Search

Objective This systematic literature review determined whether there is clinical utility for dual-energy computed tomography (DECT) to inform on prognosis for patients with gout. With DECT, individualized treatment plans could be developed based on the patient's unique urate burden, with DECT being used as a clinical outcome measure in gout management. Methods To evaluate DECT as a reliable, valid, and sensitive prognostic instrument, a librarian-assisted search was undertaken in PubMed and Embase for articles on gout and DECT informing on reliability; content, construct, and criterion validity; sensitivity to change; and minimum clinically important changes. Results This systematic literature review showed that DECT has high intra- and interrater reliability. Tophus burden correlates with functional loss to show content validity. DECT volume is positively correlated with death, cardiovascular risk factors, and the risk for future gout flares. DECT has excellent sensitivity to change with effective urate-lowering therapies. Conclusion DECT is a promising prognostic tool based on its high reliability, sensitivity to change, and emerging validity. Additional large, well-designed, prospective cohort studies are needed to fully evaluate its prognostic utility. This systematic review suggests that DECT very likely has additional prognostic information beyond clinical tophi assessment alone.

Background: Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase+methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here.Methods: Uncontrolled gout patients (serum urate [SU]≥6 mg/dL and SU≥6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4-weeks before and during pegloticase therapy. Twelve-month responder rate (SUResults: Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4 year gout history, pre-therapy SU: 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24-weeks, one patient exited the study per-protocol at 24-weeks (enrolled prior to treatment extension amendment), and 10 remained in study through Week 52. Of the 10, 8 completed 52-weeks of pegloticase+methotrexate and were 12-month responders. The remaining two discontinued pegloticase+methotrexate at Week 24 (met treatment goals) and stayed in study under observation (allopurinol prescribed at physicians’ discretion); one remained a responder at 12-months. At 52-weeks, change from baseline in SU was -8.2 ± 4.1 mg/dL (SU: 1.1 ± 2.4 mg/dL, n=10). Gout flares were common early in treatment but progressively decreased while on therapy (Weeks 1-12: 13/14 [92.9%], Weeks 36-52: 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titres; fewer patients had trough concentrations (Cmin) below quantitation limit (BQL) and median Cmin was higher (1.03 mg/mL vs. BQL) than in pegloticase monotherapy trials.Conclusions: Methotrexate+pegloticase co-therapy was well-tolerated over 12-months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates.Trial registration: ClinicalTrials.gov: NCT03635957, registered 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03635957

ObjectiveTo examine the efficacy and safety of pegloticase in combination with methotrexate (MTX) in patients with uncontrolled gout in an exploratory, open-label clinical trial (ClinicalTrials.gov: NCT03635957) prior to a randomized, controlled trial.MethodsA multicenter, open-label efficacy and safety study of pegloticase with MTX co-treatment was conducted in patients with uncontrolled gout. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as serum uric acid (sUA) < 6 mg/dL for ≥ 80% of the time during Month 6 (Weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥ 1 pegloticase infusion.ResultsSeventeen patients were screened and 14 patients (all men, average age 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL, and 12 of the 14 patients had visible tophi. At the 6-month timepoint, 11/14 (78.6%, 95% CI 49.2–95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (preinfusion sUA values > 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. No new safety concerns were identified.ConclusionIn this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase as compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of MTX or placebo with pegloticase to validate these open-label findings.

OBJECTIVE To investigate the safety and efficacy of ABT-122, a tumor necrosis factor (TNF)- and interleukin-17A (IL-17A)-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate. METHODS Patients (n = 240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week double-blind, parallel-group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12-week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis. RESULTS In both ABT-122 dose groups, ACR20 response rates at week 12 (64.8-75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT-122 dose groups (36.6-53.4% and 22.5-31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT-122 120 mg every week, and ABT-122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment-emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT-122. CONCLUSION Dual neutralization of TNF and IL-17A with ABT-122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12-week treatment course in patients with PsA.

The dual-variable domain immunoglobulin ABBV-257 binds tumor necrosis factor-α and interleukin 17A. Following single ascending doses ( 0.3, 1.0, and 3.0 mg/kg intravenously; 0.3 and 3.0 mg/kg subcutaneously) in a randomized, double-blind, placebo-controlled study in healthy subjects (n = 40; n = 29 evaluated for pharmacokinetics), maximum observed serum concentration (Cmax ) increased dose-proportionally, whereas area under the serum concentration-versus-time curve trended to more than dose-proportional increase. Absolute subcutaneous bioavailability was ∼80%, and the time to Cmax (tmax ) occurred 6 to 8 days after subcutaneous administration. The terminal-phase harmonic mean elimination half-life (t½ ) ranged from 5.5 to 11 days following intravenous and subcutaneous administration. In another randomized, placebo-controlled study, rheumatoid arthritis (RA) patients (n = 8) received ABBV-257 30 mg/kg subcutaneously every other week for 8 weeks. Following the fourth dose, Cmax was 7.69 μg/mL, and tmax occurred ∼4 days after dosing; t½ was ∼16 days. Most individuals (single-dose study, 97%; multiple-dose study, 83%) developed antidrug antibodies (ADAs). Generally, subjects with higher ADA titers had shorter ABBV-257 t½ and lower exposure. One serious adverse event (cerebral ischemia, considered unrelated to treatment, resolved with interventions) occurred in an RA patient who received ABBV-257. Because of the high incidence of ADA-mediated drug clearance, ABBV-257 is no longer being developed.

