Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.

BACKGROUND: We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis. METHODS: We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12. RESULTS: Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group. CONCLUSIONS: Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).

Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study.

OBJECTIVES: The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA. METHODS: Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo. RESULTS: Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs -1.9%, respectively; all p<0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (>30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p<0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)). CONCLUSIONS: These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.

Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs: results of the GO-MORE study.

OBJECTIVES: To evaluate the efficacy and safety of subcutaneous golimumab as add-on therapy in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6 months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28-ESR remission was measured. RESULTS: 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6 years and mean DAS28-ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (∼25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. CONCLUSIONS: Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen.

The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways.

The dynamic interplay between dendritic cells (DCs) and human immunodeficiency virus type-1 (HIV-1) is thought to result in viral dissemination and evasion of antiviral immunity. Although initial observations suggested that the C-type lectin receptor (CLR) DC-SIGN was responsible for the trans-infection function of the virus, subsequent studies demonstrated that trans-infection of CD4(+) T cells with HIV-1 can also occur through DC-SIGN-independent mechanisms. We demonstrate that a cell surface molecule designated DCIR (for DC immunoreceptor), a member of a recently described family of DC-expressing CLRs, can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4(+) T cells from human immature monocyte-derived DCs. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Data from transfection experiments indicated that DCIR acts as a ligand for HIV-1 and is involved in events leading to productive virus infection. Finally, we show that the neck domain of DCIR is important for the DCIR-mediated effect on virus binding and infection. These results point to a possible role for DCIR in HIV-1 pathogenesis by supporting the productive infection of DCs and promoting virus propagation.

Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain.

OBJECTIVE: The present randomized, double-blinded, crossover study compared the efficacy and safety of a seven-day buprenorphine transdermal system (BTDS) and placebo in patients with low back pain of moderate or greater severity for at least six weeks. METHODS: Prestudy analgesics were discontinued the evening before random assignment to 5 microg/h BTDS or placebo, with acetaminophen 300 mg/codeine 30 mg, one to two tablets every 4 h to 6 h as needed, for rescue analgesia. The dose was titrated to effect weekly, if tolerated, to 10 microg/h and 20 microg/h BTDS. Each treatment phase was four weeks. RESULTS: Fifty-three patients (28 men, 25 women, mean [+/- SD] age 54.5+/-12.7 years) were evaluable for efficacy (completed two weeks or more in each phase). Baseline pain was 62.1+/-15.5 mm (100 mm visual analogue scale) and 2.5+/-0.6 (five-point ordinal scale). BTDS resulted in lower mean daily pain scores than in the placebo group (37.6+/-20.7 mm versus 43.6+/-21.2 mm on a visual analogue scale, P=0.0487; and 1.7+/-0.6 versus 2.0+/-0.7 on the ordinal scale, P=0.0358). Most patients titrated to the highest dose of BTDS (59% 20 microg/h, 31% 10 microg/h and 10% 5 microg/h). There were improvements from baseline in pain and disability (Pain Disability Index), Pain and Sleep (visual analogue scale), Quebec Back Pain Disability Scale and Short-Form 36 Health Survey scores for both BTDS and placebo groups, without significant differences between treatments. While there were more opioid-related side effects with BTDS treatment than with placebo, there were no serious adverse events. A total of 82% of patients chose to continue BTDS in a long-term open-label evaluation, in whom improvements in pain intensity, functionality and quality of life were sustained for up to six months without analgesic tolerance. CONCLUSION: BTDS (5 microg/h to 20 microg/h) represents a new treatment option for initial opioid therapy in patients with chronic low back pain.

A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of controlled-release (CR) tramadol and immediate-release (IR) tramadol in patients with moderate or greater intensity chronic noncancer pain. METHODS: A total of 122 patients underwent washout from all opioids 2 to 7 days before randomization to 1 of 2 groups: active CR tramadol 200 mg every morning plus placebo IR tramadol 50 mg every 4 to 6 hours PRN rescue, or placebo CR tramadol 200 mg every morning plus active IR tramadol 50 mg every 4 to 6 hours PRN rescue. After 2 weeks, the doses were increased to CR tramadol 400 mg or placebo and IR tramadol 100 mg every 4 to 6 hours PRN or placebo, as rescue. After 4 weeks in the first phase, patients crossed over to the alternative treatment for another 4 weeks. Pain intensity (100-mm visual analog scale [VAS] and 5-point ordinal scales) was assessed twice daily in diaries. Pain intensity, Pain and Disability Index (PDI; 0-10 ordinal scale), Pain and Sleep Questionnaire (100-mm VAS), and analgesic effectiveness (7-point ordinal scale) were assessed at biweekly clinic visits. RESULTS: Sixty-five patients (35 men, 30 women) completed the study. Mean (SD) age was 56.5 (12.7) years; mean (SD) weight was 82.0 (18.5) kg. Daily diary pain intensity (mean [SD]) was significantly lower in the CR tramadol group than in the IR tramadol group in the last 2 weeks of each phase (completers: VAS, 29.9 [20.5] vs 36.2 [20.4] mm, P < 0.001; ordinal scale, 1.41 [0.7] vs 1.64 [0.6], P < 0.001; intent-to-treat [ITT] population: VAS, 32.5 [22.9] vs 38.6 [21.2] mm, P < 0.003; ordinal scale, 1.50 [0.8] vs 1.72 [0.7], P < 0.002). The overall pain intensity scores from the daily diary were also significantly better with CR tramadol for both the completers and ITT. Similar results were obtained on the biweekly VAS pain intensity questionnaire. No differences were found between treatments in total PDI or overall Pain and Sleep scores in either population. For the completers, both patients and investigators rated effectiveness higher for CR tramadol than for IR tramadol (P < 0.004 and P < 0.008 for patients and investigators, respectively). CONCLUSION: This study reports significant improvement in pain intensity with CR tramadol as compared with IR tramadol.

