Nonbiologic Disease-modifying Antirheumatic Drugs Research Articles

Tumor Necrosis Factor-α Inhibitor Use and the Risk of Incident Hypertension in Patients with Rheumatoid Arthritis.

To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy. We conducted a cohort study using insurance claims data (2001-2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension. We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators. Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.See Video Abstract at http://links.lww.com/EDE/B36.

Depression and Insomnia in Patients With Psoriasis and Psoriatic Arthritis Taking Tumor Necrosis Factor Antagonists.

Psoriasis patients with moderate to severe disease often present with depression and insomnia. Treatment targeting both psoriasis and psychological comorbidities is needed to improve the quality of life of these patients.In this nationwide cohort study, a total of 980 patients with psoriatic arthritis or psoriasis who had received nonbiological disease-modifying antirheumatic drugs and biologics therapy between 2009 and 2012 were identified. The prevalence rates of patients taking medications for depression and insomnia were compared before and after biologics therapy. Logistic regression method was used to investigate the risk factors for depression and insomnia. Further stratified analyses were performed to examine the prevalence of use of medications for depression and insomnia among different patient subgroups.The prevalence of patients taking regular antidepressants before starting biologics therapy was about 20%. There was a more than 40% reduction in this prevalence after biologics therapy for 2 years. Age higher than 45 years, female sex, presence of comorbidities, and psoriatic arthritis were independently associated with depression and insomnia. Further stratified analyses revealed a more rapid and significant reduction in depression/insomnia in those undergoing continuous biologics therapy, younger than 45 years, without psoriatic arthritis and not taking concomitant methotrexate, when compared with their counterparts.The results suggest that biologics therapy may be associated with reduced rates of depression and insomnia, and a reduced rate of regular antidepressants use in psoriasis patients.

Identifying factors associated with concordance with the American College of Rheumatology rheumatoid arthritis treatment recommendations.

BackgroundFactors associated with care concordant with the American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) are unknown.MethodsWe identified a national cohort of biologic-naive patients with RA with visits between December 2008 and February 2013. Treatment acceleration (initiation or dose escalation of biologic and nonbiologic DMARDs) in response to moderate to high disease activity (using the Clinical Disease Activity Index) was assessed. The population was divided into two subcohorts: (1) methotrexate (MTX)-only users and (2) multiple nonbiologic DMARD users. In both subcohorts, we compared the characteristics of patients who received care consistent with the ACR recommendations (e.g., prescriptions for treatment acceleration) and their providers with the characteristics of those who did not at the conclusion of one visit and over two visits, using logistic regression and adjusting for clustering of patients by rheumatologist.ResultsOur study included 741 MTX monotherapy and 995 multiple nonbiologic DMARD users cared for by 139 providers. Only 36.2 % of MTX monotherapy users and 39.6 % of multiple nonbiologic DMARD users received care consistent with the recommendations after one visit, which increased over two visits to 78.3 % and 76.2 %, respectively (25–30 % achieved low disease activity by the second visit without DMARD acceleration). Increasing time since the ACR publication on RA treatment recommendations was not associated with improved adherence.ConclusionsAllowing two encounters for treatment acceleration was associated with an increase in care concordant with the recommendations; however, time since publication was not.

One-year maintenance with routine assessment of patient index data 3-based remission may inhibit radiographic progression in patients with rheumatoid arthritis treated with routine clinical therapy: A retrospective comparison of radiographic outcome and its prognostic factors between maintained remissions with patient-reported outcome index and physician-oriented disease activity indices

Objectives: We investigated whether the maintenance of routine assessment of patient index data 3 (RAPID3) remission for one year (RAPID3-MR) may predict good radiographic outcomes. We also compared radiographic progression to prognostic factors among patients with RAPID3-MR, with the maintenance of clinical disease activity index remission for one year (CDAI-MR) or with the maintenance of 28 joint count disease activity score remission for one year (DAS28-MR).Methods: Of 1220 patients with available clinical data, 92 with RAPID3-MR, 80 with RAPID3-NMR (not satisfying RAPID3-MR), 45 with CDAI-MR, and 75 with DAS28-MR were retrospectively investigated. CDAI and DAS28 for clinical outcomes and the modified total Sharp score (mTSS) for radiographic joint damage were investigated for at least one year.Results: RAPID3, CDAI, DAS28, and their categories remained unchanged or significantly improved in RAPID3-MR patients but significantly deteriorated in RAPID3-NMR patients. The mean annual ΔmTSS was significantly lower in RAPID3-MR patients (0.12 ± 0.55) than in RAPID3-NMR patients (0.54 ± 1.27) (p = 0.025). There was no significant difference among RAPID3-MR patients, CDAI-MR patients (0.06 ± 0.85), and DAS28-MR patients (0.11 ± 0.89). The baseline mTSS (p = 0.038) and monotherapy with nonbiological disease-modifying antirheumatic drugs (p = 0.033) were good prognostic factors in RAPID3-MR patients.Conclusions: One-year RAPID3 remission maintenance may predict good radiographic outcomes.

Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist.

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

Updated RA guidelines: Implications for self-care

R arthritis (RA) is a chronic in ammatory condition characterized by polyarticular joint in ammation and pain, as well as fever, fatigue, myalgias, and loss of appetite.1 Extra-articular involvement may result in pleuritis, vasculitis, rheumatoid nodules, and conjunctivitis. The cause of RA is unknown, and many drug therapies have been approved for treatment. These include synthetic, biologic, or nonbiologic disease-modifying antirheumatic drugs (DMARDs), which target the in ammatory response through various mechanisms. Medications such as NSAIDs and corticosteroids are often used adjunctively to provide additional relief of pain and in ammation. Given that RA is considered incurable, optimizing therapy involves use of the available agents in the appropriate combination, sequence, and timeframe to prevent disease progression and complications.2

Examining Time to Initiation of Biologic Disease-modifying Antirheumatic Drugs and Medication Adherence and Persistence Among Texas Medicaid Recipients With Rheumatoid Arthritis

PurposeLittle is known about the transition from nonbiologic disease-modifying antirheumatic drugs (DMARDs) to biologic DMARDs or about individual nonbiologic DMARD use patterns among patients with rheumatoid arthritis (RA). This study examined time to initiation of biologic DMARDs and nonbiologic DMARD medication adherence and persistence among Texas Medicaid recipients with RA taking nonbiologic DMARDs. MethodsIn this retrospective study (July 1, 2003–December 31, 2010) of the Texas Medicaid database, patients were aged 18 to 62 years at index, were diagnosed with RA (International Classification of Diseases, Ninth Revision, Clinical Modification, code 714.xx), had no claims for nonbiologic or biologic DMARDs in the preindex period, and had a minimum of 2 prescription claims for the same nonbiologic DMARD in the postindex period. Kaplan-Meier survival analysis and log-rank tests were used to compare time to initiation of biologic DMARDs according to nonbiologic DMARD type and therapy. Adherence and persistence were examined according to nonbiologic type and therapy by using ANOVA models and χ2, Duncan, and t tests. FindingsOn average, patients were 47.9 (±10.4) years of age, mostly female (89.1%) and Hispanic (55.2%). Methotrexate (MTX) and leflunomide (LEF) users took the shortest time to initiate biologic DMARDs (207 [190] days and 188 [205] days, respectively). LEF users had the highest mean adherence of 37.5% (27.5%), which was similar to MTX users (35.7% [26.9%]), whereas dual-therapy users had the lowest mean adherence at 17.1% (14.4%). Sulfasalazine users (108 [121] days) had the lowest persistence, whereas LEF (227 [231] days) and MTX (211 [222] days) users had the longest persistence. Nonbiologic DMARD monotherapy users were more adherent than dual-therapy users (32.6% [25.8%] vs 17.1% [14.4%]). ImplicationsThese results should be interpreted in light of some study limitations, such as using proportion of days covered as a proxy for adherence, not having clinical data to control for RA severity, and lack of generalizability to all US populations. Given the study findings, both clinicians and other decision makers may want to investigate the potential driving factors of initiation of biologic DMARDs to provide effective RA management and consider patient education programs to enhance medication adherence and persistence to RA medications.

Indirect comparisons of the efficacy of subsequent biological agents in patients with psoriatic arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis.