Background:Gout development follows persistent serum uric acid (sUA) elevation. Patients who are refractory to or cannot tolerate oral urate lowering therapies (ULTs) have limited treatment options. Pegloticase is effective in treating refractory gout, but many patients develop anti-drug antibodies (ADAs), which are associated with loss of urate-lowering efficacy1-3 and infusion reactions (IRs).1,2 In phase 3 trials, the pooled pegloticase responder rate during Months 3 and 6 combined was 42% (8 mg infusion every 2 weeks), with high-titer ADA positive patients losing efficacy prior to 6 months.1 The 6-month results from the MIRROR open-label trial (79% response rate [11/14], 95%CI 49-95%)4 suggest that methotrexate (MTX) administered in conjunction with pegloticase increases treatment responder rate.Objectives:To examine longer-term (12-month) exploratory endpoints from the MIRROR open-label trial, including joint, overall health, and gout global assessments. Serial dual-energy computed tomography (DECT) images were also examined when available.Methods:Adult patients with uncontrolled gout (sUA ≥6 mg/dL with ≥1 of the following: sUA ≥6 mg/dL despite ULT use, intolerance to ULT, or functionally limiting tophaceous deposits) were included. Patients with immunocompromised status, G6PD deficiency, severe renal impairment, or MTX contraindication were excluded. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase therapy (8 mg biweekly infusion for up to 52 weeks). Exploratory outcomes included mean change from baseline (CFB) in number of affected joints (tophi, swollen, tender), Health Assessment Questionnaire (HAQ) scores (Disability Index [DI; score 0−3], Pain [score 0−100], Health [score 0−100]), and Gout Global Assessments (Patient, Physician; score 0−10). A decrease in these measures reflects clinical/patient-reported health improvement. Change in urate deposition volume, as measured on DECT imaging, was also examined as available. Analyses were performed on the modified intent-to-treat (mITT) population (≥1 pegloticase infusion received).Results:14 patients (all male, mean±SD age: 49.3±8.7 years) made up the mITT population. Mean±SD sUA prior to pegloticase treatment was 9.2±2.5 mg/dL and 13 patients had visible tophi. 3 patients discontinued due to 2 consecutive sUA levels >6 mg/dL and 1 patient completed the study at week 24 (pre-protocol amendment extending treatment from 24 to 52 weeks). 10 patients completed the 52-week study. Of these, 8 patients received 26 infusions and 2 patients received 12 infusions, discontinued pegloticase after meeting their treatment goal at 24 weeks, and started allopurinol while remaining in study under observation. At week 52 (n=10, sUA=1.1±2.5 mg/dL), the number of affected joints improved, along with HAQ measures (Figure 1). Global Assessments of Gout also improved (Physician: CFB=-5.7±2.6, Patient CFB=-4.6±2.1) and majority of subjects had a score of 0 or 1 (0=“excellent health”) at week 52 (Physician: 0.3±0.5, Patient: 1.1±1.3). Two patients had available DECT imaging. One received pegloticase/methotrexate co-therapy thru week 52 and had a marked reduction in total urate volume (baseline: 128.76 cm3, week 52: 1.33 cm3). The other received only 5 pegloticase infusions, but also showed total urate volume reduction (baseline: 59.20 cm3, week 10: 25.07 cm3). Both patients displayed improvement in bone erosion healing.Conclusion:These 12-month exploratory endpoints of the MIRROR open-label trial suggest that MTX/pegloticase co-therapy results in meaningful changes in clinical evaluations (tophaceous, tender, and swollen joint counts), and patient-reported outcomes (pain, disability) in patients with uncontrolled gout.References:[1]Sundy JS et al. JAMA 2011;306:711-20[2]Baraf HS et al. J Clin Rheumatol 2014;20:427-32[3]Lipsky PE et al. Arthritis Res Ther 2014, 16:R60[4]Botson JK et al. J Rheum 2020 [Epub ahead of print]Disclosure of Interests:John Botson Speakers bureau: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Consultant of: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Grant/research support from: Horizon Therapeutics and Radius Health, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Lycera, Can-Fite BioPharma, Scipher Medicine, Inmedix, and Vorso, Consultant of: Bristol Myers Squibb, Corona, Lilly, AbbVie, Amgen, Arena, GlaxoSmithKline, Gilead Sciences, Horizon Therapeutics, Lycera, Novartis, Pfizer, Roche, Samsung, Scipher Medicine, and Set Point, Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, Lilly and Sanofi, Jeff Peterson Speakers bureau: Horizon Therapeutics plc, Grant/research support from: Horizon Therapeutics plc.

Background:In an open-label, single-arm trial in adult patients with uncontrolled gout (MIRROR open-label [OL] trial) evaluating pegloticase co-treatment with methotrexate (MTX); 78.6% patients were responders, defined as maintenance of serum uric acid 1. MTX co-treatment is shown to improve the pharmacokinetics (PK) of biologics by attenuating the formation of anti-drug antibodies2.Objectives:To determine the systemic exposures of pegloticase and methotrexate polyglutamate(s) (MTX-PGs) in uncontrolled gout patients receiving pegloticase and MTX; to evaluate the effect of MTX on the PK of pegloticase in comparison to historical pegloticase monotherapy trials (C0405 and C0406)3, 4; and to evaluate the immunogenicity of pegloticase in co-treatment with MTX.Methods:In the MIRROR OL trial, MTX (15 mg/week) was given orally 4 weeks prior to the first pegloticase dose and continued weekly, in combination with pegloticase 8 mg given intravenously every 2 weeks, for a treatment duration of up to 52 weeks. Pre-infusion samples were collected to measure MTX-PGs in red blood cells. Pre- and post-infusion blood samples were obtained to measure the peak (Cmax) and trough (Cmin) concentrations of pegloticase at multiple visits. Anti-drug antibody blood samples were collected at multiple visits. The impact of MTX on pegloticase PK was evaluated by comparing pegloticase exposures with MTX from this trial to historical monotherapy data (C0405 and C0406)3, 4. The observed pegloticase concentrations with MTX were also overlaid with the 90% prediction interval based on the population PK model5 from C0405 and C0406.Results:Pegloticase and MTX-PG levels were determined in 14 patients. The 11 responders were generally associated with higher pegloticase exposures than the non-responders, especially Cmin (Figure 1). Concomitant treatment of MTX resulted in fewer patients with Cmin below quantitation limit (BQL) (5/14 [36%] with MTX vs 63/82 [77%] without MTX), and higher overall Cmin (median: 1.03 µg/ml with MTX vs BQL without MTX); Cmax was slightly higher (median [Q1, Q3]: 2.11 [1.65, 2.59] µg/mL with MTX vs 1.51 [BQL, 2.48] µg/mL without MTX). Pegloticase co-treatment with MTX resulted in more concentrations above the predicted median value of pegloticase, compared to monotherapy. ADA data is consistent with pegloticase PK and efficacy. Significant increase in ADA titers were only observed in 2 subjects (both were non-responders) at time corresponding to the loss of pegloticase exposure and increases in sUA levels. Concentrations of MTX-PGs were maintained during the treatment course, suggesting compliance of MTX administration. There was no apparent difference in concentrations of MTX-PGs between responders and non-responders.Conclusion:Pegloticase 8 mg IV every 2 weeks co-treatment with MTX 15 mg weekly resulted in fewer patients with pegloticase Cmin below the quantification limit (BQL) and gave higher overall trough concentrations (Cmin) compared to pegloticase monotherapy in the phase 3 studies.Pegloticase 8 mg IV every 2 weeks co-treatment with MTX 15 mg weekly was associated with an improved response rate for pegloticase in association with improved drug levels in these patients with uncontrolled gout compared to pegloticase monotherapy in the phase 3 studies.References:[1]Botson J., et al. J Rheumatol. 2020; doi: 10.3899/jrheum.200460[2]Goss S. L., et al. Clin Ther;2018, 40 (2).[3]Lipsky P. E., et al. Arthritis Res Ther;2014, 16 (2).[4]Sundy J. S., et al. JAMA;2011, 306 (7).[5]Yue C. S., et al. ASCPT, Atlanta, 2010.Disclosure of Interests:Yang Song Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Yan Xin Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Canfite, Inmedix, Lycera, Vorso, Scipher, Grant/research support from: Crescendo Bioscience, Bristol Myers Squibb, Sanofi, Eli Lilly, Amgen, Jason Chamberlain Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Colleen Canavan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Srini Ramanathan Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

