Enthesitis in psoriatic arthritis (Part 1): pathophysiology.

Enthesitis is a key manifestation of PsA and current knowledge supports the concept that it may be among the primary events in the development of this disease, as well as other forms of SpA. Patients with PsA seem to have a different threshold to mechanical stress, which may be genetically determined. Hence patients with psoriatic disease respond pathologically with inflammation after being exposed to physiological mechanical stress. Activation of pro-inflammatory mediators such as IL-17 and TNF-α as well as the influx of innate immune cells are key events in the development of enthesitis in PsA. Chronic entheseal inflammation is accompanied by new bone formation, leading to bony spurs in peripheral (entheseophytes) and axial (syndesmophytes) structures. This article reviews the current knowledge on the mechanisms involved in the development of enthesitis in patients with PsA.

Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: Results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study.

OBJECTIVES: To date, all studies addressing on anti-inflammatory drugs in PsA have been carried out in psoriatic arthritis (PsA) patients with polyarticular disease. Specific studies on enthesitis are missing. IL-23 is considered to play a central role in the development of enthesitis. We therefore speculated that therapeutic inhibition of IL-12/IL-23 is particularly effective in enthesitis-driven PsA patients. METHODS: Enthesial CLearance In PSoriatic Arthritis (ECLIPSA) is a prospective randomized-controlled open-label study. Patients with PsA with active enthesitis were randomized 1:1 to receive either ustekinumab (UST; arm 1) or tumor necrosis factor inhibitors (TNFi; arm 2). Primary endpoint was complete clearance of enthesitis, defined by Spondyloarthritis Research Consortium of Canada (SPARCC) index equal to zero at 24 weeks. RESULTS: 51 patients (UST = 25; TNFi = 26) were screened, 47 enrolled (UST = 23; TNFi = 24) and 46 completed the study. Mean ±â€¯SD SPARCC index at baseline was 4.8 ±â€¯2.6 in the UST group and 3.5 ±â€¯2.3 in the TNFi group with no significant difference. After 24 weeks, 73.9% of UST patients and 41.7% of TNFi patients reached the primary endpoint (SPARCC = 0) indicating clearance from enthesitis (p = 0.018). UST achieved superior responses as compared to TNFi with respect to enthesitis (p = 0.007) and psoriatic skin disease (p = 0.030) but not for arthritis (p = 0.95). CONCLUSION: These results indicate that p40-IL-12/IL-23 inhibition is superior to TNFi in the clearance of enthesitis. Future stratified therapeutic approaches in PsA patients may therefore consider the presence or absence of enthesitis as a discriminator of response between different cytokine blocking modalities.

Imaging of gout: New tools and biomarkers?

While joint aspiration and crystal identification by polarizing microscopy remain the gold standard for diagnosing tophaceous gout, agreement among medical and ancillary health personnel examining synovial fluid using polarizing microscopy for the detection of monosodium urate (MSU) crystals appears to be poor. Imaging modalities, including conventional radiography (CR), ultrasonography (US), magnetic resonance imaging (MRI), and dual-energy computed tomography (DECT), have been found to provide information on the deposition of MSU crystals in tissues, and the consequences of such deposition. CR can demonstrate typical "punched out lesions" with marginal overhangs, but the sensitivity for erosion detection is better for DECT and US. US is inexpensive and can identify tophus deposition in and around joints, erosions, and tissue inflammation if power Doppler US is used. MRI can show tophi, bone marrow edema, and inflammation, but MRI findings of tophi may be nonspecific. DECT can identify and color-code tophaceous material, and provide an overview of the tophus burden of a joint area. Because of the lower number of available studies, the strength of evidence for the newer imaging can be improved through further research.

Prevalence of monosodium urate deposits in a population of rheumatoid arthritis patients with hyperuricemia.

OBJECTIVES: To investigate the prevalence of monosodium urate (MSU) crystal deposits, indicative for gout, in a population of rheumatoid arthritis (RA) patients with concomitant hyperuricemia and to analyze the clinical and disease-specific characteristics of RA patients who exhibit MSU crystal deposits. METHODS: Overall, 100 consecutive patients with the diagnosis of RA and a serum urate level above 6mg/dl underwent dual energy computed tomography (DECT) of both feet and hands to search for MSU crystals in a prospective study between October 2011 and July 2013. Presence and extent of MSU crystal deposits on DECT was assessed by automated volume measurement. Demographic and disease-specific characteristics were recorded and included into two logistic regression models to test for the factors associated with MSU crystal deposits in RA. RESULTS: Hyperuricemic RA patients were mostly male (55%), over 60 years of age (63 ± 11 years), had established disease (8.7 ± 10.5 years) and a mean disease activity score 28 (DAS 28) of 3.2. In total, 20 out of 100 patients displayed MSU crystal deposits in DECT. Interestingly, the majority (70%) of the RA patients positive for MSU crystal deposits were seronegative RA patients. Hence, every third seronegative RA patient had MSU crystal deposits. According to logistic regression model analysis, seronegative status correlated positively with presence of urate deposits (p = 0.019). CONCLUSIONS: These data show that a considerable number of RA patients display periarticular MSU crystal deposits. Seronegative patients were shown to be predominantly affected with every third patient being positive for urate deposits.

