Long‐term high‐physiological‐dose growth hormone reduces intra‐abdominal fat in HIV‐infected patients with a neutral effect on glucose metabolism

Objectives

The aim of the study was to investigate the effect of long‐term high‐physiological‐dose recombinant human growth hormone (rhGH) therapy on fat distribution and glucose metabolism in HIV‐infected patients.

Methods

Forty‐six HIV‐infected Caucasian men on highly active antiretroviral therapy (HAART), with an age range of 21–60 years and no significant comorbidity, were included in this randomized, placebo‐controlled, double‐blind, single‐centre trial. Twenty‐eight subjects were randomized to 0.7 mg/day rhGH, and 18 subjects to placebo, administered as daily subcutaneous injections between 1 and 3 pm for 40 weeks. Endpoints included changes in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), limb fat mass, percentage of limb fat, plasma lipids, insulin resistance and glucose tolerance.

Results

VAT and trunk fat mass decreased significantly in the GH group compared with the placebo group [−19 cm² (−11%) vs. 12 cm² (6%), P=0.03, and −548 g (−9%) vs. 353 g (6%), P<0.01, respectively]. The beneficial fat redistribution in the GH group occurred without concomitant changes in subcutaneous fat at the abdomen or extremities. rhGH therapy was well tolerated. Insulin resistance, glucose tolerance, and total plasma cholesterol and triglycerides did not significantly change during intervention.

Conclusions

Daily 0.7 mg rhGH treatment for 40 weeks reduced abdominal visceral fat and trunk fat mass in HIV‐infected patients. This treatment appeared to be safe with respect to glucose tolerance and insulin sensitivity.

     

The CCL5/CCR5 axis promotes interleukin‐6 production in human synovial fibroblasts

Objective

CCL5 (RANTES) was originally identified as a product of activated T cells and plays a crucial role in the inflammatory response. This study was undertaken to investigate the intracellular signaling pathways involved in CCL5‐induced interleukin‐6 (IL‐6) production in human synovial fibroblasts.

Methods

CCL5‐mediated IL‐6 expression was assessed by quantitative polymerase chain reaction and enzyme‐linked immunosorbent assay. The mechanisms of action of CCL5 in different signaling pathways were studied using Western blotting. Knockdown of CCR5 and protein kinase Cδ (PKCδ) protein was achieved by transfection of small interfering RNA (siRNA). Chromatin immunoprecipitation assays were used to study in vivo binding of c‐Jun to the IL‐6 promoter. Transient transfection was used to examine IL‐6 and activator protein 1 (AP‐1) activity.

Results

Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCL5 and CCR5, and expression was higher than that in normal synovial fibroblasts. Stimulation of OASFs with CCL5 induced concentration‐ and time‐dependent increases in IL‐6 production. CCL5‐mediated IL‐6 production was attenuated by CCR5 monoclonal antibody, CCR5 inhibitor (Met‐RANTES), and CCR5 siRNA. Pretreatment with a PKCδ inhibitor (rottlerin), a c‐Src inhibitor (PP2), or an AP‐1 inhibitor (tanshinone IIA) also blocked the potentiating action of CCL5. Treatment of OASFs with CCL5 increased the accumulation of phosphorylated c‐Jun in the nucleus, AP‐1 luciferase activity, and c‐Jun binding to the AP‐1 element on the IL‐6 promoter. CCL5‐mediated AP‐1 luciferase activity and c‐Jun binding to the AP‐1 element were inhibited by Met‐RANTES, rottlerin, and PP2.

Conclusion

The present results suggest that the interaction between CCL5 and CCR5 increases IL‐6 production in human synovial fibroblasts via the PKCδ/c‐Src/c‐Jun and AP‐1 signaling pathways.

     

Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric‐onset systemic lupus erythematosus

Objective

To characterize atherosclerotic risk factors and endothelial function in pediatric‐onset systemic lupus erythematosus (SLE).

Methods

Lipoproteins, oxidized state, and autoantibodies to oxidized low‐density lipoprotein (Ox‐LDL) were assessed. Endothelial function was evaluated using brachial artery reactivity.