Background:Gout is a painful inflammatory arthritis caused by persistently elevated serum uric acid (sUA) levels. Pegloticase, an infused recombinant PEGylated uricase, rapidly lowers sUA levels by converting uric acid to allantoin, a water-soluble molecule that is readily excreted by the kidneys. In the phase 3 clinical trials, 42% of patients1dosed with pegloticase every two weeks maintained sUA levels below 6.0 mg/dL during months 3 and 6 of pegloticase treatment. The loss of pegloticase efficacy has been attributed to the development of anti-drug antibodies (ADAs)1-3and these ADAs have been associated with infusion reactions (IRs).1,2Case reports4and prospective case series5, 6indicate that methotrexate (MTX) may allow patients to attain more complete therapeutic benefits, presumably through attenuation of pegloticase immunogenicity. The current study prospectively examines the efficacy and safety of MTX-pegloticase co-therapy in patients with uncontrolled gout.Objectives:To assess efficacy and safety of concomitant pegloticase and MTX therapy in patients with uncontrolled gout.Methods:Adult patients with uncontrolled gout who were beginning pegloticase therapy were considered for enrollment in this ongoing multicenter, open-label, efficacy and safety study of pegloticase with MTX co-treatment (NCT03635957). Patients were administered oral MTX (15 mg/week) and folate (1 mg/day) 4 weeks prior to the first pegloticase infusion (Day 1) and throughout the pegloticase treatment period. Blood was drawn prior to each infusion to measure sUA level, monitor clinical parameters, and examine for ADA development. All patients followed typical IR prophylaxis protocols (fexofenadine one day before and the morning of each infusion and acetaminophen and IV corticosteroid the morning of each infusion). Patients also received gout flare prophylaxis with either NSAIDs, colchicine or prednisone initiated at least 1 week prior to Day 1. The primary study outcome was the proportion of responders, defined as sUA Results:A total of 17 patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 months timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting stopping rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. One serious AE of bacterial sepsis occurred (resolved). AEs that occurred in >1 patient during the co-treatment period were: diarrhea and upper respiratory tract infection in 3 patients each, sinusitis, muscle strain, and hypertension in 2 patients each. Gout flares occurred in 12/14 (85.7%) patients. No new safety concerns were identified.Conclusion:An increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase (78.6%) when compared to the previously reported 42% using pegloticase alone.1These results support and reflect the improved response rates demonstrated in two prior case series.5,6A definitive randomized double-blinded trial evaluating pegloticase with MTX vs. pegloticase with placebo is ongoing.References:[1]Sundy JS et al.JAMA2011;306:711-20.[2]Baraf HS et al.J Clin Rheumatol2014;20:427-32.[3]Lipsky PE et al.Arthritis Res Ther2014;16:R60.[4]Bessen SY et al.Semin Arthritis Rheum2019;49:56-61.[5]Botson J, Peterson J.Ann Rheum Dis2019;78:A1289.[6]Albert JA et al.Arthritis & Rheumatology2019;71(S10):A1236.Disclosure of Interests: :John Botson Grant/research support from: Horizon Therapeutics (PI and study site), Radius Health (study site), Consultant of: Horizon Therapeutics, Speakers bureau: Celgene, Eli Lilly, Horizon Therapeutics, Mallinckrodt, Novartis, Pfizer, Paul M. Peloso Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Jeff Peterson Grant/research support from: Abbvie, UCB, Smith Klein, Horizon Therapeutics, Consultant of: Lilly, Norvartis, Horizon Therapeutics, Speakers bureau: Lilly, Novartis, Horizon Therapeutics, Abbvie, Genentech

To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain.Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate.Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV 550.8%) and 78.2% at 200 mg twice daily (Elaris EMIV 575.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.5% at 150 mg once daily (Elaris EM-IV 566.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV 567.2%).”After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings.Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use.ClinicalTrials.gov, NCT01760954 and NCT02143713.

Objectives ABT-122 is a dual-variable-domain immunoglobulin that neutralizes both TNF-α and IL-17A. The objective of this work was to characterize exposure-response relationships for ABT-122 relative to adalimumab (TNF-α inhibitor) using ABT-122 phase 2 trials in patients with RA or PsA. Methods Patients received subcutaneous doses of ABT-122 ranging from 60 mg every other week (EOW) to 240 mg every week, adalimumab 40 mg EOW, or placebo (PsA patients only) for 12 weeks. Relationships between ABT-122 or adalimumab serum concentrations and time course of ACR20, ACR50 and ACR70 and PASI50, PASI75 and PASI90 responses were characterized using a non-linear mixed-effects Markov modelling approach. Results A total of 221 RA patients and 240 PsA patients were included in the analyses. At comparable molar exposures, there was no differentiation of efficacy between ABT-122 and adalimumab and there were no consistent differences between ABT-122 and adalimumab in the potency estimates for different efficacy endpoints based on the Markov models. Plateau of ABT-122 efficacy was achieved at exposures associated with the 120 mg EOW dose in patients with RA, which were comparable to molar exposures of adalimumab 40 mg EOW, and at the lowest dose of 120 mg every week in patients with PsA. Conclusion The exposure-response relationships for ABT-122 were not distinguishably different from those of adalimumab in patients with RA or PsA. Overall, there was no clear evidence that inhibition of the IL-17 pathway provided incremental benefit in the presence of TNF-α inhibition. Trial registration ClinicalTrials.gov, NCT02433340, NCT02349451.

Objectives To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies. Methods All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study). Results The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36-43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42-53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6-3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks. Conclusion ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895.

Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERW trials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6 weeks or less, and 12 (median, 334) lasted 12 to 26 weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials.

Objective Tumor necrosis factor (TNF) and interleukin-17A (IL-17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). This study sought to evaluate the safety and efficacy of ABT-122, a novel dual variable domain immunoglobulin targeting human TNF and IL-17A, in patients with RA who have experienced an inadequate response to methotrexate. Methods Patients with active RA who were receiving treatment with methotrexate and had no prior exposure to biologic agents (n = 222) were enrolled in a 12-week phase II randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive either ABT-122 at dosages of 60 mg every other week, 120 mg every other week, or 120 mg every week or adalimumab at 40 mg every other week, administered subcutaneously. The primary efficacy end point was the proportion of patients achieving a ≥20% improvement response based on the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Results Treatment-emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT-122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT-122 60 mg every other week, 120 mg every other week, and 120 mg every week, respectively, compared with an ACR20 response rate of 68% with 40 mg adalimumab every other week. The corresponding response rates for ACR50 and ACR70 improvement in the ABT-122 dose groups and adalimumab group were 35%, 46%, 47%, and 48%, respectively, and 22%, 18%, 36%, and 21%, respectively. Conclusion Over the 12-week study period, dual inhibition of TNF and IL-17A with ABT-122 produced a safety profile consistent with that of adalimumb used for inhibition of TNF alone. The efficacy of ABT-122 over 12 weeks at dosages of 120 mg every other week or 120 mg every week was not meaningfully differentiated from that of adalimumab at a dosage of 40 mg every other week in patients with RA receiving concomitant methotrexate.