Granulocyte macrophage-colony stimulating factor reduces the affinity of SHP-2 for the ITIM of CLECSF6 in neutrophils: a new mechanism of action for SHP-2.

Proteins that bear immunoreceptor tyrosine based inhibitory motifs (ITIM) are believed to participate in the repression of cell activation via phosphatases such as SHP-1, SHP-2 and/or SHIP-1. CLECSF6, also called DCIR, is a transmembrane protein expressed on leukocytes and predominantly on neutrophils that bears one ITIM pattern. This feature confers to CLECSF6 a role in the repression of cell activation. In order to better understand its role in neutrophil signalling, we analysed the binding of phosphatases to the ITIM of CLECSF6. We showed that a peptide bearing the ITIM of CLECSF6 in its phosphorylated form associates with both SHP-1 and SHP-2. Phosphorylated SHP-1 binds the ITIM whereas phosphorylated SHP-2 does not. In addition, granulocyte macrophage-colony stimulating factor (GM-CSF) reduces the binding of SHP-2 to the ITIM of CLECSF6 while enhancing the phosphorylation level of SHP-2. GM-CSF is known to recruit SHP-2 to its receptor. These data suggest that the phosphorylation of SHP-2 by GM-CSF promotes the binding of SHP-2 to the GM-CSF receptor to the disadvantage of CLECSF6. Therefore, upon a treatment with GM-CSF, SHP-2 could move from a CLECSF6 associated signalosome with a repressor function to a GM-CSF receptor associated signalosome with an activator function.

Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study.

BACKGROUND: In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24-month, randomised, double-blind, double-dummy, controlled, comparative exploratory study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA. METHODS: qMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher's exact, Wilcoxon Mann-Whitney, and Student's t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population. RESULTS: In the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib -8.1 % ± 4.2, CS -6.3 % ± 3.2; p = 0.018) and medial condyle (-7.7 % ± 4.7, -5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib -5.6 % ± 3.0, CS -4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib -8.4 % ± 4.2, CS -6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib -8.1 % ± 4.7, CS -5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS -0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs. CONCLUSION: This study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01354145 . Registered 13 May 2011.

The expression pattern of the ITIM-bearing lectin CLECSF6 in neutrophils suggests a key role in the control of inflammation.

In our study of the modulation of the expression of inflammation-related genes in neutrophils, we have found a gene called CLECSF6 (C-type lectin superfamily 6). CLECSF6 expresses two mRNA species at low levels in resting neutrophils. Here, we describe for the first time the sequence of the short mRNA version. It lacks amino acids that are likely to affect the functionality of its protein product. GM-CSF, IL-3, IL-4, and IL-13 caused an accumulation of the short CLECSF6 mRNA in neutrophils. The surface expression of the CLECSF6 protein was reduced by TNF-alpha, IL-1alpha, LPS, and Matrigel. CLECSF6 bears the immunoreceptor tyrosine-based inhibition motif (ITIM) involved in signal transduction resulting in the inhibition of leukocyte activation. We propose that some neutrophil activators modulate the expression of CLECSF6 at the mRNA (GM-CSF, IL-3, IL-4, and IL-13) or protein (TNF-alpha, IL-1alpha, LPS, and Matrigel) levels in ways that block ITIM-based transduction of anti-inflammatory signals and therefore promote inflammation.

The presence of meniscal lesions is a strong predictor of neuropathic pain in symptomatic knee osteoarthritis: a cross-sectional pilot study.