Results

Thirty‐three SLE patients and 30 controls were studied. SLE subjects had significantly decreased mean high‐density lipoprotein (HDL) cholesterol (41 mg/dl versus 51 mg/dl; P = 0.002) and apolipoprotein A‐I (97 mg/dl versus 199 mg/dl; P = 0.0004). There was no difference between groups in markers of oxidized state (including nitric oxide metabolites, isoprostanes, and Ox‐LDL) or in endothelial function. However, SLE subjects had increased median anti‐Ox‐LDL IgG (2,480 relative light units [RLU] versus 1,567 RLU; P = 0.0007) and IgG immune complexes with LDL (4,222 RLU versus 2,868 RLU; P = 0.002).

Conclusion

Pediatric SLE patients had significantly decreased levels of HDL cholesterol and apolipoprotein A‐I and elevated titers of autoantibodies to Ox‐LDL. Despite these atherosclerotic risk factors, SLE patients had normal measures of oxidized state and endothelial function.

     

Persistence of CCR5 usage among primary human immunodeficiency virus isolates of individuals receiving intermittent interleukin‐2

Objective

To investigate the impact of intermittent interleukin‐2 (IL‐2) plus combination antiretroviral therapy (cART) on HIV‐1 entry co‐receptor use.

Methods

Primary HIV‐1 isolates were obtained from 54 HIV‐1‐positive individuals at baseline and after 12 months using co‐cultivation of peripheral blood mononuclear cells (PBMC) with activated PBMC of HIV‐negative healthy donors. HIV‐1 co‐receptor use was determined on U87‐CD4 cells.

Results

Fourteen out of the 21 (67%) IL‐2‐treated individuals harbouring a primary CCR5‐dependent (R5) HIV‐1 isolate at baseline confirmed an R5 virus isolation after 12 months in contrast to 3 out of 7 (43%) of those receiving cART only. After 12 months, only 1 R5X4 HIV‐1 isolate was obtained from 21 cART+IL‐2‐treated individuals infected with an R5 virus at entry (5%) vs. 2/7 (29%) patients receiving cART alone, as confirmed by a 5‐year follow‐up on some individuals.

Conclusions

Intermittent IL‐2 administration plus cART may prevent evolution towards CXCR4 usage in individuals infected with R5 HIV‐1.

     

Treatment outcomes amongst previously antiretroviral-naïve HIV-infected patients starting lopinavir/ritonavir-containing antiretroviral regimens at the Royal Free Hospital

Objective

To describe outcomes in patients starting first‐line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting.

Methods

Previously naïve patients starting LPV/r‐containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV‐1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan–Meier methods.

Results

A total of 195 individuals had a median follow‐up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50–200 and >200 cells/μL, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow‐up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/μL, respectively.

Conclusions

Few patients experienced virological failure whilst on a LPV/r‐based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r.

     

Rheumatoid arthritis synovial macrophages express the Fas‐associated death domain–like interleukin‐1β–converting enzyme–inhibitory protein and are refractory to Fas‐mediated apoptosis

Objective

The chronic inflammation and progressive joint destruction observed in rheumatoid arthritis (RA) are mediated in part by macrophages. A paucity of apoptosis has been observed in RA synovial tissues, yet the mechanism remains unknown. The present study sought to characterize the expression of Fas, Fas ligand (FasL), and Fas‐associated death domain–like interleukin‐1β–converting enzyme–inhibitory protein (FLIP), and to quantify the apoptosis induced by agonistic anti‐Fas antibody, using mononuclear cells (MNC) isolated from the peripheral blood (PB) and synovial fluid (SF) of RA patients.

Methods

The expression of Fas, FasL, and FLIP and apoptosis induced by agonistic anti‐Fas antibody in MNC from the PB and SF of RA patients were determined by flow cytometry. Immunohistochemistry employing a monospecific anti‐FLIP antibody was performed on RA and osteoarthritis (OA) synovial tissue.