Tophus resolution with pegloticase: a prospective dual-energy CT study.

OBJECTIVE: To investigate the effect of intensive lowering of serum uric acid (SUA) levels by pegloticase on the resolution of tophi in patients with refractory gout. METHODS: Descriptive study in patients with refractory gout receiving pegloticase treatment. SUA levels were measured before and after each infusion. Dual-energy CT (DECT) scans were taken from all patients before the first infusion and after the last infusion. Computerised tophus volumes were calculated for the baseline and follow-up assessments and compared with each other. RESULTS: 10 patients with refractory gout and baseline mean SUA level of 8.1 mg/dL were enrolled. Patients were treated for a mean of 13.3 weeks. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of SUA level below 6 mg/dL during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localisation, resolution of tophi showed different dynamics, with articular tophi showing fast, and tendon tophi slow, resolution. CONCLUSIONS: Tophi are highly sensitive to pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses.

Psychometric properties of three single-item pain scales in patients with rheumatoid arthritis seen during routine clinical care: a comparative perspective on construct validity, reproducibility and internal responsiveness.

OBJECTIVE: To investigate the construct validity, reproducibility (ie, retest reliability) and internal responsiveness to treatment change of common single-item scales measuring overall pain in patients with rheumatoid arthritis (RA) and to investigate the corresponding effect of common pain-related comorbidities and medical consultation on these outcomes. METHODS: 236 patients with RA completed a set of questionnaires including a visual analogue scale (VAS), a numerical rating scale (NRS) and a verbal rating scale (VRS) measuring overall pain before and immediately after routine medical consultation as well as 1 week after the patient's visit. Construct validity and retest reliability were evaluated using the Bravais-Pearson correlation while standardised response means (SRM) were calculated for evaluating internal responsiveness. Differences in the perception of pain were calculated using dependent samples t-tests. RESULTS: In the total sample, construct validity was good across all three time points (convergent validity of pain scales: rT1-T3=0.82-0.92, p<0.001; discriminant validity as correlation of pain scales with age: rage=0.01-0.16, p>0.05). In patients maintaining antirheumatic treatment, retest reliability of pain scales was confirmed for all scales and across time points (rVAS=0.82-0.95, rNRS=0.89-0.98, rVRS=0.80-0.90, p<0.001), while the internal responsiveness of scales to a change in treatment was low across all scales (SRM=0.08-0.21). The VAS especially suggested a change in pain perception after medical consultation in patients maintaining therapy. CONCLUSIONS: The VAS, NRS and VRS are valid and retest reliable in an outpatient clinical practice setting. The low pain scales' internal responsiveness to treatment change is likely to be due to the short follow-up period. Patients with RA maintaining antirheumatic therapy seem to experience less pain after medical consultation.

High incidence of disease recurrence after discontinuation of disease-modifying antirheumatic drug treatment in patients with psoriatic arthritis in remission.

OBJECTIVE: To investigate the possibility of drug-free remission in patients with psoriatic arthritis (PsA) in continuous remission. METHODS: Prospective observational study in disease-modifying antirheumatic drug (DMARD)-treated PsA patients in continuous disease remission (no musculoskeletal symptoms, no or minimal skin/nail disease) for at least 6 months. Demographic, disease-specific and ultrasound parameters were assessed at baseline. DMARDs (traditional or biologic) were discontinued at the initial visit, and patients were followed for a maximum of 6 months for recurrence of disease. RESULTS: 26 patients (methotrexate monotherapy: N=14; tumour necrosis factor inhibitors: N=12) with a mean age of 55.2 years, absence of musculoskeletal symptoms and minimal skin disease (mean Psoriasis Area Severity Index (PASI): 0.21) were enrolled. Incidence of recurrence of disease was high (N=20, 76.9%) and occurred rapidly (74.50±51.72 days) after treatment discontinuation. Male PsA patients were significantly more likely to lose remission. Long disease duration, more severe skin involvement and the presence of synovial hypertrophy by ultrasonographic examination at baseline decreased the likelihood for drug-free remission. Reinitiation of DMARDs promptly restored remission in all PsA patients with recurrence of disease. CONCLUSIONS: This study shows that the chance to reach drug-free remission in PsA patients is low. Discontinuation of DMARD therapy cannot be recommended in patients with PsA.

