Propensity score matching/reweighting analysis comparing intravenous golimumab to infliximab for ankylosing spondylitis using data from the GO-ALIVE and ASSERT trials.

OBJECTIVE: To compare the relative efficacy of intravenous golimumab (GOL IV) and infliximab (IFX) for active ankylosing spondylitis (AS). METHODS: Propensity score (PS) methods were used to compare the efficacy of GOL IV 2 mg/kg and IFX 5 mg/kg using individual patient data (IPD) from the active arms of the phase 3 GO-ALIVE and ASSERT studies. Outcomes included the proportion of patients with a ≥ 20% improvement in the Assessment of Spondyloarthritis International Society Criteria (ASAS20), change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) score, and change from baseline in C-reactive protein (CRP) levels from weeks 4-52. RESULTS: Before matching, 105 patients were treated with GOL IV and 201 patients were treated with IFX. After matching on all covariates, 118 patients were included in the ASAS20 analysis, 96 in the BASFI analysis, and 160 in the CRP analysis. After matching, GOL IV showed significantly greater improvement in ASAS20 response than IFX for weeks 28-44 (e.g., OR = 9.05 [95% CI 1.62-50.4] at week 44) and was comparable in change from baseline in BASFI scores and CRP levels to IFX at all time points. Results were robust for inclusion of different sets of covariates in scenario analyses. CONCLUSIONS: This is the first analysis of its kind to leverage clinical trial data to compare two biologics using PS methods in the treatment of active AS. Overall, GOL IV was associated with greater improvement in ASAS20 response than IFX in patients with AS at 28, 36, and 44 weeks of follow-up. Key Points • Although intravenous golimumab (GOL IV) and infliximab (IFX) are the only two IV-based tumor necrosis factor (TNF) inhibitors with demonstrated phase 3 clinical efficacy in patients with ankylosing spondylitis (AS), no study has evaluated their comparative efficacy in a head-to-head trial. • Propensity score matching was used to derive indirect treatment comparisons of GOL IV and IFX for ≥ 20% in the Assessment of Spondyloarthritis International Society Criteria (ASAS20), change in Bath Ankylosing Spondylitis Functional Index (BASFI), and change in C-reactive protein (CRP) using individual patient data from the GO-ALIVE and ASSERT phase 3 trials. • Propensity score matched indirect comparisons showed improved relative efficacy of GOL IV compared to IFX; after matching for up to 16 baseline covariates, GOL IV was associated with significantly greater odds of ASAS20 response at weeks 28, 36, and 44 than IFX as well as equivalent changes from baseline in BASFI and CRP. • This novel application of propensity score matching using data from phase 3 trials, the first analysis of its kind in AS, allowed adjustment for important imbalances in prognostic factors between trials to generate estimates of comparative efficacy between GOL IV and IFX in the absence of a head-to-head trial between these treatments.

A systematic review and network meta-analysis of current and investigational treatments for active ankylosing spondylitis.

OBJECTIVE: To compare the relative efficacy of current and investigational biologic and oral small molecule (OSM) treatments for active ankylosing spondylitis (AS). METHODS: A systematic literature review was conducted to identify all phase 2/3 randomized trials of interest in patients with AS. Outcomes assessed were ≥ 20% improvement in the Assessment of Spondyloarthritis International Society Criteria (ASAS20) and change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) and C-reactive protein (CRP) at weeks 12-16. Bayesian network meta-analyses were conducted for outcomes using a random effects model. Baseline-risk adjustment was also conducted to account for differences in placebo response across studies. Surface Under the Cumulative Ranking curve (SUCRA) values are reported, reflecting the relative probability that intervention was the best of all interventions. RESULTS: The investigational agent tofacitinib 5 mg was the top-ranked treatment (SUCRA, 93%) for ASAS20 response, followed by intravenous (IV) golimumab 2 mg/kg (90%). Golimumab IV 2 mg/kg and infliximab 5 mg/kg were the top two ranked treatments for change from baseline in BASFI (golimumab IV, 81%; infliximab, 80%) and change from baseline in CRP (infliximab, 90%; golimumab IV, 82%). CONCLUSIONS: Two approved therapies (golimumab IV, infliximab) and one investigational product ranked highest for efficacy in AS. Key Points • Although golimumab IV, infliximab, and tofacitinib ranked highest for efficacy in AS, differences in efficacy between approved and investigational therapies were not statistically significant.

Mononeuritis multiplex and vasculitis. Association with anti-neutrophil cytoplasmic autoantibody.

Mononeuritis multiplex is known to occur in many illnesses including certain types of systemic vasculitis. Anti-neutrophil cytoplasmic autoantibody (ANCA) has been described in association with Wegener's granulomatosis, polyarteritis nodosa, pauci-immune necrotizing crescentic glomerulonephritis, and so-called ANCA-associated vasculitis. We describe three patients who presented with mononeuritis multiplex and positive tests for ANCA. A careful search revealed underlying vasculitis in two of the three patients. Whereas both respiratory and renal involvement are well known in ANCA-associated vasculitis, to our knowledge the relationship of mononeuritis multiplex and ANCA positivity has not previously been described. The three patients were treated with steroids and oral cyclophosphamide. All demonstrated marked clinical improvement, as well as a decrease or disappearance of the ANCA. Since mononeuritis multiplex may be a presenting symptom of many illnesses, a serological marker may be helpful for early diagnosis and prompt treatment.

