Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial

OBJECTIVE: Current treatment options for psoriatic arthritis (PsA) are limited. Leflunomide, an oral pyrimidine synthesis inhibitor, is highly effective in the treatment of rheumatoid arthritis, and small studies have suggested similar efficacy in PsA. We undertook this double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of leflunomide in patients with PsA and psoriasis. METHODS: One hundred ninety patients with active PsA and psoriasis (at least 3% skin involvement) were randomized to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. The primary efficacy end point was the proportion of patients classified as responders by the Psoriatic Arthritis Response Criteria (PsARC). Additional efficacy (joint and skin involvement), safety, and quality-of-life assessments were performed. RESULTS: At 24 weeks, 56 of 95 leflunomide-treated patients (58.9%; 95% confidence interval [95% CI] 48.4-68.9) and 27 of 91 placebo-treated patients (29.7% [95% CI 20.6-40.2]) were classified as responders by the PsARC (P < 0.0001). Significant differences in favor of leflunomide were also observed in the proportions of patients achieving modified American College of Rheumatology 20% improvement criteria, improvement in the designated psoriasis target lesion, and mean changes from baseline in Psoriasis Area and Severity Index scores and quality-of-life assessments. Diarrhea and alanine aminotransferase increases occurred at higher rates in the leflunomide group. No cases of serious liver toxicity were observed. CONCLUSION: Leflunomide is an effective treatment for PsA and psoriasis, providing a safe and convenient alternative to current therapies.     

Outcome measures in psoriatic arthritis

Psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis usually seronegative for rheumatoid factor, has emerged as a more common and severe disease than previously appreciated. The disease is multifaceted. Thus the assessment of PsA requires attention to peripheral joint involvement, axial disease, dactylitis, and enthesitis, as well as the skin manifestations. In addition, the assessment of patient reported features such as patient assessment of disease activity, pain, fatigue, quality of life, and the new concept of participation are important. The assessment of damage and the assessment of tissue histology are also important outcome measures. This article summarizes these features of PsA as well as current knowledge on the instruments available for the assessment of these domains.     

Irreversible neutrophil aggregation. A mechanism of decreased newborn neutrophil chemotactic response.

To investigate the neutrophil-neutrophil interactions of the newborn for possible clues to the etiology of decreased newborn neutrophil (PMN) chemotaxis, the authors compared adult and newborn C5a-induced PMN aggregation and chemotaxis at various PMN concentrations. Using Craddock's technique of C5a-induced aggregation, the authors found that the newborn lacks the normal biphasic aggregation-deaggregation seen in the adult, suggesting irreversible aggregation similar to that seen when adult PMNs are pretreated with cytochalasin-B. Chemotaxis of adult and newborn PMNs was studied with a modified Gallin radiolabel technique. A linear correlation between PMN concentration and corrected chemotactic response was found with both adult (r2 = 0.93) and newborn (r2 = 0.90) PMNs in the range 0.1 X 10(6) to 20 X 10(6) PMNs/ml. Random migration was not augmented by increased PMN concentration. The augmentation of newborn PMN chemotaxis was less than that of the adult (adult slope = 2426; newborn slope = 983). Irreversible newborn PMN aggregation may be the underlying event producing decreased PMN chemotaxis and interfering with the normal chemotactic augmentation caused by increased PMN concentration.     

Neuropeptides in migraine and cluster headache

The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.     

Confirmation of hepatitis C infection: a comparison of five immunoblot assays

BACKGROUND: Recently, new immunoblot assays for the detection of antibodies to hepatitis C virus (HCV) became available. STUDY DESIGN AND METHODS: The performance of five confirmatory anti-HCV immunoblot assays was studied with samples with known HCV antibody and HCV RNA status. The assays were a third-generation strip recombinant immunoblot assay (RIBA-3, Chiron Corp., Emeryville, CA), a second-generation HCV blot (DB-2 blot, Diagnostic Biotechnology, Singapore), the Wellcozyme HCV Western blot (Murex blot, Murex Diagnostics, Dartford, UK), an immunodot HCV assay (Matrix, Abbott Laboratories, Chicago, IL), and the third-generation HCV line immunoassay (Liatek-III, Organon Teknika, Boxtel, The Netherlands). RESULTS: Sensitivity on samples from 48 HCV RNA-positive, second-generation RIBA (RIBA-2)-positive persons and specificity on samples from 31 low-risk donors was 96 percent or better for all assays. The sensitivity on 31 HCV RNA-positive, RIBA-2- indeterminate samples was as follows: Liatek-III, 94 percent; RIBA-3, 90 percent; Murex blot, 61 percent; Matrix, 55 percent; and DB-2 blot, 39 percent. In testing 39 HCV RNA-negative, RIBA-2-indeterminate donor samples, the percentage found to be negative was Liatek-III, 77 percent; RIBA-3, 67 percent; Murex blot, 49 percent; DB-2 blot, 33 percent; and Matrix, 15 percent. The order of sensitivity on four HCV seroconversion series was (from high to low): RIBA-3, Liatek-III, DB-2 blot, Murex blot, and Matrix; the differences were small. CONCLUSION: Detection of HCV antibodies was not refined by the addition of new HCV antigens (NS5, E2/NS1), but by improved classical antigens (core, NS3, NS4). Replacement of the commonly used RIBA-2 will resolve the status of a high proportion of RIBA-2-indeterminate samples.     

Soluble urokinase-type plasminogen activator receptor levels in patients with burn injuries and inhalation trauma requiring mechanical ventilation: an observational cohort study

Introduction  

Soluble urokinase-type plasminogen activator receptor (suPAR) has been proposed as a biologic marker of fibrinolysis and inflammation. The aim of this study was to investigate the diagnostic and prognostic value of systemic and pulmonary levels of suPAR in burn patients with inhalation trauma who need mechanical ventilation.     

The role of previously unmeasured organic acids in the pathogenesis of severe malaria

IntroductionSevere falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.MethodsIn this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.ResultsPatients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).ConclusionsNewly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1023-5) contains supplementary material, which is available to authorized users.     

Fibromyalgia: Should the treatment paradigm be monotherapy or combination pharmacotherapy?

Fibromyalgia (FM) is a disorder characterized by chronic widespread pain, tenderness, and associated symptoms such as fatigue, sleep disturbance, mood disorder, and cognitive dysfunction. Research on the pathophysiology of FM has focused on dysregulation of sensory processing in the central nervous system, as well as genetic and sociobiologic background factors. Abnormalities include excessive pronociceptive input and deficiency of modulatory signaling via noradrenergic and serotonergic pathways. Effective pharmacotherapy of FM includes medications that inhibit pronociceptive input and augment modulatory signaling. Several other dysregulated pathways may be involved and be potential targets for therapeutic intervention. This article reviews positive results of recent monotherapy trials of several norepinephrine and serotonin reuptake inhibitors. Although there has been little assessment of combination therapy in FM, this review outlines the basis for rational treatment using this approach (in order to most effectively treat multiple symptom domains). Controlled monotherapy trials of medications currently being approved for FM demonstrate significant effect on pain, patient global impression of change, and function. Trials are currently being developed to assess the potential additive or synergistic effects of combined central pharmacotherapy and to assess the safety and tolerability of this approach.     

High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia

Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin- fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin- fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side- effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.