INTRODUCTION: Pain in osteoarthritis (OA) has been classically attributed to joint structural damage. Disparity between the degree of radiographic structural damage and the severity of symptoms implies that factors other than the joint pathology itself contribute to the pain. Peripheral and central sensitization have been suggested as two of the underlying mechanisms that contribute to pain in OA. The aim of this study was to explore in symptomatic knee OA patients, the structural changes assessed by magnetic resonance imaging (MRI) that could be used as markers of neuropathic pain (NP). METHODS: This cross-sectional observational pilot study included 50 knee OA patients with moderate to severe pain (VAS ≥40) in the target knee. The presence of NP was determined based on the PainDETECT questionnaire. Among the 50 patients included, 25 had PainDETECT score ≤12 (unlikely NP), 9 had PainDETECT score between 13 and 18 (uncertain NP) and 16 had PainDETECT score ≥19 (likely NP). WOMAC, PainDETECT, and VAS pain scores as well as knee MRI were assessed. RESULTS: Data showed no significant difference in demographic characteristics between the three groups. However, a positive and statistically significant association was found between the WOMAC pain (P <0.001), function (P <0.001), stiffness (P = 0.007) and total (P <0.001) scores as well as higher VAS pain score (P = 0.023), and PainDETECT scores. Although no difference was found in the cartilage volume between groups, the presence of meniscal extrusion in both medial (P = 0.006) and lateral (P = 0.023) compartments, and presence of meniscal tears in the lateral compartment (P = 0.011), were significantly associated with increasing PainDETECT score. Moreover, the presence of bone marrow lesions in the lateral plateau and the extent of the synovial membrane thickness in the lateral recess were associated with increasing PainDETECT scores (P = 0.032, P = 0.027, respectively). CONCLUSIONS: In this study, meniscal lesions, particularly extrusion, were found to be among the strongest risk factors for NP in knee OA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01733277. Registered 16 November 2012.

Human plasma fibronectin potentiates the mitogenic activity of platelet-derived growth factor and complements its wound healing effects.

Integrin-mediated cell adhesion and growth factor stimuli are both required for optimal control of cell proliferation. In the context of skin injury, cell-derived fibronectin and platelet-derived growth factor play important roles in the stimulation of cell proliferation and migration, activities that are crucial to the healing process. To assess the ability of exogenously supplied plasma-derived fibronectin to stimulate wound repair and to study its ability to cooperate with platelet-derived growth factor-BB during healing, we devised a novel topical delivery formulation that allows the controlled release of both molecules to a wound. Using this topical formulation and the rabbit ear model of dermal wound healing, we show that plasma fibronectin is a potent stimulator of the wound healing process. We also show that administration of fibronectin and platelet-derived growth factor-BB in combination has additive wound healing effects. Finally, we report novel findings on the ability of soluble plasma fibronectin to potentiate the mitogenic effects of platelet-derived growth factor-BB in vitro. These findings not only show that optimal concentrations of exogenous fibronectin administered using an effective delivery system stimulate wound healing; they also suggest that PDGF-BB should be administered with fibronectin to achieve optimal therapeutic stimulation of wound healing.

The ITIM-bearing CLECSF6 (DCIR) is down-modulated in neutrophils by neutrophil activating agents.

The recently discovered CLECSF6 protein displays the features of a receptor involved in the down-modulation of leukocyte activation. Although CLECSF6 has been the focus of the interest of many researchers lately, a Western blot characterization of the protein is still lacking. This highly reduces our ability to gain full knowledge of the biological relevance of this protein in cell responses. We produced two rabbit polyclonal antisera that detected a glycosylated protein at approximately 35kDa in neutrophils. Four different CLECSF6 mRNA species have been discovered to date. When deglycosylated, the protein displayed the molecular weight expected for the longest CLECSF6 form. Neutrophil membrane fractions were strongly enriched in the protein. We showed a down-modulation of the expression of this protein in neutrophils treated with granulocyte-macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF-alpha), lipopolysaccharide (LPS), and interleukin (IL)-4. This work supports the hypothesis that CLECSF6 is involved in the control of inflammation in neutrophils.

Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee.

OBJECTIVE: Non-animal stabilized hyaluronic acid (NASHA) is a novel hyaluronan (HA) preparation with a 4-week intra-articular half-life. This study compared the efficacy of a single injection of NASHA with placebo in patients with osteoarthritis (OA) of the knee. DESIGN: This was a 26-week randomized, double-blind, multicenter study of a single intra-articular knee injection with either NASHA or placebo (saline). Assessments included the Western Ontario McMasters Universities osteoarthritis index (WOMAC, Likert Scale) and patients' overall global disease status. A positive response was defined as a reduction in WOMAC pain score for the study knee of 40% from baseline with a minimum improvement of > or =5 points. RESULTS: A total of 346 (NASHA 172; placebo 174) patients were treated. WOMAC scores and quality of life were improved in both the NASHA and placebo groups. For the overall population, there were no statistically significant between-group differences in response rates for any efficacy parameters. In patients with OA confined to the knee (N=216), a greater response to NASHA than placebo was observed at week 6 (P=0.025). There were few treatment-related events. CONCLUSIONS: NASHA was not superior to placebo for the primary efficacy analysis. However, these data may be confounded by the inclusion of patients with OA at other sites, as significant benefits over placebo were found among patients with OA confined to the knee. Future trials of OA that examine a local therapy might need to consider restricting the study population to those patients having OA of only the signal joint.