Significant portion of patients with psoriatic arthritis (PsA) could not tolerate or do not have a satisfactory response to either non-steroidal anti-inflammatory drugs (NSAIDs), non-biologic disease-modifying anti-rheumatic drugs (DMARDs), or even TNF inhibitors. Non-TNF inhibitor biologic agents have emerged as second-line therapy in such situation. However, the comparative efficacy of these agents remains unknown as head-to-head randomized controlled trials (RCTs) are not available. RCTs examining the efficacy of non-TNF inhibitor biologic agents in patients with PsA who experienced inadequate response or intolerance of TNF inhibitors were identified. If more than one RCT was available for a given biologic agent, the pooled odds ratio (OR) and 95% confidence interval (CI) of achieving 20% improvement according to American College of Rheumatology criteria (ACR20) response across trials were calculated. The pooled OR for each biologic agent was then compared using the indirect comparison technique. Five RCTs of four non-TNF inhibitor biologic agents, including abatacept, secukinumab, ustekinumab, and apremilast, with 675 participants were identified and included in the data analyses. We found no significant difference in any comparisons, with the p values ranging from 0.14 to 0.98. Our study demonstrates that the likelihood of achieving the ACR20 response in patients with TNF inhibitor experience is not significantly different between the four non-TNF biologic agents. However, the interpretation of this analysis is limited by the small sample sizes. Head-to-head comparisons are still required to confirm the comparative efficacy.

Drug-specific risk, and associated factors, of vasculitis-like events in patients exposed to tumour necrosis factor alpha inhibitor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA)

BackgroundThe association between TNF inhibitors and vasculitis-like events, possibly secondary to induction of autoantibodies, has been well reported. However, the incidence, drug-specific differences, and associated factors have been poorly characterised. The aim of this study was to assess the drug-specific risk, and associated factors, of vasculitis-like events in patients with rheumatoid arthritis treated with TNF inhibitors and non-biologic disease modifying antirheumatic drugs (nbDMARDs). MethodsThis analysis included two cohorts from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) recruited from Oct 1, 2001, to May 31, 2015: patients starting first TNF inhibitors (adalimumab, etanercept, infliximab, certolizumab) and a comparison cohort receiving nbDMARDs. After identification of vasculitis-like events, additional information from hospital consultants was sought for verification. The risk of an event was compared between the two cohorts with Cox proportional hazard models, adjusted using propensity scores (inverse probability of treatment weighting). FindingsThere were 95 incident vasculitis-like events (14 in 3640 patients on nbDMARD, 81 in 12 745 patients starting first TNF inhibitors) with 20 365 and 52 428 patient-years of follow-up generating crude incidence rates of 7 per 10 000 and 16 per 10 000 person-years, respectively. After adjustment, the hazard ratio (HR) of vasculitis-like events in patients on TNF inhibitors versus nbDMARD was 1·3 (95% CI 0·4–4·0). Drug specific HRs were highest in patients on infliximab (HR 2·7, 95% CI 1·4–5·2) and etanercept (2·6, 1·4–4·8), but these associations were not significant after adjustment. Factors associated with vasculitis-like events included baseline disease activity (HR 1·4, 95% CI 1·2–1·7), rheumatoid factor positive status (1·8, 1·2–2·8), health assessment questionnaire score (1·7, 1·2–2·3), and sulfasalazine use (0·6, 0·3–0·9). InterpretationIn one of the largest registers of patients receiving biological drugs, the absolute risk of vasculitis-like events was low, irrespective of whether patients received TNF inhibitors or nbDMARDs. There were no significant differences in risk between TNF inhibitors after adjustment. Higher baseline disease activity and seropositive status were associated with higher rates of vasculitis events, whereas baseline sulfasalazine use was associated with lower rates. To our knowledge, this is the first study to date to assess the risk of this outcome in a prospective, observational cohort. FundingMedical Research Council.

Nonbiologic disease-modifying antirheumatic drugs in pregnancy

Rheumatic disease often affects young females and males in the reproductive age group. Management of these diseases with immunosuppressive disease-modifying antirheumatic drugs (DMARDs) is fraught with potential risks for the developing fetus as well as adverse pregnancy outcomes. In developing countries like India, most patients are treated with conventional DMARDs. We reviewed recent literature on safety during pregnancy for conventional disease-modifying agents, in view of the recently published landmark guidelines of the British Society for Rheumatology and the European League against Rheumatism. Exposure to leflunomide and cyclophosphamide is contraindicated in mothers during pregnancy and preconception phase, and fathers during conception due to risks for the developing fetus. Maternal exposure to methotrexate (MTX) during pregnancy or preconception confers higher risk of adverse pregnancy and fetal outcomes although paternal exposure may not be harmful. Sulfasalazine is safe during pregnancy; however, paternal exposure may reduce fertility, but this is reversible with cessation of the drug. Hydroxychloroquine, azathioprine, cyclosporine, and tacrolimus are compatible with maternal and paternal exposures without evidence for increased risk to the developing fetus. Insufficient data exist regarding safety profile of tofacitinib and apremilast during pregnancy. Rheumatologists should be cautious while starting these drugs in women and men of reproductive age group, and counsel patients accordingly to minimize the risk of adverse fetomaternal outcomes.

