Real-world effectiveness of golimumab in the treatment of patients with active rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis who failed initial TNF-α inhibitor therapy: a pooled analysis of European prospective observational studie.

OBJECTIVES: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients often experience secondary non-response to a first-line tumour necrosis factor alpha inhibitor (TNFαi). This pooled analysis of six observational studies in Europe (GO-BEYOND program) provides an estimate of second-line golimumab (GLM) effectiveness for these rheumatic diseases. METHODS: The GO-BEYOND studies included common disease-specific endpoints allowing for a pooled analysis. Patients had discontinued one prior TNFαi (due to loss of efficacy, tolerability, or inconvenience) and were followed for 12 months after GLM initiation. Primary endpoints included the proportion of patients achieving low disease activity (LDA, DAS28-CRP<3.2) in RA, minimal disease activity (MDA, fulfilment of 5 of 7 outcome measures) in PsA, or low disease activity (ASDAS<2.1) in axSpA at 6 months. Disease activity at 3 and 12 months and quality of life (QoL; EQ-5D-3L) were also assessed. Adverse events were monitored. Protocol-specified analyses were based on observed data. RESULTS: In 712 patients, (n=325, RA; 186, PsA; 201, axSpA), mean age was 54 years, 64% were female, and median disease duration was 5 years. Primary endpoints were achieved in 58.3% (RA), 45.5% (PsA), and 45.4% (axSpA) of patients; disease activity improvements were observed at 3 and 12 months and EQ-5D-3L results showed improved QoL over time. The treatment persistence rate at 12 months was 67.8% of patients. No new safety signals were observed. CONCLUSIONS: This pooled analysis of the GO-BEYOND studies showed that treatment with GLM was effective and represented a valid second-line option for RA, PsA, and axSpA patients.

Clinical and quality of life improvements with golimumab or infliximab in a real-life ankylosing spondylitis population: the QUO-VADIS study.

OBJECTIVES: The QUO VADIS study evaluated disease activity and health-related quality-of-life (HRQoL) in ankylosing spondylitis (AS) patients treated with golimumab (GLM) or infliximab (IFX, originator) during routine clinical care. METHODS: This prospective observational study followed biologics-naïve AS patients newly treated with GLM or IFX for 6 months. Disease activity (BASDAI, BASFI, ASAS, and ASDAS) and HRQoL improvement (≥5 points of SF-36 Physical Component Summary [PCS] score; PCS response) were measured. A Classification and Regression Trees (CART) analysis evaluated association of baseline parameters with PCS response at 6 months. RESULTS: 963 patients (mean age 43 years, 61% male, 64% HLA-B27 positive) received ≥1 dose of medication (78% GLM; 22% IFX). Disease activity was reduced; mean (SD) changes from baseline at month 6 of -2.7 (BASDAI) and -2.1 (BASFI) and 40% and 35% achievement of BASDAI50 and ASAS40 response, respectively, were observed. PCS response was achieved at month 6 in 52% of patients. Using CART analysis, baseline parameters (cut-off values) associated with HRQoL improvement were ASDAS (≥3.48), C-reactive protein (≥8.55 mg/L), age (≤35.5 years), and BASFI (≥1.15). This algorithm correctly identified 57.5% (sensitivity) of PCS responders (≥5 points) and 61.0% (specificity) of PCS non-responders (<5points) with ROC-AUC=0.61. Serious adverse events (AEs) occurred in 1.8% of patients; the most common AEs were infections (7.7%). CONCLUSIONS: We demonstrated clinical and HRQoL improvements over 6 months in a large, real-world population of AS patients newly treated with GLM or IFX; higher ASDAS, elevated CRP, and younger age were associated with improvements in HRQoL and an overall more robust response.

Partial remission in ankylosing spondylitis and non-radiographic axial spondyloarthritis in treatment with infliximab plus naproxen or naproxen alone: associations between partial remission and baseline disease characteristics.