Results

CD14‐positive monocyte/macrophages from normal and RA PB and from RA SF expressed equivalent levels of Fas and FasL. Furthermore, unlike the CD14‐positive PB monocytes, RA SF monocyte/macrophages were resistant to the addition of agonistic anti‐Fas antibody. In contrast, both CD14‐positive PB and SF monocyte/macrophages were sensitive to apoptosis mediated by a phosphatidylinositol 3‐kinase inhibitor. Intracellular staining of the caspase 8 inhibitor, FLIP, in CD14‐positive SF monocyte/macrophages revealed a significant up‐regulation of FLIP compared with normal and RA PB monocytes. Immunohistochemical analysis of synovial tissue from RA and OA patients revealed increased FLIP expression in the RA synovial lining compared with the OA synovial lining. Furthermore, FLIP expression was observed in the CD68‐positive population in the RA synovial lining. Forced reduction of FLIP by a chemical inhibitor resulted in RA SF macrophage apoptosis that was enhanced by agonistic anti‐Fas antibody, indicating that FLIP is necessary for SF macrophage survival.

Conclusion

These data suggest that up‐regulation of FLIP in RA macrophages may account for their persistence in the disease. Thus, the targeted suppression of FLIP may be a potential therapeutic strategy for the amelioration of RA.

     

Treatment of giant cell arteritis using induction therapy with high‐dose glucocorticoids: A double‐blind,placebo‐controlled,randomized prospective clinical trial

Objective

Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high‐dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy.

Methods

Twenty‐seven patients with biopsy‐proven GCA were enrolled in a randomized, double‐blind, placebo‐controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking ≤5 mg/day prednisone were compared. Cumulative prednisone dose, number of relapses, and development of adverse GC effects were assessed.

Results

Ten of the 14 IV GC–treated patients, but only 2 of 13 control patients, were taking ≤5 mg/day prednisone at 36 weeks (P = 0.003). This difference was maintained; there was a higher number of sustained remissions after discontinuation of treatment in the IV GC–treated group and a lower median daily dose of prednisone at 78 weeks (P = 0.0004). The median cumulative dose of oral prednisone, excluding the IV GC dose, was 5,636 mg in the IV GC–treated group compared with 7,860 mg in the IV saline–treated group (P = 0.001).

Conclusion

Initial treatment of GCA with IV GC pulses allowed for more rapid tapering of oral GCs and had long‐term benefits, with a higher frequency of patients experiencing sustained remission of their disease after discontinuation of treatment.

     

sE‐selectin for stratifying outcome in rheumatoid arthritis

Objectives

To determine the usefulness of sE‐selectin as a marker for early diagnosis and stratification of rheumatoid arthritis.

Methods

We investigated several markers of disease activity, including circulating adhesion molecules and other standard laboratory tests, in a 2–3 year followup analysis of patients with rheumatoid arthritis.

Results

The mean ± SD levels of sE‐selectin (91.68 ± 31.8 ng/ml versus 49.83 ± 14.76 ng/ml) and rheumatoid factor (375.7 ± 394.4 U versus 44.66 ± 37.63 U) were strongly elevated in severe (n = 15) versus mild (n = 7) courses of disease. Statistical calculation of mean and standard deviation revealed that sE‐selectin represents a highly significant marker for the presence of persistent and aggressive disease over time, regardless of therapeutic intervention and observation time points (P = 0.0004). Notably, regression analysis identified constant values for all parameters analyzed and, therefore, a stable course of the disease could be predicted from the beginning.

Conclusion

sE‐selectin appears to be a powerful marker to predict the severity of rheumatoid arthritis.

     

A randomized controlled trial to evaluate the slow‐acting symptom‐modifying effects of colchicine in osteoarthritis of the knee: A preliminary report

Objective

To determine if colchicine added to nimesulide may have a beneficial effect on osteoarthritis (OA) of the knee.