Ouabain inhibits monocyte activation in vitro: prevention of the proinflammatory mCD14(+)/CD16(+) subset appearance and cell-size progression.

Classically described as a potent inhibitor of the sodium-potassium adenosine triphosphatase enzyme, ouabain has been further shown to act as an effective immunomodulator in mammals. Recently, our group showed that this hormone downregulates membrane CD14 (mCD14) in human monocytes, though it is not known whether monocyte activation status could modify ouabain influence. Hence, we aimed to investigate ouabain effect during monocyte activation in vitro, analyzing mCD14, CD16 and CD69 expression in total monocytes after two periods of adhesion (2 hours and 24 hours) or in small and large monocyte subpopulations separately. Ouabain (100 nM) inhibited monocyte-size increase, characteristic of activation, only when added to cells immediately after 2 hours' adhesion. Moreover, downregulation of both mCD14 and CD16 expression by ouabain was more effective in small monocytes and in cells after 2 hours' adhesion. Since monocytes after 24 hours' adhesion showed no lack of ouabain binding and no CD69 upregulation, it seems that ouabain is somehow incapable of triggering an appropriate cell-signaling induction once monocytes become activated. Furthermore, though p38 MAPK activation was crucial for the impairment in cell-size progression induced by ouabain, its inhibition did not alter ouabain-induced CD69 upregulation, suggesting that other molecules may participate in the response to this hormone by monocytes. Our data suggest that ouabain inhibits monocyte activation in vitro, preventing both cell-size increase and the appearance of the proinflammatory mCD14(+)/CD16(+) subpopulation. Thus, the findings suggest that individuals suffering from disorders commonly associated with high ouabain plasma levels, like hypertension, may present defective monocyte activation under inflammation or infection.

The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages.

Macrophages infected with HIV-1 sustain viral replication for long periods of time, functioning as viral reservoirs. Therefore, recognition of factors that maintain macrophage survival and influence HIV-1 replication is critical to understanding the mechanisms that regulate the HIV-1-replicative cycle. Because HIV-1-infected macrophages release the nerve growth factor (NGF), and NGF neutralization reduces viral production, we further analyzed how this molecule affects HIV-1 replication. In the present study, we show that NGF stimulates HIV-1 replication in primary macrophages by signaling through its high-affinity receptor Tropomyosin-related Kinase A (TrKA), and with the involvement of reticular calcium, protein kinase C, extracellular signal-regulated kinase, p38 kinase, and nuclear factor-κB. NGF-induced enhancement of HIV-1 replication occurred during the late events of the HIV-1-replicative cycle, with a concomitant increase in viral transcription and production. In addition, NGF reduced the synthesis of the cellular HIV-1 restriction factor APOBEC3G and also overrode its interferon-γ-induced up-regulation, allowing the production of a well-fitted virus. Because NGF-TrKA signaling is a crucial event for macrophage survival, it is possible that NGF-induced HIV-1 replication plays a role in the maintenance of HIV-1 reservoirs. Our study may contribute to the understanding of the immunopathogenesis of HIV-1 infection and provide insights about approaches aimed at limiting viral replication in HIV-1 reservoirs.

IL-4 increases GABAergic phenotype in rat retinal cell cultures: involvement of muscarinic receptors and protein kinase C.

Interleukin-4 (IL-4) is an anti-inflammatory cytokine. During injuries, infections and neurodegenerative diseases, high levels of this molecule are expressed in the brain. In the present work, we investigated the effect of IL-4 on GABAergic differentiation of retinal cells kept in vitro. We analyzed either the uptake of [3H]-gamma-aminobutyric acid (GABA) or the expression of glutamic acid decarboxylase (GAD-67) following IL-4 treatment. We have also investigated the pharmacological modulation of the [3H]-GABA uptake by cholinergic activation. Our results demonstrate that IL-4 increases the uptake of [3H]-GABA after 48 h in culture in a dose-dependent manner (0.5-100 U/ml). The maximal effect was obtained with 5 U/ml (75% increase). This effect was blocked by 1 mM of nipecotic acid, demonstrating the involvement of the GAT-1 subtype of GABA transporter. The IL-4 effect depends on M1 muscarinic activity, an increase in intracellular calcium levels, tyrosine kinase activity and protein kinase C (PKC) activity. Treatment with IL-4 for 48 h induced an increase of 90% in the number of GAD- and GABA-immunoreactive cells when compared with control cultures. Our results indicate that IL-4 modulates the GABAergic phenotype of retinal cells in culture. This result can suggest an important role for this cytokine either during the normal development of retinal circuitry or during neuroprotection after injuries.