OBJECTIVES: To evaluate partial remission during treatment with infliximab (IFX) + naproxen (NPX) vs NPX alone in patients from the two subgroups of SpA and explore baseline predictors of partial remission. METHODS: Infliximab as First Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial was a double-blind, randomised controlled trial of IFX in biologic-naïve patients with early, active axial SpA. Patients were randomised (2:1) to receive 28 weeks of treatment with i.v. IFX 5 mg/kg (weeks 0, 2, 6, 12, 18 and 24) + NPX 1000 mg/day or i.v. placebo (PBO) + NPX 1000 mg/day. The current post hoc analysis evaluated outcomes in patients who did or did not meet modified New York radiographic criteria for AS. RESULTS: The analysis included 94 patients who met AS criteria and 56 with non-radiographic axial SpA (nr-axSpA). At week 28, Assessment of SpondyloArthritis international Society (ASAS) partial remission was greater with IFX + NPX than PBO + NPX for both the AS group (70.5 vs 33.3%, respectively) and the nr-axSpA group (50.0 vs 37.5%, respectively). A similar pattern occurred with several efficacy measures. Larger treatment effects occurred in the AS group than the nr-axSpA group, possibly due to baseline differences in disease characteristics. Multivariable analyses identified the type of treatment, age and HLA-B27 status as predictors of ASAS partial remission in the total study population. MRI sacroiliac joint scores were associated with partial remission during IFX + NPX treatment. CONCLUSION: Patients with AS had greater partial remission with IFX + NSAID than NSAID therapy alone; patients with nr-axSpA had a smaller treatment effect. Baseline disease characteristics and age were associated with partial remission with IFX therapy.

Prediction of remission and low disease activity in disease-modifying anti-rheumatic drug-refractory patients with rheumatoid arthritis treated with golimumab.

OBJECTIVE: To create a tool to predict probability of remission and low disease activity (LDA) in patients with RA being considered for anti-TNF treatment in clinical practice. METHODS: We analysed data from GO-MORE, an open-label, multinational, prospective study in biologic-naïve patients with active RA (DAS28-ESR ⩾3.2) despite DMARD therapy. Patients received 50 mg s.c. golimumab (GLM) once monthly for 6 months. In secondary analyses, regression models were used to determine the best set of baseline factors to predict remission (DAS28-ESR <2.6) at month 6 and LDA (DAS28-ESR ⩽3.2) at month 1. RESULTS: In 3280 efficacy-evaluable patients, of 12 factors included in initial regression models predicting remission or LDA, six were retained in final multivariable models. Greater likelihood of LDA and remission was associated with being male; younger age; lower HAQ, ESR (or CRP) and tender joint count (or swollen joint count) scores; and absence of comorbidities. In models predicting 1-, 3- and 6-month LDA or remission, area under the receiver operating curve was 0.648-0.809 (R(2) = 0.0397-0.1078). The models also predicted 6-month HAQ and EuroQoL-5-dimension scores. A series of matrices were developed to easily show predicted rates of remission and LDA. CONCLUSION: A matrix tool was developed to show predicted GLM treatment outcomes in patients with RA, based on a combination of six baseline characteristics. The tool could help provide practical guidance in selection of candidates for anti-TNF therapy.

Treatment persistence among patients with rheumatoid disease (RA, AS, PsA) treated with subcutaneous biologics in Germany.

Patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are frequently treated with subcutaneous biologic therapies when disease progresses or when response to synthetic disease-modifying antirheumatic drugs (DMARDs) is inadequate. This study analyzed treatment persistence and treatment patterns for RA, AS, and PsA patients in Germany initiating subcutaneous biologic therapies with and without prior DMARDs use. A retrospective cohort study was conducted using the Electronic Medical Record database of IMS Disease Analyzer, Germany. Patients who were ≥18 years old; had at least one ICD-10 diagnosis code of RA, AS, or PsA during the study period; and had exposure to a subcutaneous biologic agent between January 1, 2009 and June 30, 2012 were selected. Patients were required to have continuous observation ≥12 months prior to and after index medication date. Persistence was defined as consecutive days from treatment initiation until treatment discontinuation (≥60-day lapse in medication coverage). Patients were stratified by pre-index use of DMARDs. Kaplan-Meier analysis was conducted to assess time to discontinuation, and logistic regression was conducted to identify characteristics associated with persistence. A total of 576 RA, 108 AS, and 197 PsA patients without biologic experience during the pre-index period were selected. The percentages of RA, AS, and PsA patients persistent ≥12 months were 51.9, 48.1, and 57.9 %, respectively. Median persistent time over 12 months was 365.0 days for RA (mean 245.9 days), 281.0 for AS (mean 228.5), and 365.0 for PsA (mean 264.1). In the RA cohort, a significantly higher proportion of those with pre-index DMARD use were persistent compared to those without pre-index DMARD (56.1 vs. 33.3 %, p = 0.0001). No significant differences were observed for the AS and PsA cohorts. Multivariate analyses confirmed that DMARD-experienced patients were 2.45 times more likely to be persistent with subcutaneous biologic therapy in the RA cohort. Switching between subcutaneous biologics occurred in <10 % of patients in all three cohorts. In the subpopulations with at least two prescriptions for the index subcutaneous biologic and who remained persistent on the index subcutaneous biologic, dose escalation of ≥50 % occurred in 50, 60, and 49 % in the RA, AS, and PsA cohorts, respectively. Among RA, AS, and PsA patients newly initiating subcutaneous biologic agents in Germany, persistence at 12 months is relatively low (48-58 %). For the RA cohort, patients with pre-index DMARD use are more persistent than patients without. The majority of patients do not switch between subcutaneous biologics. A notable proportion of patients who remained persistent on their index subcutaneous biologic had a dose escalation. There are opportunities to improve outcomes of patient with rheumatoid disease through improved medication persistence.

Factors influencing the patient evaluation of injection experience with the SmartJect autoinjector in rheumatoid arthritis.

OBJECTIVES: To evaluate factors influencing injection patterns and patient evaluations of an autoinjector device in biologic-naïve patients beginning golimumab (GLM) treatment. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active rheumatoid arthritis (RA) (28-joint disease activity score based on erythrocyte sedimentation rate [DAS28-ESR] ≥3.2). Patients injected 50 mg subcutaneous GLM once monthly for 6 months. Patients reported use preferences and autoinjector evaluations by questionnaire. Responses were analysed descriptively. Effects of patient variables were evaluated with chi-square tests or t-tests. RESULTS: Of 3,280 efficacy-evaluable patients, 67.7% self-injected with the autoinjector. Compared with patients who self-injected, patients who had someone else administer injections had greater baseline disease activity (e.g., DAS28-ESR 5.84 vs. 6.23, respectively), but not more tender/swollen joints in hands/wrists. Month 6 efficacy was greater for patients who self-injected. In those who self-injected, injection site (thigh [75.2%; 1,563/2,077], abdomen [17.4%; 363/2,077], upper arm [7.2%; 151/2,077]) was not associated with wrist swelling or tender/swollen joints in the hand used for injection. Autoinjector ratings were similar across injection sites, yet less pain/discomfort was associated with abdomen injection. Patient autoinjector ratings were favourable overall (e.g. ease of use, pain). Patients with baseline functional impairment had slightly less favourable ratings. CONCLUSIONS: Biologic-naïve patients who self-injected had less baseline disease activity and higher response rates than patients who did not self-inject. Although patients prefer to inject in the thigh, injection in the belly may be less painful. Most patients who self-injected had favourable autoinjector evaluations; patients with functional impairment had slightly less favourable ratings.

Long-term golimumab persistence: Five-year treatment retention data pooled from pivotal Phase III clinical trials in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