Objectives: The objective was to evaluate the effects of elagolix on dyspareunia in women with endometriosis-associated pain. Methods: Data were pooled from two similar, randomized, double-blind, placebo-controlled, 6-month phase 3 studies (Elaris Endometriosis-I and Elaris Endometriosis-II) of elagolix at two doses (150 mg QD and 200 mg BID) in women with endometriosis-associated pain. In this post hoc analysis, dyspareunia responders were defined as having a clinically meaningful decrease from baseline in the dyspareunia score and decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. Sexual relationship was assessed using the 30-item Endometriosis Health Profile questionnaire sexual relationship module. Results: A total of 1384 women reported ⩾1 day of sexual activity at baseline (35 days prior to and including day 1 of treatment). Of these 1384 women, 1297 (94%) reported ⩾1 day of any dyspareunia (mild, moderate, or severe), of which 51% reported ⩾1 day of severe dyspareunia. Among sexually active women who reported any dyspareunia at baseline, both elagolix doses led to improvements in dyspareunia. Women in the 200-mg BID group showed more months at which the dyspareunia response rates were statistically significantly greater than placebo, particularly in a subgroup of women with severe dyspareunia at baseline. Compared to placebo, both elagolix doses led to statistically significantly greater improvements in the mean 30-item Endometriosis Health Profile sexual relationship module score. Conclusion: Up to 6 months of elagolix treatment improved dyspareunia in women with endometriosis-associated pain in a dose-dependent manner, with 200-mg BID dose showing the most significant improvements in dyspareunia and quality of sexual relationships compared with placebo.

Objectives: To conduct an overview (review-of-reviews) on pharmacological interventions for neck pain. Search Strategy: Computerized databases and grey literature were searched from 2006 to 2012. Selection Criteria: Systematic reviews of randomized controlled trials (RCT) in adults with acute to chronic neck pain reporting effects of pharmacological interventions including injections on pain, function/disability, global perceived effect, quality of life and patient satisfaction. Data Collection & Analysis: Two independent authors selected articles, assessed risk of bias and extracted data The GRADE tool was used to evaluate the body of evidence and an external panel provided critical review. Main Results: We found 26 reviews reporting on 47 RCTs. Most pharmacological interventions had low to very low quality methodologic evidence with three exceptions. For chronic neck pain, there was evidence of: 1) a small immediate benefit for eperison hydrochloride (moderate GRADE, 1 trial, 157 participants); 2) no short-term pain relieving benefit for botulinum toxin-A compared to saline (strong GRADE; 5 trial meta-analysis, 258 participants) nor for subacute/chronic whiplash (moderate GRADE; 4 trial meta-analysis, 183 participants) including reduced pain, disability or global perceived effect; and 3) no long-term benefit for medial branch block of facet joints with steroids (moderate GRADE; 1 trial, 120 participants) over placebo to reduce pain or disability; Reviewers' Conclusions: While in general there is a lack of evidence for most pharmacological interventions, current evidence is against botulinum toxin-A for chronic neck pain or subacute/chronic whiplash; against medial branch block with steroids for chronic facet joint pain; but in favour of the muscle relaxant eperison hydrochloride for chronic neck pain.

Background: Controversy persists regarding medicinal injections for mechanical neck disorders (MNDs). Objectives: To determine the effectiveness of physician-delivered injections on pain, function/disability, quality of life, global perceived effect and patient satisfaction for adults with MNDs. Search Methods: We updated our previous searches of CENTRAL, MEDLINE and EMBASE from December 2006 through to March 2012. Selection Criteria: We included randomized controlled trials of adults with neck disorders treated by physician-delivered injection therapies. Data Collection and Analysis: Two authors independently selected articles, abstracted data and assessed methodological quality. When clinical heterogeneity was absent, we combined studies using random-effects models. Results: We included 12 trials (667 participants). No high or moderate quality studies were found with evidence of benefit over control. Moderate quality evidence suggests little or no difference in pain or function/disability between nerve block injection of steroid and bupivacaine vs bupivacaine alone at short, intermediate and long-term for chronic neck pain. We found limited very low quality evidence of an effect on pain with intramuscular lidocaine vs control for chronic myofascial neck pain. Two low quality studies showed an effect on pain with anaesthetic nerve block vs saline immediately post treatment and in the short-term. All other studies were of low or very low quality with no evidence of benefit over controls. Authors' Conclusions: Current evidence does not confirm the effectiveness of IM-lidocaine injection for chronic mechanical neck pain nor anaesthetic nerve block for cervicogenic headache. There is moderate evidence of no benefit for steroid blocks vs controls for mechanical neck pain.

We describe patterns of treatment of rheumatoid arthritis with biologics in the United States during 2000–2010 using longitudinal data in the IMS LifeLink™ health plan claims database. Rheumatoid arthritis prevalent and incident cases were identified by ICD-9 diagnostic codes. The proportion of prevalent rheumatoid arthritis cases using biologics increased from 18.7% in 2005 to 26.3% in 2010. Tumor necrosis factor α antagonists constituted 99.1% of biologics in 2005 and 84.4% in 2010. During 2000–2010, 58.1% of incident cases were treated with 1st-line non-steroidal anti-inflammatory drugs and/or corticosteroids and 36.5% were treated with 1st-line synthetic disease-modifying anti-rheumatic drugs. Biologics constituted 5.4% of 1st-line therapies for incident rheumatoid arthritis cases and 30.9%–56.3% of 2nd-to-≥5th line therapies. For those who started on 1st-line non-steroidal anti-inflammatory drugs/corticosteroids, the duration of pharmacotherapy before switching to biologics was 7.2 years for those st...

Background Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease. Methods This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0–100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study. Results In total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (p = 0.004 for 60 mg and p = 0.034 for 90 mg for DAS28-CRP; p

OBJECTIVE: To estimate the prevalence of inadequate pain relief (IPR) among patients with symptomatic knee OA prescribed analgesic therapy and to characterize patients with IPR. METHODS: Patients ≥50 years old with physician-diagnosed knee OA who had taken topical or oral pain medication for at least 14 days were recruited for this prospective non-interventional study in six European countries. Pain and function were assessed using the Brief Pain Inventory (BPI) and the WOMAC; quality of life (QoL) was assessed using the 12-item short form. IPR was defined as an average pain score of >4 out of 10 on BPI question 5. RESULTS: Of 1187 patients enrolled, 68% were female and the mean age was 68 years (s.d. 9); 639 (54%) met the definition of IPR. Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman r = 0.64, P < 0.001). In multivariate logistic regression, patients with IPR had greater odds of being female [adjusted odds ratio (adjOR) 1.90 (95% CI 1.46, 2.48)] and having OA in both knees [adjOR 1.48 (95% CI 1.15, 1.90)], higher BMI, longer OA duration, depression or diabetes. Patients with IPR (vs non-IPR) were more likely to have worse QoL, greater function loss and greater pain interference. CONCLUSION: IPR is common among patients with knee OA requiring analgesics and is associated with large functional loss and impaired QoL. Patients at particular risk of IPR, as characterized in this study, may require greater attention towards their analgesic treatment options. Trial registration: https://clinicaltrials.gov/ (NCT01294696).

s / Osteoarthritis and Cartilage 20 (2012) S54–S296 S178 JSN scores, medially or laterally. Progression was compartment specific for the various clusters. Medial progression occurred only in clusters 1, 2 and 4, most dramatically so in cluster 4 (48%). Cluster 3 again only showed lateral progression (61%). Conclusions: We found clear differences between the various clusters. Cluster 1 could be described as amild type of OA,with nodenuded bone and limited OA progression. Cluster 3 and 4weremore severe and erosive types of OA, showing strong increases in area of denudedbonewith increasingOA severity, and a high prevalence of progression. Interestingly, cluster 3 was purely a lateral type of OA, while cluster 4was purelymedial in all respects. The causes that led to differences between the clusters remain speculative. The higher prevalence of reported trauma in cluster 3 and 4, the more aggressive OA types might suggest a difference in OA initiation. Wekept the complexityof themodels lowtoreduce the riskofoverfittingand increase the likelihood that our findings are generalizable to other cohorts. The fact that clusters also differed on data not included in cluster finding (trauma and progression) indicates that the found clusters are meaningful. In conclusion, latent class cluster analysis confirmed the suspected existence of distinct subtypes of knee OA.