Assessment of the Therapeutic Effect of Total Glucosides of Peony for Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children; some clinical trials have reported the effects of total glucosides of peony (TGP) in the treatment of JIA. However, no systematic review has yet been conducted. In this study, we assessed the efficacy and safety in patients with JIA enrolled in randomized controlled trials (RCTs) of TGP. We extracted data for studies searched from 8 electronic databases that were searched and also evaluated the methodological quality of the included studies. We assessed the following outcome measures: overall response rate, pain, tender joint count (TJC), swollen joint count (SJC), duration of morning stiffness (DMS), grip strength (GS), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and adverse effects (AEs) in short term (4–8 weeks), intermediate term (9–26 weeks), and long term (>26 weeks). The final analysis showed that TGP acted as a unique nonbiologic disease-modifying antirheumatic drug (nonbiologic DMARD), and its therapeutic effects were safe and efficacious for the treatment of JIA with few AEs. However, more high-quality RCTs are needed to confirm these therapeutic effects.

Impact of Out-of-Pocket Costs on Prescription Fills Among New Initiators of Biologic Therapies for Rheumatoid Arthritis.

Biologic disease-modifying antirheumatic drug (DMARD) therapies are a mainstay of treatment for rheumatoid arthritis (RA), yet high member out-of-pocket (OOP) costs for such therapies may limit patient access to these therapies. To understand whether there is a relationship between OOP costs and the initial fill and subsequent refills of biologic DMARD treatments for RA members. Members of a national Medicare Advantage and Prescription Drug (MAPD) plan with an adjudicated (paid or reversed) claim for a biologic DMARD indicated for RA were identified from July 1, 2007, to December 31, 2012, and followed retrospectively. The first adjudicated claim date was the index date. Members were required to have 180 days of continuous enrollment pre- and post-index and ≥ 1 diagnosis for RA (ICD-9-CM: 714.0 or 714.2) during pre-index or ≤ 30 days post-index. Low-income subsidy and Medicaid-Medicare dual-eligible patients were excluded. The analysis used multivariate regression models to examine associations between initial prescription (Rx) abandonment rates and OOP costs and factors influencing the refill of a biologic DMARD therapy based on pharmacy claims. The final sample size included 864 MAPD members with an adjudicated claim for a biologic DMARD. The majority were female (77.4%) and mean age was 63.5 years (SD = 10.9). Most (78%) had conventional nonbiologic DMARD utilization during pre-index. The overall initial abandonment rate was 18.2% for biologic DMARDs, ranging from 1.3% for the lowest OOP cost group ($0-$250) to 32.7% for the highest OOP cost group (> $550; P < 0.0001 for Cochran-Armitage trend test). ORs for abandonment rose from 18.4 to 32.7 to 41.2 for OOP costs of $250.01-$400.00, $400.01-$550.00, and > $550.00 respectively, relative to OOP costs of ≤ $250.00 (all P < 0.0001). Meeting the catastrophic coverage limit and utilization of a specialty pharmacy for the index claim were both associated with a decreased likelihood of abandoning therapy (OR = 0.29 and OR = 0.14, respectively; both P < 0.05). Among the subset of 533 members with a paid claim, 82.4% had at least 1 refill post-index. The negative association between OOP cost and likelihood of refilling an Rx was highly significant (P < 0.0001). This study suggests that the higher the member OOP cost, the less likely an MAPD member is to initiate or refill a biologic DMARD therapy for RA. Further research is needed to understand reasons for initial Rx abandonment and lack of refills, including benefit design and adverse events.