INTRODUCTION: Golimumab, a monoclonal antibody against tumor necrosis factor-α (TNF-α), is used widely for treatment of rheumatic diseases. Long-term persistence is an important factor influencing therapeutic benefit and is a surrogate measure of efficacy. We compared five-year golimumab treatment persistence across studies, indications, and lines of therapy using pooled data from pivotal golimumab Phase III clinical trials. METHODS: This post-hoc analysis evaluated use of golimumab administered subcutaneously (50 or 100 mg every four weeks) for up to five years in 2228 adult participants with rheumatoid arthritis (RA; GO-BEFORE, GO-AFTER, and GO-FORWARD studies), psoriatic arthritis (PsA; GO-REVEAL study), or ankylosing spondylitis (AS; GO-RAISE study). Retention rate differences were evaluated by study, indication, and line of therapy using log-rank tests, and probability of treatment persistence was estimated by Kaplan-Meier analysis. RESULTS: Golimumab retention rates at Year 5 were consistently high when used as 1st-line therapy (69.8%) and did not differ significantly across the three indications tested (p = 0.5106) or across 1st-line studies (p = 0.2327). Retention at Year 5 was better in participants using golimumab as 1st-line than in those using it as 2nd-line (41.6%) therapy. Participants on 2nd-line golimumab therapy had a longer disease duration (median 9.2 years versus 3.7 years) than those on 1st-line golimumab therapy. CONCLUSIONS: These data support the value of long-term golimumab therapy in patients with chronic, immune-mediated rheumatic diseases when used as 1st-line (RA, PsA, AS) or 2nd-line (RA) therapy. Key Points • Golimumab is a human monoclonal antibody directed against tumor necrosis factor-α (TNF-α) and is approved widely for the treatment of rheumatic autoimmune diseases. • We compared the probability of treatment persistence, or the time of continuous drug use, for golimumab across five Phase III studies spanning multiple rheumatic indications over five years. • Treatment persistence was favorable and did not differ significantly for participants with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, but persistence was greater when golimumab was used as 1st-line than as 2nd-line biologic therapy.

Low Occurrence of Colectomy With Long-Term (up to 4 Years) Golimumab Treatment in Patients With Moderate-to-Severe Active Ulcerative Colitis: Data From the PURSUIT Maintenance and Long-Term Extension Studies.

Background: This analysis evaluated the incidence of all-cause colectomies (total or partial) among patients with moderate-to-severe active ulcerative colitis (UC) in the golimumab (GLM) Program of Ulcerative Colitis Utilizing an Investigational Treatment (PURSUIT)-maintenance (-M) and long-term extension (-LTE) studies. Methods: Eligible PURSUIT-M trial participants completed a 6-week GLM induction trial without requiring colectomy. Responders to GLM induction were randomized 1:1:1 to GLM 50 mg, GLM 100 mg, or placebo (PBO) maintenance for up to 1 year, administered every 4 weeks (q4w). Nonresponders to GLM or PBO induction received GLM 100 mg; responders to PBO induction received PBO (each administered q4w for up to 1 year). Participants who completed PURSUIT-M were eligible to continue their treatment in the 3-year PURSUIT-LTE study. Results: A total of 60 (4.9%) colectomies were reported among the 1228 patients who enrolled in the 1-year PURSUIT-M study, which included 672 participants who continued into the 3-year PURSUIT-LTE LTE study (of which 666 were treated). The colectomy rate during the 3-year extension was lower than that observed during the maintenance phase of the study (9/666 [1.4%] compared to 51/1228 [4.2%]). The majority (43/60 [71.7%]) of the reported colectomies occurred in patients who had not responded to induction therapy and who tended to have had more severe disease characteristics at baseline. Conclusions: This retrospective evaluation of colectomy data from the PURSUIT-M and -LTE studies in patients with moderate-to-severe active UC demonstrated a low (<5%) occurrence of colectomy with long-term (up to 4 years) GLM treatment. PURSUIT-M (NCT00488631; EudraCT, 2006-003399-37).

Patient-reported continuous clinical response to golimumab in adults with moderately to severely active ulcerative colitis: results from GO OBSERVE, a real-world European observational study.