A composite responder index for chronic low-back pain (CLBP) has recently been proposed to evaluate the efficacy of CLBP treatments in clinical trials. We compared the responsiveness of this composite measure with a number of single-item responder definitions.We pooled data from 2 placebo-controlled studies of etoricoxib in CLBP to evaluate 5 response criteria: 30% pain intensity (PI) reduction; 50% PI reduction; 20 mm absolute reduction (100 mm PI visual analog scale); patient global assessment of response to therapy (PGART); and the composite criteria of 30% reduction in PI+30% improvement in PGART of disease status+no worsening in function. We used bootstrap analysis and logistic regression to assess the ability to differentiate etoricoxib and placebo, and the κ coefficient to assess agreement among the responder criteria.The criterion of a 20 mm improvement in PI resulted in the greatest proportion (71.5%) of patients being classified as responders and all criteria separated etoricoxib from placebo (P≤0.0001). PGART had the highest discriminant ability (odds ratio 5.90), and was significantly (P0.05) more discriminant than the 20 mm and ≥30% improvements and the composite criteria. After adjusting for all other measures, only PGART continued to show a significant treatment effect for etoricoxib versus placebo (P=0.0003). Kappa values contrasting the composite criteria and the single-item measures ranged from 0.59 to 0.85.These findings do not support the superiority of a composite index over single-item ratings of PI and PGART ratings, but do suggest that PGART ratings may be more responsive to treatment, perhaps because they measure something in addition to change in PI.

Background This analysis evaluated whether osteoarthritis patients achieving the greatest pain control and lowest pain states also have the greatest improvement in functioning and quality of life. Methods Patients (n = 419) who failed prior therapies and who were switched to etoricoxib 60 mg were categorized as pain responders or non-responders at 4 weeks based on responder definitions established by the Initiative on Methods, Measurement, and Pain (IMMPACT) criteria, including changes from baseline of ≥15%, ≥30%, ≥50%, ≥70% and a final pain status of ≤3/10 (no worse than mild pain). Pain was assessed at baseline and 4 weeks using 4 questions from the Brief Pain Inventory (BPI) (worst pain, least pain, average pain, and pain right now), and also using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. We examined the relationship between pain responses with changes from baseline in two functional measures (the BPI Pain Interference questions and the WOMAC Function Subscale) as well as changes from baseline in quality of life (assessed on the SF-36 Physical and Mental Component Summaries). We also sought to understand whether these relationships were influenced by the choice of the pain instrument used to assess response. We contrast the mean difference in improvements in the functional and quality of life instruments based on pain responder status (responder versus non-responder) and the associated 95% confidence limits around this difference. Results Patients with better pain responses were much more likely to have improved functional responses and improved quality of life, with higher mean changes in these outcomes versus pain nonresponders, regardless of the choice of IMMPACT pain response definition (e.g., using any of 15%, 30%, 50%, 70% change from baseline) or the final pain state of ≤3/10. There was an evident gradient, where higher levels of pain response were associated with greater mean improvements in function and quality of life. The finding that greater pain responses led to greater functional improvements and quality of life gains was not dependent on the manner in which pain was evaluated. Five different pain instruments (e.g., the 4 questions on pain from the BPI pain questionnaire and the WOMAC pain subscale) consistently demonstrated that pain responders had statistically significantly greater improvements in function and quality of life compared to pain non-responders. This suggests these results are likely to be generalizable to any validated pain measure for osteoarthritis. Conclusions Pain is an efficient outcome measure for predicting broader patient response in osteoarthritis. Patients who do not achieve timely, acceptable pain states over 4 weeks were less likely to experience functional or quality of life improvements. Implications Good pain improvements in osteoarthritis with a valid pain instrument are a proxy for good improvements in both function and quality of life. Therefore proper osteoarthritis pain assessment can lead to efficient evaluations in the clinic.

SUMMARY Introduction: The increased thrombotic cardiovascular (CV) risk in trials of cyclo- oxygenase-2 (COX-2) inhibitors versus placebo, and the apparent similar risk with nons- teroidal antiinflammatory drugs (NSAIDs), may be related to their potential to elevate blood pressure (BP). Aims: We evaluated the relationship between baseline BP and change in BP on CV events (CVEs) in patients receiving NSAIDs or COX-2 inhibitors in the prospec- tive randomized, double-blind, Multinational Etoricoxib and Diclofenac Arthritis Long-term Program (N = 34,701) comparing etoricoxib 60 or 90 mg or diclofenac 150 mg daily for a mean duration of 18 months. The main outcome measure was confirmed thrombotic CVEs. The Antiplatelet Trialists' Collaboration endpoint, all-cause mortality, CV/congestive heart failure (CHF) mortality, and CHF incidence were similarly evaluated. Results: We found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001). Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P = 0.016) except CV/CHF mortality (P = 0.054). There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P = 0.019). Only CHF risk (P = 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4. These findings were not meaningfully altered after covariate adjustment for baseline CV risk. Conclusions: Baseline BP, but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The CV risk of COX-2s and NSAIDs did not appear to be related to the BP- elevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship.

Objective. Nonsteroidal anti-inflammatory drug (NSAID) responses in osteoarthritis (OA) are highly variable, often requiring multiple medication changes. We sought to determine pre-randomization predictors of response to NSAIDs in OA. Methods. Data were pooled from two identical 26-week double-blind, randomized flare design trials comparing etoricoxib 30 mg/day (N = 475), celecoxib 200 mg/day (N = 488), and placebo (N = 244) in patients with OA of the hip or knee. This analysis was limited to the 12-week placebo-controlled period. Response at Week 12 was defined using Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT–OARSI) criteria. Factors were analyzed using logistic regression and included age, race, gender, body mass index, index joint, screening (pre-washout) and baseline (post-washout) Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain, physical function, and stiffness, and patient global assessment of disease status, prior NSAID/coxib or acetaminophen use, American Rheumatology Association functional class, and disease duration. Results. We found that screening WOMAC physical function was the only factor that predicted response in all treatment groups; worse function was associated with lower odds of achieving an OMERACT–OARSI response at 12 weeks (odds ratio 0.84 placebo; 0.87 etoricoxib; 0.89 celecoxib; P < 0.05 for all). However, the differences in WOMAC physical function between responders and nonresponders were small (∼5 mm on a 100-mm scale). No factor discriminated between the ability to predict placebo response from active treatment response. Conclusions. Lower levels of physical function decreased the odds of a response to NSAID treatment in OA, although the clinical significance is unknown given the small differences between responders and nonresponders. No other measured baseline variables consistently predicted response in these studies, which may reflect the known individual variability in NSAID response.