Tumor Necrosis Factor-Alpha Inhibitor Medications for Inflammatory Conditions and Incidence of Multiple Myeloma

PurposeTumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that regulates a wide variety of cellular responses including proliferation and differentiation. This potent mediator of inflammation and bone resorption is elevated in plasma of multiple myeloma (MM) patients, and inhibition of TNF-α is hypothesized to enhance the effects of MM treatments. However, the effects of TNF-α inhibitors on incidence of MM have not been fully characterized. Some reports indicate a possible increased risk of hematological malignancies with anti-TNF therapies. The purpose of this study was to examine incidence of MM among adults with inflammatory conditions treated with anti-TNF monoclonal antibodies and TNF fusion protein.Patients and MethodsWe conducted a retrospective cohort study of new users of TNF-α inhibitors from 2009-2013 using the Truven Health MarketScan Database. Patients were required to be 20+ years old and have 12 months of continuous enrollment prior to first TNF-α inhibitor use. Exclusion criteria included presence of the following in the year prior to first TNF-α inhibitor use: any malignancy, HIV+, and hematopoietic stem cell transplant.We used longitudinal pharmacy claims data to measure continuous use of infliximab, adalimumab, golimumab, certolizumab and etanercept, as well as other immunosuppressive medications. MM cases were identified using a validated algorithm for administrative claims data and ICD-9 diagnosis codes. Data from the year prior to first TNF-α inhibitor use were also used to calculate Charlson comorbidity index scores and document diagnoses of inflammatory conditions, including rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease (Crohn's disease, ulcerative colitis) and ankylosing spondylitis. Incidence rates of MM per 100,000 person-years (PY) with 95% confidence intervals (CI) were calculated for the cohort with stratification by gender, age group (20-49, 50-64, 65+ years) and type of TNF-α inhibitor (anti-TNF antibody, TNF fusion protein). Observed rates were compared to MM incidence rates from Surveillance, Epidemiology and End Results Program registries in the same time period and geographic regions. Standardized incidence ratios (SIR) and exact 95% CIs were calculated for those strata using Poisson regression.ResultsAmong 114,045 incident users of TNF-α inhibitors, 82,003 (72%) used anti-TNF antibodies and 41,468 (36%) used TNF fusion protein alone or consecutively (after switching) during median follow up of 27 months and 205,635 PY overall. Rheumatoid arthritis (47%), psoriasis (21%) and inflammatory bowel disease (22%) were the most prevalent indications for TNF-α inhibitors, while fewer had psoriatic arthritis (15%) and ankylosing spondylitis (6%). There were 51 patients that developed MM during follow up, for a crude incidence rate (25 per 100,000 PY) that was higher than the expected rate (9 per 100,000 PY, age-standardized). TNF-α inhibitor users that developed MM were older (median: 57 vs. 49 years in non-cases) and had more concurrent treatment with corticosteroids (84% vs. 56%).The overall age-standardized incidence ratio for MM was SIR=3.2 (95% CI 2.4-4.2), with even higher than expected incidence in younger age groups (20-49 years: SIR=5.5, 95% CI 2.5-10.5; 50-64 years: SIR=8.0, 95% CI 5.1-11.5) but not in older patients (65+ years: SIR=1.8, 95% CI 1.0-3.1). Estimates were slightly higher for anti-TNF antibodies (SIR=3.6, 95% CI 2.6-5.0) vs. TNF fusion protein (SIR=2.8, 95% CI 1.6-4.5) and slightly lower in females (SIR=3.0, 95% CI 2.0-4.3) vs. males (SIR=3.5, 95% CI 2.3-5.2).ConclusionsIn this large sample of patients treated with TNF-α inhibitors, we observed a higher incidence of MM diagnoses than would be expected from a similarly aged population. Other than a causal association between TNF-α inhibitors and increased MM risk, a possible explanation for these findings could be the relationship between the underlying autoimmune, inflammatory conditions and myeloma etiology, particularly with the greater disease severity that would warrant these medications vs. other, non-biologic disease-modifying antirheumatic drugs (DMARDs). Future research on the comparative safety with long-term use of TNF-α inhibitors and other DMARDs that can incorporate clinical information on disease severity is needed to better understand these conditions, their treatment and subsequent MM risk. DisclosuresNo relevant conflicts of interest to declare.

Epidemiology and Treatment of New-Onset and Established Rheumatoid Arthritis in an Insured US Population.