BACKGROUND: In PURSUIT, golimumab (GLM) was efficacious in patients with moderate-to-severe ulcerative colitis (UC). We assessed whether remote monitoring of combined patient-reported Mayo stool frequency and rectal bleeding scores is an effective real-world outcome measure for assessing maintenance of GLM-induced clinical response. METHODS: This was a 54-week prospective, observational cohort study conducted at 43 European outpatient clinics in adults with moderate-to-severe UC who were biologic naïve or had received a maximum of one other biological therapy. Patients were treated according to European GLM UC label/local practice. Clinical response (based on partial or full Mayo score) was assessed at week 6, 10, or 14 of induction, depending on local practice. Investigators remotely monitored scores every 4 weeks. The primary endpoint was the proportion of induction responders in patient-reported continuous clinical response (pCCR) at week 54, defined as absence of UC flare based on combined patient-reported Mayo stool frequency and rectal bleeding scores every 4 weeks and full or partial Mayo score. A key secondary endpoint was the proportion of induction responders in clinical remission at week 54. RESULTS: Among 109 patients, 37 (34.0%) received at least two GLM induction doses and completed induction in clinical response (induction responders). At week 54, 15/37 (40.5%) induction responders were in pCCR, and 21/37 (56.8%) were in clinical remission. CONCLUSION: In daily clinical practice, regular remote monitoring of combined patient-reported Mayo stool frequency and rectal bleeding scores appears to be a meaningful real-world outcome measure for monitoring maintenance of GLM-induced clinical response in UC.

Real-world treatment persistence of golimumab in the management of immune-mediated rheumatic diseases in Europe: a systematic literature review.

OBJECTIVES: To summarise real-world data from studies reporting golimumab persistence in European immune-mediated rheumatic disease (IMRD) populations and to report pooled estimates. DESIGN: Systematic literature review. DATA SOURCES: Relevant literature was identified through searching Medline and Embase via Ovid as well as the conference databases of European League Against Rheumatism and American College of Rheumatology-Association of Rheumatology Health Professionals. ELIGIBILITY CRITERIA: We screened records using predefined patients, interventions, comparators, outcomes and study design criteria. Eligible studies included reports of persistence among adult IMRD patients in Europe receiving treatment with subcutaneous golimumab. Clinical trials, randomised controlled trials, literature reviews, editorials, guidelines and studies with <20 patients receiving golimumab were excluded. DATA EXTRACTION AND SYNTHESIS: Following double screening by two independent reviewers, 27 studies out of 578 identified records were selected for inclusion and subsequent data extraction. Persistence was most commonly reported at 12and 24 months; hence, pooled persistence estimates were calculated for these two time points and reported according to indication. RESULTS: Persistence ranged between 58.1% (psoriatic arthritis (PsA) patients regardless of treatment line) and 75.7% (biological-naïve rheumatoid arthritis patients) at 12 months; at 24 months, the range was 43% (axial spondyloarthritis (AxSpA) patients regardless of treatment line) and 69.6% (biological-naïve PsA patients). On the basis of data from 12 studies, persistence with golimumab treatment was either significantly higher or not significantly different from other tumour necrosis factor inhibitors (TNFi). CONCLUSIONS: Golimumab persistence at 24 months approximates 50%, with a lower persistence among AxSpA (43%) patients. However, as the number of studies in these populations was low, they warrant further research. In 12 studies comparing various TNFi treatments, golimumab was shown to have significantly better or equal persistence to its comparators.

Treatment with golimumab or infliximab reduces health resource utilization and increases work productivity in patients with ankylosing spondylitis in the QUO-VADIS study, a large, prospective real-life cohort.

AIM: We evaluated the effects of anti-tumor necrosis factor (TNF) agents on health economics in ankylosing spondylitis (AS) patients. METHODS: QUality of Life as Outcomes and its VAriation with DIsease States (QUO-VADIS) was a prospective observational study following bio-naïve AS patients (modified New York criteria) newly treated with golimumab (GLM) or infliximab (IFX; originator) in a clinical practice setting over 6 months. We evaluated use of concomitant medications, hospitalizations (in-patient care or acute care) and visits in day care and out-patient settings for the assessment of healthcare resource utilization (HCRU). Work productivity and activity impairment (WPAI) was assessed by the number of work days missed and quantifying absenteeism, presenteeism, work impairment, and activity using the WPAI instrument adapted to spondyloarthritis (WPAI-SpA). RESULTS: Nine hundred and sixty-three patients received ≥1 dose of medication (78%, n = 751 GLM; 22%, n = 221 IFX). Mean age was 42.7 years; 61.4% were male. At baseline, the percentage of patients who reported hospitalizations (in-patient care) was 13.6%, which decreased to 3.1% at 6 months, while out-patient care at baseline was reported by 39.4% of patients, which decreased to 19.0% at 6 months. The percentage of patients receiving acute emergency at baseline reduced from 1.6% to 0.3% at 6 months. The mean (SD) number of days of work missed due to AS, was reduced from 6.3 (31.1) days at baseline to 2.7 (12.3) days at 6 months. CONCLUSION: In patients with AS newly treated with GLM or IFX for 6 months, HCRU was reduced and work productivity and activity increased.

