has authorized new biosimilar drugs, which provides an excellent opportunity to advance the efficiency of health care. In this new scenario of increased therapeutic offer of biologics, the SER considers it crucial to preserve the freedom of prescription of physicians who prescribe drugs based exclusively on the characteristics and individual circumstances of each patient, without forgetting the economic aspects there of.

Chemical exposure-induced systemic fibrosing disorders: Novel insights into systemic sclerosis etiology and pathogenesis.

Numerous drugs and chemical substances are capable of inducing exaggerated tissue fibrotic responses. The vast majority of these agents cause localized fibrotic tissue reactions or fibrosis confined to specific organs. Although much less frequent, chemically-induced systemic fibrotic disorders have been described, sometimes occurring as temporally confined outbreaks. These include the Toxic Oil Syndrome (TOS), the Eosinophilia-Myalgia Syndrome (EMS), and Nephrogenic Systemic Fibrosis (NSF). Although each of these disorders displays some unique characteristics, they all share crucial features with Systemic Sclerosis (SSc), the prototypic idiopathic systemic fibrotic disease, including vasculopathy, chronic inflammatory cell infiltration of affected tissues, and cutaneous and visceral tissue fibrosis. The study of the mechanisms and molecular alterations involved in the development of the chemically-induced systemic fibrotic disorders has provided valuable clues that may allow elucidation of SSc etiology and pathogenesis. Here, we review relevant aspects of the TOS, EMS, and NSF epidemic outbreaks of chemically-induced systemic fibrosing disorders that provide strong support to the hypothesis that SSc is caused by a toxic or biological agent that following its internalization by endothelial cells induces in genetically predisposed individuals a series of molecular alterations that result in the development of SSc clinical and pathological alterations.

Tofacitinib in Patients With Psoriatic Arthritis and Metabolic Syndrome: A Post hoc Analysis of Phase 3 Studies.

OBJECTIVE: Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. METHODS: Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C-reactive protein, HAQ-DI, Patient's/Physician's Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. RESULTS: Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. CONCLUSION: Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials.

OBJECTIVE: Psoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA. METHODS: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re-randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double-blind treatment continued to week 52; patients could continue apremilast during an open-label, long-term treatment phase. RESULTS: In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure-adjusted incidence rate [EAIR]/100 patient-years, 265.1) versus placebo (47.5%; EAIR/100 patient-years, 200.7) in the placebo-controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast-exposed patients were diarrhea (13.9%; EAIR/100 patient-years, 18.6), nausea (12.3%; EAIR/100 patient-years, 16.0), headache (9.4%; EAIR/100 patient-years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient-years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient-years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient-years, 1.8). Major adverse cardiac events (EAIR/100 patient-years, 0.5), malignancies (EAIR/100 patient-years, 0.9), and serious opportunistic infections (EAIR/100 patient-years, 0.0) were infrequent over the 3-year exposure period. Discontinuation rates due to AEs were low (<7.5%) across all apremilast-exposure periods. Incidences of clinically meaningful abnormalities in postbaseline laboratory values was low; most values returned to baseline levels with continued treatment and without intervention. CONCLUSION: Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks.

Influence of age on the occurrence of adverse events in rheumatic patients at the onset of biological treatment: data from the BIOBADASER III register.

OBJECTIVES: To assess whether age, at the beginning of biologic treatment, is associated with the time a first adverse event (AE) appears in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). METHODS: All patients in the BIOBADASER registry diagnosed with RA, AS, and PsA, and classified as young (< 25 years old), adult (25-64 years old), elderly (65-75 years old) or very elderly (> 75 years old) at start of biological treatment were included. Factors associated with the appearance of a first AE using adjusted incidence rate ratios (IRR) (Poisson regression) were analyzed. Survival to first AE was studied by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. RESULTS: 2483 patients were included: 1126 RA, 680 PsA, and 677 AS. Age group stratification was as follows: 63 young, 2127 adults, 237 elderly, and 56 very elderly. Regression model revealed an increased probability of suffering a first AE at age 65 years or older [IRR elderly: 1.42 (CI95% 1.13-1.77)]. Other characteristics associated with AE were female gender, the use of DMARDs, including methotrexate, the presence of comorbidities, and the time of disease duration. Factors that had the greatest impact on survival over a first AE were age > 75 years [HR 1.50 (1.01-2.24)] and female gender [HR 1.42 (1.22-1.64)]. CONCLUSION: Age at the start of treatment and female gender are key factors associated with the appearance of a first AE with biologics. Other factors related to patient status and treatment were also associated with a first AE in rheumatic patients treated with biologics.

Visfatin as a therapeutic target for rheumatoid arthritis.