This study was conducted to evaluate the dose range of etoricoxib in acute pain using the postoperative dental pain model further.This double-blind, randomized controlled study evaluated etoricoxib (90 and 120 mg), ibuprofen (600 mg), and acetaminophen (600 mg/codeine) (60 mg, (A/C)) in patients aged ≥ 18 years with moderate or severe pain after surgical extraction of ≥ 2 third molars (≥ 1 impacted). The patients reported pain intensity and pain relief over 24 hours. The primary efficacy endpoint was total pain relief over 6 hours (TOPAR6). Adverse events were evaluated throughout the study.There were 588 patients randomized to placebo (n=46),etoricoxib (90 mg (n=191)), etoricoxib (120 mg (n=97)), ibuprofen(2400 mg (n=192)), and A/C (n=62). The overall analgesic effect (TOPAR6) of etoricoxib (90, 120 mg) was significantly greater than that of placebo (P ≤ 0.001), and not inferior to that of ibuprofen; no discernible difference was observed between etoricoxib 90 and 120 mg. Both etoricoxib doses were superior to A/C (P ≤ 0.001). Etoricoxib (90 and 120 mg) and ibuprofen(2400 mg) were generally well tolerated and had a similar incidence of adverse events (AEs). A/C was associated with significantly more AEs that led to discontinuation (ie, nausea and vomiting).Etoricoxib (90 and 120 mg) showed similar efficacy in the postoperative dental pain model, which was noninferior to ibuprofen and superior to A/C. A higher number of tooth extractions or a higher mean impaction score may have led to a greater separation in efficacy between the 2 etoricoxib doses.

Numbers-needed-to-treat (NNT) are useful for presenting treatment response, conveying the clinical relevance of results. NNTs are typically calculated at a landmark endpoint (end of trial), but often using the last observation carried forward (LOCF), which ignores patient discontinuations. We compared NNTs in chronic low back pain (CLBP) using three separate imputation methods, using data from two identical 12-week trials comparing etoricoxib 60 mg (N = 210), 90 mg (N = 212), and placebo (N = 217). We calculated the number of patients with improvements in pain intensity from baseline of ⩾15%, ⩾30%, ⩾50%, and ⩾70% at 2, 4, 8, and 12 weeks of treatment. For longitudinal response over time, patient discontinuations were assigned a 0% improvement from dropout forward. Landmark response at week 12 was assessed using LOCF and completer approaches, using only observed (non-missing) data. The longitudinal approach was most conservative; after 12 weeks 65% of patients taking etoricoxib had ⩾15% improvement, 60% had ⩾30% improvement, 45% had ⩾50%, improvement, and 30% had ⩾70% improvement, with placebo rates approximately 55%, 45%, 30%, and 15%, respectively. Response rates were higher with landmark analyses. Landmark NNTs at week 12 were generally similar or slightly lower (better) than those from a longitudinal approach, but results were inconsistent. Landmark analyses provide no information on response variability, as is obtained with longitudinal analysis. Outcome, imputation method, and reporting method are intimately connected and need to be considered alongside trial quality and validity to make sensible comparisons between treatments.

INTRODUCTION:Long-term safety and efficacy of elagolix, an oral, non-peptide GnRH antagonist for the management of endometriosis-associated pain, was evaluated in two 6-month (M) extension studies (Elaris EM-III and IV) of the pivotal, 6M, phase 3 studies (12M-overall treatment with 150 mg once dail

Background:Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration.Methods:The numbers of patients with pain relief over baseline (⩾15%, ⩾30%, ⩾50%, ⩾70%) at 2, 4, 8 and 12 weeks of treatment were obtained using the WOMAC 100 mm visual analogue pain subscale score for each treatment group in seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting ⩾6 weeks. Dropouts were assigned 0% improvement from baseline from then on. The numbers needed to treat (NNTs) were calculated at each level of response and time point.Results:3554 patients were treated with placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60–80% experienced minimally important pain relief (⩾15%), 50–60% moderate pain relief (⩾30%), 40–50% substantial pain relief (⩾50%) and 20–30% extensive pain relief (⩾70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2–12 weeks. Ibuprofen showed lessening of effectiveness with time.Conclusion:Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost one in two patients having substantial benefit.

Study Design Best evidence synthesis. Objective To undertake a best evidence synthesis on the burden and determinants of whiplash-associated disorders (WAD) after traffic collisions. Summary of Background Data Previous best evidence synthesis on WAD has noted a lack of evidence regarding incidence of and risk factors for WAD. Therefore there was a warrant of a reanalyze of this body of research. Methods A systematic search of Medline was conducted. The reviewers looked for studies on neck pain and its associated disorders published 1980–2006. Each relevant study was independently and critically reviewed by rotating pairs of reviewers. Data from studies judged to have acceptable internal validity (scientifically admissible) were abstracted into evidence tables, and provide the body of the best evidence synthesis. Results The authors found 32 scientifically admissible studies related to the burden and determinants of WAD. In the Western world, visits to emergency rooms due to WAD have increased over the past 30 years. The annual cumulative incidence of WAD differed substantially between countries. They found that occupant seat position and collision impact direction were associated with WAD in one study. Eliminating insurance payments for pain and suffering were associated with a lower incidence of WAD injury claims in one study. Younger ages and being a female were both associated with filing claims or seeking care for WAD, although the evidence is not consistent. Preliminary evidence suggested that headrests/car seats, aimed to limiting head extension during rear-end collisions had a preventive effect on reporting WAD, especially in females. Conclusion WAD after traffic collisions affects many people. Despite many years of research, the evidence regarding risk factors for WAD is sparse but seems to include personal, societal, and environmental factors. More research including, well-defined studies with accurate denominators for calculating risk, and better consideration of confounding factors, are needed.

Study Design Best evidence synthesis. Objective To identify, critically appraise, and synthesize literature from 1980 through 2006 on noninvasive interventions for neck pain and its associated disorders. Summary of Background Data No comprehensive systematic literature reviews have been published on interventions for neck pain and its associated disorders in the past decade. Methods We systematically searched Medline and screened for relevance literature published from 1980 through 2006 on the use, effectiveness, and safety of noninvasive interventions for neck pain and associated disorders. Consensus decisions were made about the scientific merit of each article; those judged to have adequate internal validity were included in our best evidence synthesis. Results Of the 359 invasive and noninvasive intervention articles deemed relevant, 170 (47%) were accepted as scientifically admissible, and 139 of these related to noninvasive interventions (including health care utilization, costs, and safety). For whiplash-associated disorders, there is evidence that educational videos, mobilization, and exercises appear more beneficial than usual care or physical modalities. For other neck pain, the evidence suggests that manual and supervised exercise interventions, low-level laser therapy, and perhaps acupuncture are more effective than no treatment, sham, or alternative interventions; however, none of the active treatments was clearly superior to any other in either the short- or long-term. For both whiplash-associated disorders and other neck pain without radicular symptoms, interventions that focused on regaining function as soon as possible are relatively more effective than interventions that do not have such a focus. Conclusion Our best evidence synthesis suggests that therapies involving manual therapy and exercise are more effective than alternative strategies for patients with neck pain; this was also true of therapies which include educational interventions addressing self-efficacy. Future efforts should focus on the study of noninvasive interventions for patients with radicular symptoms and on the design and evaluation of neck pain prevention strategies.