To investigate the epidemiology and treatment of rheumatoid arthritis (RA) in a population broadly representative of employed adults in the US, using a retrospective cohort design. Incident and prevalent RA cohorts were defined from a sample of 4.66 million adults with complete followup data from the period of January 2005 through September 2008 in the Pharmetrics medical claims database. Demographics, comorbidity, and medical therapies were summarized using descriptive statistics. Median duration in the database was 5.7 years. Age- and sex-adjusted incidence in 2006 was 0.71 per 1,000 persons at risk (n = 3,992) and prevalence in 2005 was 0.63% (n = 30,530). Within 12 months after diagnosis, 65%, 64%, and 20% of the incident cohort had been prescribed corticosteroids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and tumor necrosis factor (TNF) inhibitors, respectively. Median time to first anti-TNF prescription was 6 months; 31% switched to a second drug and 15% to a third. An aggressive subcohort (11% of incident patients) received more DMARDs (83%) and TNF inhibitors (43%), and was more likely to switch. Twenty-eight percent of incident patients received only symptomatic therapy over a minimum of 1.75 years of followup; these patients were older with more comorbidities and contraindications to methotrexate. In this insured population-based cohort, only two-thirds of newly diagnosed RA patients were prescribed a DMARD in year 1 and 28% received no antirheumatic therapy. Although limited by lack of clinical information and by left-censoring, administrative databases capture clinical practice and suggest that gaps exist in treatment options available to a significant number of patients.

Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis.

The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans’ Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC-attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06–5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17–0.74]; p = 0.01 and HR 0.39 [CI 0.20–0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31–1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death.

Disease-modifying Antirheumatic Drugs (DMARD) and Combination Therapy of Conventional DMARD in Patients with Spondyloarthritis and Psoriatic Arthritis with Axial Involvement.

Treatment with nonsteroidal antiinflammatory drugs (NSAID) is the recommended first-line therapy in patients with axial spondyloarthritis (axSpA); and for those patients who have persistently active disease, the introduction of tumor necrosis factor-α (TNF-α) inhibitors is indicated. Conventional nonbiological disease-modifying antirheumatic drugs (DMARD), although effective and used in clinical practice for peripheral arthritis, are not recommended. Few studies have been conducted with the aim of evaluating the effect of conventional DMARD, either alone or in combination, in axSpA. As for psoriatic arthritis (PsA), DMARD are widely used, but few trials are available about their effects on axial involvement, which is not often assessed as a primary outcome in clinical trials. In rheumatoid arthritis, combination therapy of 2 or more conventional DMARD appears to confer better response than methotrexate monotherapy, and may even be a viable alternative to TNF-α inhibitors. In peripheral PsA, combination therapy can be used after treatment failure with 1 DMARD, but few studies have been conducted. However, available evidence for the combination of conventional DMARD indicates a lack of any significant benefit on axial symptoms; thus this treatment approach does not represent an effective alternative to anti-TNF-α therapy.

Apremilast for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints that occurs in patients with psoriasis. The spectrum of PsA includes arthritis, dactylitis, enthesitis, axial involvement, and skin lesions. Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and leflunomide, and biologic DMARDs such as tumor necrosis factor (TNF) antagonists and ustekinumab, have been used to treat PsA. Apremilast is a novel therapy that inhibits phosphodiesterase 4, increases intracellular cAMP levels, and modulates expression of inflammatory mediators in favor of anti-inflammatory activity. It decreases the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-23 and increases the anti-inflammatory cytokine IL-10 under certain conditions. One phase II and four phase III clinical trials as well as long-term extension studies showed significant and sustained clinical efficacy and an adequate safety profile for apremilast in patients with active psoriatic arthritis.

Prevention of Stroke in Rheumatoid Arthritis.

The risk of cerebrovascular disease is increased among rheumatoid arthritis (RA) patients and remains an underserved area of medical need. Only a minor proportion of RA patients achieve suitable stroke prevention. Classical cardiovascular risk factors appear to be under-diagnosed and undertreated among patients with RA. Reducing the inflammatory burden is also necessary to lower the cardiovascular risk. An adequate control of disease activity and cerebrovascular risk assessment using national guidelines should be recommended for all patients with RA. For patients with a documented history of cerebrovascular or cardiovascular risk factors, smoking cessation and corticosteroids and non-steroidal anti-inflammatory drugs at the lowest dose possible are crucial. Risk score models should be adapted for patients with RA by introducing a 1.5 multiplication factor, and their results interpreted to appropriately direct clinical care. Statins, angiotensin-converting enzyme inhibitors, and angiotensin-II receptor blockers are preferred treatment options. Biologic and non-biologic disease-modifying anti-rheumatic drugs should be initiated early to mitigate the necessity of symptom control drugs and to achieve early alleviation of the inflammatory state. Early control can improve vascular compliance, decrease atherosclerosis, improve overall lipid and metabolic profiles, and reduce the incidence of heart disease that may lead to atrial fibrillation. In patients with significant cervical spine involvement, early intervention and improved disease control are necessary and may prevent further mechanical vascular injury.