Structure-activity relationships of a series of novel (piperazinylbutyl)thiazolidinone antipsychotic agents related to 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate.

HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS) liability. The synthesis of these compounds, details of their structure-activity relationships, and discovery of a new lead, compound 50, as well as further development of the profiles of compounds 50 and 54 are described.

Neonatal hippocampal lesions induced hyperresponsiveness to amphetamine: behavioral and in vivo microdialysis studies.

The effect of neonatal hippocampal lesions on behavioral sensitivity to amphetamine (AMPH) and dopamine (DA) release in the nucleus accumbens (NAc) were examined. The ventral hippocampus was damaged bilaterally by ibotenic acid on postnatal day 7 (PD7). Spontaneous exploration and AMPH-stimulated locomotor activity were examined on postnatal day 35 (PD35) and day 56 (PD56). Extracellular DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were sampled using in vivo microdialysis while simultaneously AMPH-stimulated locomotion was examined in freely moving rats on PD56. Spontaneous exploration increased in rats with hippocampal lesions relative to controls on PD56 but not PD35. AMPH (0, 0.187, 0.375, 0.75, 1.5, and 3 mg/kg) enhanced locomotion dose-dependently in both control and lesioned groups. Locomotor activity was higher in lesioned rats than controls following AMPH at the dose of 0.75 mg/kg on PD35 and at the doses of 1.5 and 3.0 mg/kg on PD56. The basal level of DA in the NAc was not different between the hippocampal and control groups. AMPH (1.5 mg/kg) induced hyperlocomotion in lesioned rats relative to controls. DA release in the NAc for both groups was enhanced following injections of AMPH. However, neonatal hippocampal lesions had no further enhancement on AMPH-stimulated release of DA as compared to the control group. The levels of DOPAC and HVA in the NAc were altered by AMPH but not lesions. The level of 5-HIAA was not influenced by either lesions or AMPH. The results of neonatal lesion-induced hyperlocomotion suggest that an emergence of behavioral hyperresponsiveness to AMPH was dependent on an interaction of lesions, age of examination, and dose of the drug. A dissociation between the effect of AMPH on lesion-enhanced hyperlocomotion and a lack of a lesion-enhanced DA release in the NAc suggest that presynaptic release of DA had no major contribution to lesion-enhanced DA transmission in the mesolimbic DA system.

Selective adenosine A2A receptor/dopamine D2 receptor interactions in animal models of schizophrenia.

In the apomorphine-induced climbing mouse assay, the potencies of the selective adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), and the selective A2A adenosine receptor agonist, 2-p-(2-carboxyethyl) phenethylamino 5'-N-ethyl-carboxamidoadenosine (CGS 21680), and various dopamine receptor antagonists were as follows: SCH 23390 = haloperidol > raclopride > CHA = CGS 21680. While in catalepsy, their potencies were SCH 23390 > haloperidol > raclopride > CGS 21680. CHA failed to induce catalepsy due to significant sedation/ataxia. The combined administration of the ED15 dose of CHA failed to potentiate the ED50 value of SCH 23390, raclopride, or haloperidol in the apomorphine-induced climbing mouse assay. However, the combined administration of the ED15 dose of CGS 21680 significantly decreased the ED50 of raclopride by 8.0-fold and haloperidol by 35-fold. The adenosine A2A receptor antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), significantly decreased catalepsy induced by raclopride and haloperidol, while the adenosine A1 receptor antagonist, 1,3-dimethyl-8-phenylxanthine (8-PT), was ineffective. The present results show that in behavioral assays predictive for antipsychotic activity, adenosine receptor agonists block behaviors in a similar manner to dopamine receptor antagonists.

Novel ring contraction of 3-hydroxy-2,4(1H,3H)-quinolinediones in aqueous alkali. The first convenient route to 2-hydroxyindoxyls.

Ring contraction of 3-hydroxy-2,4(1H,3H)-quinolinediones (1) in aqueous potassium hydroxide resulted in the formation of 2-hydroxyindoxyls and/or dioxindoles. The choice of N-substituent and the reaction conditions govern the chemoselectivity of the reaction. N-Phenyl-substituted derivatives 1 give 2-hydroxyindoxyls, while N-alkyl- and N-benzyl-substituted derivatives afford the corresponding dioxindols. On the basis of byproduct analysis, as well as independent experiments, the most plausible reaction mechanism is proposed.

[Psychic development of children under conditions of longterm isolation (author's transl)]. / Beobachtungen zur psychischen Entwicklung von Kindern unter langdauernder Isolationsbehandlung. 10 Jahre Erfahrungen.

Three children with severe combined immunodeficiency have been isolated for 19-22 months. Two of the children have been placed into the isolation system directly after delivery; on child entered the isolation system at the age of 5 months. The influence of this situation on the psychic development of the children was studied by the means of direct observation as well as by psychometric test methods. An additional child which has been isolated between the age of 6 and 32 months was retested at the age of 4 and 6 years. The reported observation which include those of the parents and the team allow the conclusion, that a normal development is possible under these extreme conditions, when an optimal clinical and psychological support is maintained.