Methods

Colchicine 0.5 mg twice daily or placebo was added to nimesulide (a nonsteroidal antiinflammatory drug) in 36 patients with OA of the knee in a randomized, double‐blind, placebo‐controlled trial over a 5‐month period.

Results

The 30% improvement rate at 20 weeks was higher in the colchicine group than in the control group receiving placebo, as measured by total Western Ontario and McMaster University Osteoarthritis scores (57.9% versus 23.5%) and visual analog scale for index knee pain (52.6% versus 17.6%) (primary measures of response). The significance persisted on combined analysis by Mantel‐Haenszel test (P = 0.062). Comparison of means also showed significant improvement in the colchicine group versus the control group in a multivariate analysis performed using T² test (P = 0.0115).

Conclusion

Among patients with OA of the knee, the group receiving colchicine plus nimesulide exhibited significantly greater symptomatic benefit at 20 weeks than did the control group receiving nimesulide plus placebo.

     

Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee.

Methods

Patients with OA of the knee were enrolled in a multicenter, double‐blind, placebo‐controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients.

Results

Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half‐life of anakinra in serum after intraarticular injection was ∼4 hours.

Conclusion

Anakinra was well tolerated as a single 50‐mg or 150‐mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

     

Effect of simplification from protease inhibitors to boosted atazanavir‐based regimens in real‐life conditions

Background

Atazanavir (ATV) boosted with ritonavir (ATV/r) is a potent, well‐tolerated, once‐daily protease inhibitor (PI). Few data are available on this agent as a treatment simplification option for patients taking other PIs.

Objective

The aim of the study was to determine the effectiveness and safety of ATV‐containing regimens in patients who have simplified their antiretroviral treatment.

Methods

SIMPATAZ was a multicentre, prospective, noninterventional study in patients who had undetectable HIV RNA on their current PI‐containing therapy and who were switched to an ATV/r‐based regimen. Patients underwent a routine physical examination, and data were collected on HIV RNA levels, CD4 cell counts, liver function, lipid parameters, adverse reactions, adherence to treatment and patient satisfaction.

Results

A total of 183 patients were enrolled in the study and included in the analysis (80% were male, 29% had AIDS, and 52% were coinfected with HIV and hepatitis B virus or hepatitis C virus). The median baseline CD4 count was 514 cells/μL. Median exposure to previous HIV therapy was 8 years, and 32% of patients had a history of PI failures. Lopinavir boosted with ritonavir was the most frequent PI replaced (62%) and tenofovir+lamivudine /emtricitabine the backbone most used during the study (29%). The study drug was discontinued early by 25 patients (14%), two of whom discontinued as a result of adverse events (Hodgkin lymphoma and vomiting). Two patients died (lung cancer and myocardial infarction). At month 12, 93% of the study population had an undetectable HIV RNA viral load. Hyperbilirubinaemia >3 mg/dL and increased alanine aminotransferase levels>200 IU/L were observed in 38.5% and 4.4% of patients, respectively. Median changes from baseline to month 12 in total cholesterol, triglycerides and low‐density lipoprotein cholesterol were ?13 mg/dL (?7%; P<0.0001), ?19 mg/dL (?13%; P<0.0001) and ?7 mg/dL (?6%; P=0.021), respectively.

Conclusions

In a real‐world setting, switching from other PIs to ATV/r is a well‐tolerated and safe option for improving the lipid profile and for retaining virological response in controlled pretreated patients.

     

Peripheral blood T lymphocytes from patients with early rheumatoid arthritis express RANKL and interleukin‐15 on the cell surface and promote osteoclastogenesis in autologous monocytes

Objective

To investigate the osteoclastogenic potential of T cells from the peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) on autologous monocytes, and to study the cytokines implicated in this process.

Methods

T cells and monocytes were isolated from the PB of 20 healthy subjects and 20 patients with early RA, and from the SF of 20 patients with established RA. Autologous T cell/monocyte cocultures were established in the absence of exogenous cytokines or growth factors in order to examine spontaneous ex vivo osteoclast differentiation by tartrate‐resistant acid phosphatase staining and calcified matrix resorption activity.