Association of tocilizumab treatment with changes in measures of regional left ventricular function in rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging.

The goal of this study was to determine whether the powerful anti-inflammatory effect of anti-interleukin-6 with tocilizumab (TCZ) might lead to a reduction in left ventricular (LV) dysfunction in patients with rheumatoid arthritis (RA). Consecutive RA patients with active disease and healthy control subjects without a clinical diagnosis of cardiovascular disease were enrolled. The RA patients each had inadequate clinical response to non-biologic disease-modifying anti-rheumatic drugs and were prescribed TCZ therapy. All subjects underwent baseline evaluation of LV function, as measured by cardiac magnetic resonance imaging (CMRI). Peak systolic regional radial strain (Err, %) was calculated by feature tracking of cine CMRI. After baseline (BL) CMRI measurements, treatment with TCZ was initiated, and patients were followed for 52 weeks. We compared peak Err of RA patients at BL and at 52 weeks. Thirteen RA patients (mean age 52.6 ± 5.4 years) were assessed at BL and at 52 weeks, and these patients were compared with 10 non-RA controls (mean age 55.7 ± 4.6 years). Disease Activity Score of 28 joints - erythrocyte sedimentation rate and Simple Disease Activity Index were significantly lower in RA patients at 52 weeks than at BL. Mean peak Err at BL in RA patients was significantly lower than in normal subjects (P = 0.03). Mean peak Err was significantly higher at 52 weeks than at BL (P = 0.028) in RA patients. We showed that TCZ was associated with left ventricular dysfunction in RA patients which correlated with a reduction in RA disease activity.

Biologic Cost per Effectively Treated Rheumatoid Arthritis Patient in a Large Managed Care Population: A Retrospective Cohort Study.

Background: Until recently, the lack of clinical outcomes information for rheumatoid arthritis (RA) in administrative claims databases limited their use in comparative effectiveness research. A validated claims-based algorithm has been developed to estimate the effectiveness of biologics for RA, allowing for estimation of cost and effectiveness in the same database. Objectives: To implement a validated claims-based effectiveness algorithm in a US managed care claims database to compute the 1-year biologic cost per effectively treated patient among first-line biologics approved for moderate-to-severe RA (abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab). Methods: This retrospective cohort study used administrative claims data for individuals in the HealthCore Integrated Research Database (HIRDSM). The first claim for a first-line biologic between July 1, 2009, and January 31, 2013, after 6 months of continuous enrollment, was defined as the index event and date. Patients were aged 18-63 years on the index date and had at least one claim for RA in the 6-month pre- index period. Biologic costs included plan and patient paid amounts on claims for the biologic drug and administration. The algorithm defined effectiveness during the 12-month post-index period as achieving all six of the following: high adherence (medication possession ratio ≥80% or infusions consistent with the product label); no increase in biologic dose or decrease in dosing interval; no new biologic; no new nonbiologic disease-modifying antirheumatic drug; no new or increased oral glucocorticoid use; and ≤1 glucocorticoid injection. Cost per effectively treated patient was calculated as the total biologic cost (drug and administration) divided by the number of patients categorized by the algorithm as effectively treated. Results: The cohort comprised 4844 patients (mean age 48.6 years, 76.4% female). Average first-year biologic cost ranged from $14 795 (golimumab) to $19 520 (abatacept). Average first-year biologic cost per effectively treated patient was significantly lower for etanercept ($50 217) than for golimumab ($56 427, p<0.001) adalimumab ($56 879, p<0.001), abatacept ($68 062, p<0.001), certolizumab pegol ($76 427, p<0.001), and infliximab ($95 126, p<0.001). Conclusions: In this application of a validated claims-based algorithm to a large managed care population, etanercept had the lowest 1-year biologic cost per effectively treated patient among first-line biologics.