Study Design Best evidence synthesis. Objective To identify, critically appraise, and synthesize literature from 1980 through 2006 on surgical interventions for neck pain alone or with radicular pain in the absence of serious pathologic disease. Summary of Background Data There have been no comprehensive systematic literature or evidence-based reviews published on this topic. Methods We systematically searched Medline for literature published from 1980 to 2006 on percutaneous and open surgical interventions for neck pain. Publications on the topic were also solicited from experts in the field. Consensus decisions were made about the scientific merit of each article; those judged to have adequate internal validity were included in our Best Evidence Synthesis. Results Of the 31,878 articles screened, 1203 studies were relevant to the Neck Pain Task Force mandate and of these, 31 regarding treatment by surgery or injections were accepted as scientifically admissible. Radiofrequency neurotomy, cervical facet injections, cervical fusion and cervical arthroplasty for neck pain without radiculopathy are not supported by current evidence. We found there is support for short-term symptomatic improvement of radicular symptoms with epidural corticosteroids. It is not clear from the evidence that long-term outcomes are improved with the surgical treatment of cervical radiculopathy compared to nonoperative measures. However, relatively rapid and substantial symptomatic relief after surgical treatment seems to be reliably achieved. It is not evident that one open surgical technique is clearly superior to others for radiculopathy. Cervical foramenal or epidural injections are associated with relatively frequent minor adverse events (5%–20%); however, serious adverse events are very uncommon ( Conclusion Surgical treatment and limited injection procedures for cervical radicular symptoms may be reasonably considered in patients with severe impairments. Percutaneous and open surgical treatment for neck pain alone, without radicular symptoms or clear serious pathology, seems to lack scientific support.

Study Design Best evidence synthesis. Objective To critically appraise and synthesize the literature on assessment of neck pain. Summary of Background Data The published literature on assessment of neck pain is large and of variable quality. There have been no prior systematic reviews of this literature. Methods The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders conducted a critical review of the literature (published 1980–2006) on assessment tools and screening protocols for traumatic and nontraumatic neck pain. Results We found 359 articles on assessment of neck pain. After critical review, 95 (35%) were judged scientifically admissible. Screening protocols have high predictive values to detect cervical spine fracture in alert, low-risk patients seeking emergency care after blunt neck trauma. Computerized tomography (CT) scans had better validity (in adults and elderly) than radiographs in assessing high-risk and/or multi-injured blunt trauma neck patients. In the absence of serious pathology, clinical physical examinations are more predictive at excluding than confirming structural lesions causing neurologic compression. One exception is the manual provocation test for cervical radiculopathy, which has high positive predictive value. There was no evidence that specific MRI findings are associated with neck pain, cervicogenic headache, or whiplash exposure. No evidence supports using cervical provocative discography, anesthetic facet, or medial branch blocks in evaluating neck pain. Reliable and valid self-report questionnaires are useful in assessing pain, function, disability, and psychosocial status in individuals with neck pain. Conclusion The scientific evidence supports screening protocols in emergency care for low-risk patients; and CT-scans for high-risk patients with blunt trauma to the neck. In nonemergency neck pain without radiculopathy, the validity of most commonly used objective tests is lacking. There is support for subjective self-report assessment in monitoring patients' course, response to treatment, and in clinical research.

Study Design Best evidence synthesis. Objective To undertake a best evidence synthesis of the published evidence on the burden and determinants of neck pain and its associated disorders in the general population. Summary of Background Data The evidence on burden and determinants of neck has not previously been summarized. Methods The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders performed a systematic search and critical review of literature published between 1980 and 2006 to assemble the best evidence on neck pain. Studies meeting criteria for scientific validity were included in a best evidence synthesis. Results We identified 469 studies on burden and determinants of neck pain, and judged 249 to be scientifically admissible; 101 articles related to the burden and determinants of neck pain in the general population. Incidence ranged from 0.055 per 1000 person years (disc herniation with radiculopathy) to 213 per 1000 persons (self-reported neck pain). Incidence of neck injuries during competitive sports ranged from 0.02 to 21 per 1000 exposures. The 12-month prevalence of pain typically ranged between 30% and 50%; the 12-month prevalence of activity-limiting pain was 1.7% to 11.5%. Neck pain was more prevalent among women and prevalence peaked in middle age. Risk factors for neck pain included genetics, poor psychological health, and exposure to tobacco. Disc degeneration was not identified as a risk factor. The use of sporting gear (helmets, face shields) to prevent other types of injury was not associated with increased neck injuries in bicycling, hockey, or skiing. Conclusion Neck pain is common. Nonmodifiable risk factors for neck pain included age, gender, and genetics. Modifiable factors included smoking, exposure to tobacco, and psychological health. Disc degeneration was not identified as a risk factor. Future research should concentrate on longitudinal designs exploring preventive strategies and modifiable risk factors for neck pain.

Study Design Best-evidence synthesis. Objective To perform a best evidence synthesis on the course and prognostic factors for neck pain and its associated disorders in workers. Summary of Background Data Knowledge of the course of neck pain in workers guides expectations for recovery. Identifying prognostic factors assists in planning effective workplace policies, formulating interventions and promoting lifestyle changes to decrease the frequency and burden of neck pain in the workplace. Methods The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and its Associated Disorders (Neck Pain Task Force) conducted a critical review of the literature published between 1980 and 2006 to assemble the best evidence on neck pain and its associated disorders. Studies meeting criteria for scientific validity were included in a best evidence synthesis. Results We found 226 articles related to course and prognostic factors in neck pain and its associated disorders. After a critical review, 70 (31%) were accepted on scientific merit; 14 of these studies related to course and prognostic factors in working populations. Between 60% and 80% of workers with neck pain reported neck pain 1 year later. Few workplace or physical job demands were identified as being linked to recovery from neck pain. However, workers with little influence on their own work situation had a slightly poorer prognosis, and white-collar workers had a better prognosis than blue-collar workers. General exercise was associated with better prognosis; prior neck pain and prior sick leave were associated with poorer prognosis. Conclusion The Neck Pain Task Force presents a report of current best evidence on course and prognosis for neck pain. Few modifiable prognostic factors were identified; however, having some influence over one's own job and being physically active seem to hold promise as prognostic factors.