Correction to: Regional differences in baseline disease activity and remission rates following golimumab treatment for RA: results from the GO-MORE trial.

The original publication contains two areas which require correcting. None of these errors change the results or conclusions of the article, but the authors wish to highlight the areas of change to the reader.

Regional differences in baseline disease activity and remission rates following golimumab treatment for RA: results from the GO-MORE trial.

GO-MORE (NCT00975130) was a large open-label, multinational, multicenter, prospective phase 3 trial evaluating add-on therapy with golimumab in biologic-naïve patients with active rheumatoid arthritis (RA). The objective of this post hoc analysis was to examine regional differences in baseline disease activity and remission rates following golimumab treatment for RA. This was a planned, descriptive post hoc analysis of data from the GO-MORE trial. Baseline disease activity and remission were defined as moderate or severe based on EULAR criteria. This analysis included 3280 participants from the GO-MORE trial. All participants included in this analysis had high or moderate disease activity at baseline. At baseline, high disease activity was least common in Europe (71.0%), Canada (77.0%), and the Middle East (78.2%) and most common in Latin America (90.7%), South Africa (91.5%), and Asia (92.5%). Month 6 remission rates were highest in South Africa (29.1%), Europe (27.9%), and the Middle East (27.3%) and lowest in Canada (19.7%), Latin America (17.2%), and Asia (15.0%). Higher rates of remission in each geographical region generally corresponded with lower baseline disease activity. We suspect that access to care and implementation of the treat-to-target strategy were the most important determinants, but this apparent relationship needs to be confirmed in further studies that include a statistical analysis of prognostic indicators.

Persistence with golimumab in immune-mediated rheumatic diseases: a systematic review of real-world evidence in rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis.

PURPOSE: In immune-mediated rheumatic diseases (IMRDs), persistence to treatment may be used as a surrogate marker for long-term treatment success. In previous comparisons of persistence to tumor necrosis factor α inhibitors (TNFis), a paucity of data for subcutaneous (SC) golimumab was identified. The aim of this study was to conduct a systematic review of persistence to SC golimumab in clinical practice and contextualize these data with five-year persistence estimates from long-term open-label extension (OLE) trials of SC TNFis in IMRDs. PATIENTS AND METHODS: PubMed, Embase, MEDLINE, and conference proceedings from European League Against Rheumatism (EULAR), American College of Rheumatology (ACR), and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) were searched. All studies on patients treated with SC golimumab for IMRD were included if they reported data on the persistence to golimumab. RESULTS: Of 376 available references identified through the searches, 12 studies with a total of 4,910 patients met the inclusion criteria. Furthermore, nine OLE trials were available. Among the included studies from clinical practice, at six months, one year, two years, and three years, the proportion of patients persistent to treatment ranged from 63% to 91%, 47% to 80%, 40% to 77%, and 32% to 67%, respectively. In the four studies that included comparisons to other biologics, golimumab was either statistically noninferior or statistically superior to other treatments, an observation that was supported by indirect comparisons of unadjusted point estimates of OLE trials. CONCLUSION: The data reviewed in this study indicate that golimumab may have higher persistence than other TNFis, a notion that is supported by indirect comparisons of persistence data from OLEs of randomized controlled trials (RCTs). Furthermore, the study suggests that persistence may be lower in biologic-experienced compared with biologic-naive patients and higher in axial spondyloarthritis compared with rheumatoid arthritis and psoriatic arthritis.

A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor: effect of various substitutions at the primary amino function.