Results

Surface RANKL was expressed on freshly isolated T cells from the PB of patients with early RA and the SF of patients with established RA. In addition, surface interleukin‐15 (IL‐15) was detected on freshly isolated T cells and monocytes from the PB of patients with early RA and the SF of patients with established RA. Autologous T cell/monocyte cocultures derived from the SF of patients with established RA and from the PB of patients with early RA, but not from the PB of healthy controls, resulted in osteoclast differentiation that was significantly inhibited by osteoprotegerin (OPG) and by neutralizing monoclonal antibodies to IL‐15, IL‐17, tumor necrosis factor α (TNFα), and IL‐1β. OPG, anti‐TNFα, and anti–IL‐1β demonstrated a cooperative inhibitory effect. At 1‐year followup, surface RANKL and IL‐15 and ex vivo osteoclastogenesis were no longer observed on PB T cells or monocytes from patients with early RA in whom clinical remission had been achieved with treatment.

Conclusion

T cells are important contributors to the pathogenesis of bone erosions in RA through interaction with osteoclast precursors of the monocyte/macrophage lineage.

     

Development of the tight‐skin phenotype in immune‐deficient mice

Objective

To determine if cutaneous thickening, a major phenotypic feature of the tight‐skin (Tsk) mutation, could develop in an immune‐deficient mouse.

Methods

Experimental crosses among different strains of mice were conducted to create mice that were genetically Tsk/+, and that were also homozgyous for a mutation at the Prkdc^scid locus and thus lacked mature T and B lymphocytes. Skin samples prepared from experimental and control genotypic groups of mice were evaluated for skin thickness.

Results

The data showed that the Tsk/+ mice developed the Tsk phenotype in the absence of a functional immune system.

Conclusion

Mature T and B cells are not required for the development of the cutaneous thickening in mice carrying the Tsk mutation.

     

A randomized,placebo‐controlled,double‐masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA).

Methods

Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of ≥1+ or requiring topical corticosteroid ≥3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open‐label etanercept for an additional 6 months.

Results

Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo‐treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept‐treated and 2 of the 5 placebo‐treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58).

Conclusion

In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.

     

JNK‐1 deficiency limits macrophage‐mediated antigen‐induced arthritis

Objective

To elucidate the nonredundant roles of JNK‐1 and JNK‐2 in antigen‐induced arthritis (AIA).

Methods

Mice that were genetically disrupted in Jnk1 or Jnk2 were primed by injection of methylated bovine serum albumin (mBSA) in Freund's complete adjuvant and then challenged on day 21 by intraarticular injection of mBSA into the right knee. Bone marrow chimeras were generated and similarly treated. Joints were harvested and prepared for histologic assessment. T cell responses were verified by cytokine and proliferation responses, and relative immunoglobulin responses were measured by enzyme‐linked immunosorbent assay. Cytokine messenger RNA expression levels were measured by quantitative polymerase chain reaction analysis. Thioglycollate‐elicited and zymosan A–elicited macrophage recruitment was tested in vivo, and cell migration was tested in vitro. The peptide inhibitor D‐JNKi was injected daily starting 4 days after intraarticular injection of mBSA into wild‐type (WT) mice, and inflammation was scored histologically.

Results

JNK‐1–deficient, but not JNK‐2–deficient, mice had a reduction in inflammatory cell infiltration and joint damage. This effect was primarily restricted to hematopoietic cells, but B and T cell responses were preserved in mBSA‐injected mice. JNK‐1–deficient macrophages produced cytokines and chemokines at a level comparable to that in their WT counterparts. However, macrophage migration was impaired in vivo and in vitro. Targeting JNK with the peptide inhibitor D‐JNKi dramatically reduced inflammation and joint destruction in WT mice.

Conclusion

AIA is dependent on JNK‐1, but not JNK‐2. JNK‐1 is a promising molecular target for reducing autoimmune inflammation, since its inhibition impairs macrophage migration.