Introduction: The rising prevalence of musculoskeletal pathologies in developed countries has caused a dramatic impact on social welfare. Amidst these musculoskeletal pathologies is Rheumatoid arthritis (RA), a chronic systemic autoimmune disease that mostly affects the synovium. RA metabolic-associated alterations, including distorted adipokine production, enhance RA inflammatory environment. Among the altered adipokines, visfatin is particularly involved in RA inflammation and catabolism and stands out as an essential enzyme linked to critical cell features. Areas covered: We discuss the potential mechanism supporting the contribution of visfatin to RA and the association between RA and obesity. We discuss the repurposing of cancer-tested drugs to inhibit visfatin in the context of RA. Additionally, we address the possibility of combining these drugs with current RA therapy. Finally, we explore the future of visfatin as an RA biomarker or therapeutic target. Expert opinion: Inhibition of visfatin has become an interesting therapeutic approach for RA pathology. Such a feat has already been attained in oncology using small molecule inhibitors, which suggest that a similar course of action would be worth pursuing in the RA context. Visfatin will become an important biomarker and therapeutic target for RA.

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.

Abatacept for the treatment of rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the initiation and perpetuation of disease. Abatacept is a fusion protein composed of the Fc region of the immunoglobulin G1 (IgG1) fused to the extracellular domain of cytotoxic T lymphocyte-associated antigen (CTLA4). It has the ability to modulate T-cell activation by interfering with co-stimulation of these cells, a necessary step to become activated. This suggests that abatacept may play a role in the progression and/or even the initiation of RA. Areas covered: a review of the different studies carried out during clinical development of abatacept was performed. Both formulations, intravenous (IV) and subcutaneous (SC), showed a similar and consistent efficacy and safety profile. Abatacept was effective both in RA patients not responding to methotrexate (MTX) and to tumor necrosis factor (TNF) inhibitors. Expert commentary: abatacept, with its unique mechanism of action, proved to be a useful therapeutic alternative in RA, also having an acceptable safety profile. Evidence points out that abatacept may be able to alter the RA disease course. Ongoing studies will clarify this issue.

Factors associated with long-term retention of treatment with golimumab in a real-world setting: an analysis of the Spanish BIOBADASER registry.

The retention rate of a biological drug (percentage of patients remaining on treatment over time) provides an index of a drug's overall effectiveness. The golimumab retention rate as first-line biological therapy was high in clinical trial extensions lasting 5 years. Real-world studies also indicate good retention rates but have been of shorter duration. The probability of retention with golimumab treatment was assessed, as any line of anti-tumor necrosis factor-alpha therapy, for up to 5 years in patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA) or psoriatic arthritis (PsA), associated factors were analyzed. A retrospective database analysis of the Spanish registry of patients with rheumatic disorders receiving biological drugs (BIOBADASER) was performed. Among 353 patients, 29.8% had RA, 41.6% SpA and 28.6% PsA. Golimumab was the first biological drug in 40.1% of patients, second in 30.1% and third/later in 29.8%. The overall probability of retention of golimumab at years 1, 2, 3, 4 and 5 was 85.9% (95% confidence interval 81.4-89.5%), 73.7% (67.1-79.1%), 68.5% (60.5-75.1%), 60.6% (50.2-69.5%) and 57.1% (44.9-67.5%), respectively. Retention was similar across indications (p = 0.070) but was greater when golimumab was used as the first biological agent compared with later therapy lines (p < 0.001). Factors associated with higher retention of golimumab treatment (Cox regression) were use as a first-line biological and concomitant methotrexate treatment; corticosteroid need was associated with lower retention. The long-term probability of golimumab retention was high in this real-world study of patients with rheumatic diseases, especially when used as the first biological drug.

Specific Association of HLA-DRB1*03 With Anti-Carbamylated Protein Antibodies in Patients With Rheumatoid Arthritis.

OBJECTIVE: Recognition of a new type of rheumatoid arthritis (RA)-specific autoantibody, the anti-carbamylated protein antibodies (anti-CarP), has provided an opportunity to improve the management and understanding of RA. The current study was undertaken to assess the relationship between anti-CarP antibodies and HLA-DRB1 alleles in RA. METHODS: Serum samples were obtained from 3 different collections, comprising a total of 1,126 RA patients. Serum reactivity against in vitro carbamylated fetal calf serum proteins was determined by enzyme-linked immunosorbent assay. HLA-DRB1 alleles were determined using either hybridization techniques or imputation from HLA-dense genotypes. Results of these analyses were combined in a meta-analysis with data from 3 previously reported cohorts. The carrier frequencies of the common HLA-DRB1 alleles were compared between the antibody-positive RA subgroups and the double-negative subgroup of RA patients stratified by anti-citrullinated protein antibody (ACPA)/anti-CarP antibody status, and also between the 4 RA patient strata and healthy controls. RESULTS: Meta-analysis was conducted with 3,709 RA patients and 2,305 healthy control subjects. Results revealed a significant increase in frequency of HLA-DRB1*03 carriers in the ACPA-/anti-CarP+ subgroup as compared to ACPA-/anti-CarP- RA patients and healthy controls; this was consistently found across the 6 sample collections. This association of HLA-DRB1*03 with ACPA-/anti-CarP+ RA was independent of the presence of the shared allele (SE) and any other confounders analyzed. No other allele was specifically associated with the ACPA-/anti-CarP+ RA patient subgroup. In contrast, frequency of the SE was significantly increased in the ACPA+/anti-CarP- and ACPA+/anti-CarP+ RA patient subgroups, without a significant distinction between them. Furthermore, some alleles (including HLA-DRB1*03) were associated with protection from ACPA+ RA. CONCLUSION: These findings indicate a specific association of HLA-DRB1*03 with ACPA-/anti-CarP+ RA, suggesting that preferential presentation of carbamylated peptides could be a new mechanism underlying the contribution of HLA alleles to RA susceptibility.

Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial.

OBJECTIVE: To demonstrate the efficacy of the anti-interleukin-6 receptor monoclonal antibody tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy (GO). DESIGN: Double-masked randomized clinical trial. METHODS: Setting and Participants: Thirty-two adults with moderate-to-severe corticosteroid-resistant GO from 10 medical centers in Spain were randomized (1:1). INTERVENTION: Randomization to either 8 mg/kg body weight tocilizumab or placebo administered intravenously at weeks 0, 4, 8, and 12, and follow-up for an additional 28 weeks. Main Outcomes and Measures: The primary outcome was the proportion of patients with a change from baseline to week 16 of at least 2 in the clinical activity score (CAS). RESULTS: The primary outcome was met by 93.3% (95% confidence interval [CI] 70.1%-98.8%) of the patients receiving tocilizumab and 58.8% (36%-78.3%) receiving placebo (P = .04; odds ratio, 9.8 [CI 1.3-73.2]). A significant difference was also observed in the proportion of patients achieving a CAS < 3 (86.7% [CI 62.1%-96.2%] vs 35.2% [CI 17.3%-58.7%], P = .005; OR 11.9 [CI 2.1-63.1]) at week 16. Additionally, a larger proportion of patients with improvement in the European Group on GO-proposed composite ophthalmic score at week 16 (73.3% [CI 48%-89.1%] vs 29.4% [CI 13.2%-53.1%]; P = .03), and exophthalmos size change from baseline to week 16 (-1.5 [-2.0 to 0.5] mm vs 0.0 [-1.0 to 0.5] mm; P = .01) were seen with tocilizumab. One patient experienced a moderate increase in transaminases at week 8; another had an acute pyelonephritis at week 32 in the tocilizumab-treated group. CONCLUSION: Tocilizumab offers a meaningful improvement in activity and severity in corticosteroid-resistant GO. This trial justifies further studies to characterize the role of tocilizumab in GO.

Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies.

OBJECTIVE: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. METHODS: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. RESULTS: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks. CONCLUSION: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years. TRIAL REGISTRATION NUMBERS: NCT01172938, NCT01212757 and NCT01212770.

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.

Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis.

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.

Clinical characteristics and patient-reported outcomes in patients with inadequately controlled rheumatoid arthritis despite ongoing treatment.

BACKGROUND: Despite the wide array of treatments available for rheumatoid arthritis (RA), some patients continue to report unmet clinical needs. We investigated the extent of inadequate disease control in patients with RA. METHODS: Data were drawn from the Adelphi 2014 RA Disease-Specific Program in France, Germany, Italy, Spain and the UK. Rheumatologists provided patient demographics, comorbidities, satisfaction with RA control and other clinical details. Patients reported their level of satisfaction and completed the EuroQoL 5-Dimensions Health Questionnaire and Work Productivity and Activity Impairment Questionnaire. Patients had been on their current therapy ≥3 months and had 28-joint disease activity scores (DAS28) reported. Adequately controlled (DAS28 ≤3.2) and inadequately controlled (DAS28 >3.2) patient cohorts were compared using univariate tests. RESULTS: Of 1147 patients, 74% were women, the mean age was 52 years and the mean time since RA diagnosis was 7 years. Twenty-seven percent of patients had inadequately controlled RA, whereas 73% had adequately controlled RA. Inadequately controlled patients were more affected clinically versus adequately controlled patients; 69% vs 13% had moderate/severe RA, the current level of pain was 4.6 vs 2.3, and 67% vs 41% experienced flares, respectively (all p<0.0001). Inadequately controlled patients had higher rates of depression (16% vs 5%; p<0.0001), worse health state, greater work and activity impairment, and lower satisfaction rates among the patients and their physicians than the adequately controlled cohort. CONCLUSION: RA was insufficiently controlled in over a quarter of patients despite their current therapy and this had a negative impact on the patients.

Correction to: Spanish transcultural adaptation and validation of the English version of the compliance questionnaire in rheumatology.

In the original published article, the family name was incorrectly tagged for two co-authors. The correct family names of authors José Ramón Maneiro Fernández is Maneiro Fernández and Alejandro Souto Vilas is Souto Vilas.