In an effort to establish the structural requirements for agonism, neutral antagonism, and inverse agonism at the human histamine H(3) receptor (H(3)R) we have prepared a series of higher homologues of histamine in which the terminal nitrogen of the side chain has been either mono- or disubstituted with several aliphatic, alicyclic, and aromatic moieties or incorporated in cyclic systems. The novel ligands have been pharmacologically investigated in vitro for their affinities on the human H(3)R and H(4)R subtypes by radioligand displacement experiments and for their intrinsic H(3)R activities via a CRE-mediated beta-galactosidase reporter gene assay. Subtle changes of the substitution pattern at the side chain nitrogen alter enormously the pharmacological activity of the ligands, resulting in a series of compounds with a wide spectrum of pharmacological activities. Among the several neutral H(3)R antagonists identified within this series, compounds 2b and 2h display an H(3)R affinity in the low nanomolar concentration range (pK(i) values of 8.1 and 8.4, respectively). A very potent and selective H(3)R agonist (1l, pEC(50) = 8.9, alpha = 0.94) and a very potent, though not highly selective, H(3)R inverse agonist (2k, pIC(50) = 8.9, alpha = -0.97) have been identified as well.

Synthesis and pharmacological identification of neutral histamine H1-receptor antagonists.

In the present study we searched for neutral antagonists for the human histamine H(1)-receptor (H(1)R) by screening newly synthesized ligands that are structurally related to H(1)R agonists for their affinity using radioligand displacement studies and by assessing their functional activity via performing a NF-kappaB driven reporter-gene assay that allows for the detection of both agonistic and inverse agonistic responses. Starting from the endogenous agonist for the H(1)R, histamine, we synthesized and tested various analogues and ultimately identified several compounds with partial inverse agonistic properties and two neutral H(1)-receptor antagonists, namely 2-[2-(4,4-diphenylbutyl)-1H-imidazol-4-yl]ethylamine (histabudifen, 18d) (pK(i) = 5.8, alpha = 0.02) and 2-[2-(5,5-diphenylpentyl)-1H-imidazol-4-yl]ethylamine (histapendifen, 18e) (pK(i) = 5.9, alpha = -0.09).

Patient and physician expectations of add-on treatment with golimumab for rheumatoid arthritis: relationships between expectations and clinical and quality of life outcomes.

OBJECTIVE: Rheumatoid arthritis (RA) management involves improving clinical outcomes and quality of life (QOL). Golimumab is used as add-on therapy for patients who have failed disease-modifying antirheumatic drugs (DMARDs). This GO-MORE subanalysis investigated relationships between patient and physician expectations and outcomes. METHODS: GO-MORE was an open-label, multinational, prospective study in biologic agent-naive patients with active RA despite DMARD treatment. Patients received 50 mg subcutaneous golimumab monthly for 6 months. At baseline and month 3, patients rated treatment expectations for the following 3 months using 5-point scales (where 1 = good and 5 = poor). Outcomes were compared among expectation tertiles: most positive, intermediate, and least positive. At baseline and month 3, physicians predicted patient disease state 3 months later. RESULTS: At baseline, 3,280 efficacy-evaluable patients with moderate (21.3%) or high (78.7%) disease activity had mean ± SD disease duration of 7.6 ± 7.9 years, mean ± SD Health Assessment Questionnaire (HAQ) disability index (DI) score of 1.44 ± 0.67, and mean ± SD EuroQol 5-domain (EQ-5D) score of 0.42 ± 0.33. Patients reported high treatment expectations (mean 1.43); 95.9% expected golimumab to be better than current treatment. Patients with fewer DMARD failures, higher disease activity, shorter disease duration, younger age, and female sex reported higher expectations (P < 0.05 for all). After 6 months, patients with the most positive expectations had higher remission rates (P < 0.0001) and greater HAQ DI (P < 0.0001) and EQ-5D (P < 0.0001) score improvements. At baseline, physicians expected 29.6% and 59.2% of patients to attain remission and low disease activity, respectively, after 3 months. CONCLUSION: Patients had high expectations for golimumab treatment. Patients with more positive expectations had greater remission rates, improvements in function, and QOL.