     

The relationship between self‐report and performance‐related measures: Questioning the content validity of timed tests

Objective

To examine the determinants of the modest correlation between self‐report and performance‐related measures in patients with osteoarthritis of the hip or knee.

Methods

Measures included the Lower Extremity Functional Scale (LEFS), the self paced walk, timed up‐and‐go, and stair test. Each performance measure consisted of 3 domains: time, pain (visual analog scale), and exertion (Borg scale). Activity specificity was assessed by examining correlations between the LEFS with single activity and multiple activity time scores. Domain specificity was examined by comparing correlations between the LEFS and single and multiple domain scores. The impact of measurement error was considered.

Results

Increasing the number of activity time scores had no effect. Forming a composite performance score based on time, pain, and exertion substantially increased the correlation from 0.44 (composite timed score) to 0.59 (pooled domain and activity score) (P = 0.009).

Conclusion

Performance scores based on time alone appear to inadequately represent the breadth of health concepts associated with functional status.

     

Etanercept therapy in children with treatment‐resistant uveitis

Objective

To evaluate the safety and efficacy of the tumor necrosis factor fusion protein etanercept in children with treatment‐resistant uveitis.

Methods

Ten children with chronic active uveitis (7 girls and 3 boys, mean age 7.5 years [range 3–12 years]) were enrolled in this prospective study. In 7 children, uveitis was associated with pauciarticular juvenile rheumatoid arthritis. Five children were antinuclear antibody positive. All patients had failed previous therapy with topical steroids and methotrexate and/or cyclosporine. All were treated with etanercept at a dosage of 0.4 mg/kg twice weekly for the first 3 months, and then, if eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg) for at least 3 additional months.

Results

At the beginning of the trial, uveitis affected 18 eyes in the 10 children. Within 3 months, 10 of 16 affected eyes (63%; P = 0.017) showed a rapid decrease in anterior chamber cell density, including remission of uveitis in 4 eyes. In children with visual acuity of less than 20/25, 4 of 10 eyes (40%) improved. An exacerbation of uveitis during etanercept therapy occurred in only 1 child (1 of 14 eyes [7%]). Other ocular outcome parameters, such as intraocular pressure, synechia formation, and lens clarity, remained unchanged. Following a dosage increase to an average of 1.1 mg/kg after 3 months in 7 children, no further improvement was noted.

Conclusion

Our data suggest that etanercept injected subcutaneously twice a week has a beneficial effect on treatment‐resistant chronic uveitis in children. Further controlled studies with etanercept in systemic or topical form are necessary to confirm its efficacy and optimal mode of administration.

     

Coinfection with hepatitis C virus,oxidative stress and antioxidant status in HIV‐positive drug users in Miami*

Background

The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV‐coinfected and HIV‐monoinfected adults.

Methods

Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB‐4) markers were calculated.

Results

Significant differences were found between HIV/HCV‐coinfected and HIV‐monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB‐4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV‐coinfected participants than in the HIV‐monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB‐4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=?0.00581; P=0.0417) as APRI increased.

Conclusion

HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.

     

Anaerobic exercise capacity in patients with juvenile‐onset idiopathic inflammatory myopathies

Objective

To 1) report the feasibility of an “all‐out” 30‐second cycling exercise test (Wingate Anaerobic Exercise Test [WAnT]) in juvenile‐onset idiopathic inflammatory myopathy (JIIM) patients, 2) describe the anaerobic exercise capacity in juvenile dermatomyositis patients, and 3) determine if the anaerobic exercise capacity could be related to disease duration or disease phase.

Methods

Twenty patients (age 14.13 ± 5.4 years) with JIIM participated in this study. All patients were able to perform the WAnT without adverse events.

Results

Comparison with healthy controls revealed a ?29.3 ± 26.58% (P = 0.001) and ?27.6 ± 25.7% (P = 0.002) impairment in mean power and peak power on the WAnT, respectively. The WAnT correlated with disease phase and with knee extensor muscle strength.

Conclusion

The WAnT might be a valuable adjunct next to other assessment tools in the followup of JIIM patients.