Study Design Best evidence synthesis. Objective To report on gaps in the literature and make methodologic recommendations based on our review of the literature on frequency and risk factors, assessment, intervention, and course and prognostic factors for neck pain and its associated disorders. Summary of Background Data The scientific literature on neck pain is large and of variable quality. We reviewed 1203 studies and judged 46% to be of sufficient scientific validity to be included in the best evidence synthesis. Scientific quality varied across study topics, and fundamental questions remain about important issues. Methods The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and its Associated Disorders (Neck Pain Task Force) conducted a critical review of the literature published between 1980 and 2006 to assemble the best evidence on neck pain and its associated disorders. Studies meeting criteria for scientific validity were included in a best evidence synthesis. Results We outline a large number of gaps in the current literature. For example, we found important gaps in our knowledge about neck pain in children (risk factors, screening criteria to rule out serious injury, management, course and prognosis); and in the prevention of neck pain-related activity limitations. Few studies addressed the impact of culture or social policies (such as governmental health policies or insurance compensation policies) on neck pain. A number of important questions remain about the effectiveness of commonly used interventions for neck pain. Conclusion The Neck Pain Task Force undertook a best evidence synthesis to establish a baseline of the current best evidence on the course and prognosis for whiplash-associated disorders. We identify a number of gaps in the current knowledge, and provide recommendations for the conduct of future studies.

Study Design Best evidence synthesis. Objective To provide a detailed description of the methods undertaken in a systematic search and perform a best evidence synthesis on the frequency, determinants, assessment, interventions, course and prognosis of neck pain, and its associated disorders. Summary of Background Data Neck pain is an important cause of health burden; however, the published information is vast, and stakeholders would benefit from a summary of the best evidence. Methods The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and its Associated Disorders conducted a systematic search and critical review of the literature published between 1980 and 2006 to assemble the best evidence on neck pain. Citations were screened for relevance to the Neck Pain Task Force mandate, using a priori criteria, and relevant studies were critically reviewed for their internal scientific validity. Findings from studies meeting criteria for scientific validity were synthesized into a best evidence synthesis. Results We found 31,878 citations, of which 1203 were relevant to the mandate of the Neck Pain Task Force. After critical review, 552 studies (46%) were judged scientifically admissible and were compiled into the best evidence synthesis. Conclusion The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and its Associated Disorders undertook a best evidence synthesis to establish a baseline of the current best evidence on the epidemiology, assessment and classification of neck pain, as well as interventions and prognosis for this symptom. This article reports the methods used and the outcomes from the review. We found that 46% of the research literature was of acceptable scientific quality to inform clinical practice, policy-making, and future research.

Study Design Best evidence synthesis. Objective To perform a best evidence synthesis on the course and prognostic factors for neck pain and its associated disorders in Grades I–III whiplash-associated disorders (WAD). Summary of Background Data Knowledge of the course of recovery of WAD guides expectations for recovery. Identifying prognostic factors assists in planning management and intervention strategies and effective compensation policies to decrease the burden of WAD. Methods The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and its Associated Disorders (Neck Pain Task Force) conducted a critical review of the literature published between 1980 and 2006 to assemble the best evidence on neck pain and its associated disorders. Studies meeting criteria for scientific validity were included in a best evidence synthesis. Results We found 226 articles related to course and prognostic factors in neck pain and its associated disorders. After a critical review, 70 (31%) were accepted on scientific merit; 47 of these studies related to course and prognostic factors in WAD. The evidence suggests that approximately 50% of those with WAD will report neck pain symptoms 1 year after their injuries. Greater initial pain, more symptoms, and greater initial disability predicted slower recovery. Few factors related to the collision itself (for example, direction of the collision, headrest type) were prognostic; however, postinjury psychological factors such as passive coping style, depressed mood, and fear of movement were prognostic for slower or less complete recovery. There is also preliminary evidence that the prevailing compensation system is prognostic for recovery in WAD. Conclusion The Neck Pain Task Force undertook a best evidence synthesis to establish a baseline of the current best evidence on the course and prognosis for WAD. Recovery of WAD seems to be multifactorial.

Study Design Best evidence synthesis. Objective To provide evidence-based guidance to primary care clinicians about how to best assess and treat patients with neck pain. Summary of Background Data There is a need to translate the results of clinical and epidemiologic studies into meaningful and practical information for clinicians. Methods Based on best evidence syntheses of published studies on the risk, prognosis, assessment, and management of people with neck pain and its associated disorders, plus additional research projects and focused literature reviews reported in this supplement, the 12-member multidisciplinary Scientific Secretariat of the Neck Pain Task Force followed a 4-step approach to develop practical guidance for clinicians. Results The Neck Pain Task Force recommends that people seeking care for neck pain should be triaged into 4 groups: Grade I neck pain with no signs of major pathology and no or little interference with daily activities; Grade II neck pain with no signs of major pathology, but interference with daily activities; Grade III neck pain with neurologic signs of nerve compression; Grade IV neck pain with signs of major pathology. In the emergency room after blunt trauma to the neck, triage should be based on the NEXUS criteria or the Canadian C-spine rule. Those with a high risk of fracture should be further investigated with plain radiographs and/or CT-scan. In ambulatory primary care, triage should be based on history and physical examination alone, including screening for red flags and neurologic examination for signs of radiculopathy. Exercises and mobilization have been shown to provide some degree of short-term relief of Grade I or Grade II neck pain after a motor vehicle collision. Exercises, mobilization, manipulation, analgesics, acupuncture, and low-level laser have been shown to provide some degree of short-term relief of Grade I or Grade II neck pain without trauma. Those with confirmed Grade III and severe persistent radicular symptoms might benefit from corticosteroid injections or surgery. Those with confirmed Grade IV neck pain require management specific to the diagnosed pathology. Conclusion The best available evidence suggests initial assessment for neck pain should focus on triage into 4 grades, and those with common neck pain (Grade I and Grade II) might be offered the listed noninvasive treatments if short-term relief is desired.

Study Design Iterative discussion and consensus by a multidisciplinary task force scientific secretariat reviewing scientific evidence on neck pain and its associated disorders. Objective To provide an integrated model for linking the epidemiology of neck pain with its management and consequences, and to help organize and interpret existing knowledge, and to highlight gaps in the current literature. Summary of Background Data The wide variability of scientific and clinical approaches to neck pain described in the literature requires a unified conceptual model for appropriate interpretation of the research evidence. Methods The 12-member Scientific Secretariat of the Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders critically reviewed and eventually accepted as scientifically admissible a total of 552 scientific papers. The group met face-to-face on 18 occasions and had frequent additional telephone conference meetings over a 6-year period to discuss and interpret this literature and to agree on a conceptual model, which would accommodate findings. Models and definitions published in the scientific literature were discussed and repeatedly modified until the model and case definitions presented here were finally approved by the group. Results Our new conceptual model is centered on the person with neck pain or who is at risk for neck pain. Neck pain is viewed as an episodic occurrence over a lifetime with variable recovery between episodes. The model outlines the options available to individuals who are dealing with neck pain, along with factors that determine options, choices, and consequences. The short- and long-term impacts of neck pain are also considered. Finally, the model includes a 5-axis classification of neck pain studies based on how subjects were recruited into each study. Conclusion The Scientific Secretariat found the conceptual model helpful in interpreting the available scientific evidence. We believe it can assist people with neck pain, researchers, clinicians, and policy makers in framing their questions and decisions.