Longitudinal Open-label Study Research Articles

Deep brain stimulation in multiple sclerosis-associated tremor. A large, retrospective, longitudinal open label study, with long-term follow-up.

Tremor affects up to 25%-58% in multiple sclerosis (MS) population. Deep-brain stimulation (DBS) of the ventral-intermediate nucleus (VIM) of the thalamus is considered as a potential option following medical treatments. Long term DBS efficacy is not well known in these patients with a poor outcome mostly related to disease progression. To report a large and retrospective study of thalamic DBS in MS tremor. We conducted a large and retrospective study of patients with MS disabling and pharmacologically resistant upper limb tremor, who underwent thalamic DBS procedure from January 1992 to January 2015 in University Hospital of Henri Mondor, France. Demographic data, clinical assessment and activity daily living were collected. A three-month and twelve-month post-operative assessment with clinical and functional rating scales have been achieved, as well as long term follow-up for most patients. One hundred and four patients underwent DBS procedure. There were 71 female (68%) and 33 male (32%). At three-month post-operative assessment, 64% patients were improved clinically and functionally. Among these, 93% of patients kept a good efficacy at one-year post-operative assessment. Mean duration of follow-up for these patients was 6 years. We described a long-term sustained clinical and functional improvement in this large and retrospective report of thalamic DBS. This neuromodulation approach could be a therapeutic option for all severe upper extremity refractory tremor in MS patients.

Saffron: A Multitask Neuroprotective Agent for Retinal Degenerative Diseases.

Both age related macular degeneration (AMD) and light induced retinal damage share the common major role played by oxidative stress in the induction/progression of degenerative events. Light damaged (LD) rats have been widely used as a convenient model to gain insight into the mechanisms of degenerative disease, to enucleate relevant steps and to test neuroprotectants. Among them, saffron has been shown to ameliorate degenerative processes and to regulate many genes and protective pathways. Saffron has been also tested in AMD patients. We extended our analysis to a possible additional effect regulated by saffron and compared in AMD patients a pure antioxidant treatment (Lutein/zeaxanthin) with saffron treatment. Methods: Animal model. Sprague-Dawley (SD) adult rats, raised at 5 lux, were exposed to 1000 lux for 24 h and then either immediately sacrificed or placed back at 5 lux for 7 days recovery period. A group of animals was treated with saffron. We performed in the animal model: (1) SDS-PAGE analysis; (2) Western Blotting (3) Enzyme activity assay (4) Immunolabelling; in AMD patients: a longitudinal open-label study 29 (±5) months in two groups of patients: lutein/zeaxanthin (19) and saffron (23) treated. Visual function was tested every 8 months by ERG recordings in addition to clinical examination. Results: Enzymatic activity of MMP-3 is reduced in LD saffron treated retinas and is comparable to control as it is MMP-3 expression. LD treated retinas do not present “rosettes” and microglia activation and migration is highly reduced. Visual function remains stable in saffron treated AMD patients while deteriorates in the lutein/zeaxanthin group. Conclusion: Our results provide evidence of an additional way of action of saffron treatment confirming the complex nature of neuroprotective activities of its chemical components. Accordingly, long term follow-up in AMD patients reveals an added value of saffron supplementation treatment compared to classical antioxidant protocol.

Efficacy and Safety of Hepatitis B Vaccination in Rheumatoid Arthritis Patients Receiving Disease-Modifying Antirheumatic Drugs and/or Biologics Therapy.

The aims of this study were to assess efficacy and safety of the hepatitis B vaccination in rheumatoid arthritis (RA) patients receiving conventional and/or biological disease-modifying antirheumatic drugs (DMARDs). A longitudinal open-label study was conducted. Of 46 RA patients, 33 received only conventional synthetic DMARDs, and 13 received both conventional synthetic DMARDs and biological DMARDs, and 9 healthy age- and sex-matched control subjects were vaccinated with 20 μg recombinant hepatitis B vaccine (EuVax B) at weeks 0, 4, and 24. Hepatitis B surface antibody levels were measured 8 weeks after the last dose of vaccination. Seroprotection was defined as hepatitis B surface antibody level of 10 mIU/mL or greater. Disease Activity Score in 28 Joints scores were recorded at weeks 0, 4, and 32 in 46 RA patients who received hepatitis B vaccination and 47 treatment-matched RA patients who did not receive it. Adverse events were recorded at each visit.Statistical analyses were performed using SPSS version 16.0. Seroprotection was lower in the RA patients than in the control subjects (64% vs. 100%, p = 0.045). Patients receiving biological DMARDs and conventional DMARDs had a lower proportion of seroprotection compared with the control group (50% vs. 100% [p = 0.02] and 69.7% vs. 100% [p = 0.09], respectively). Among RA patients, responders were younger than nonresponders with a mean age of 57.5 (SD, 9.0) years and 64.9 (SD, 10.9) years (p = 0.04) and less likely to be treated with rituximab (6.9% vs. 37.5%, p = 0.01). Overall, hepatitis B vaccination was well tolerated. The rate of RA flare was not increased after hepatitis B vaccination. Patients with RA receiving DMARDs had less humoral response to hepatitis B vaccination as compared with control subjects. Aging and rituximab use were associated with impaired response to hepatitis B vaccination. Hepatitis B vaccination is safe and well tolerated in RA patients.

Low Doses of Etanercept Can Be Effective to Maintain Remission in Psoriatic Arthritis Patients.

We realized a longitudinal open-label study to determine if increasing intervals between etanercept (ETN) administration could be effective in maintaining remission with a stable dose in a patient population affected by psoriatic arthritis (PsA) who had achieved sustained remission with ETN 25 mg biweekly. Fifty-four PsA patients were recruited at the Rheumatology Unit of Azienda Ospedaliera Universitaria Senese. Patients, who were in clinical sustained remission with biweekly ETN 25 mg at weeks 12 and 16, and were switched to a weekly regimen. If clinical remission persists at weeks 24 and 28, patients were switched to an every-other-week regimen, continuing with this administration schedule for the entire duration of the study if at weeks 36 and 40 clinical remission was maintained. If, on the contrary, in one of the check there was an increase in disease activity, the therapeutic scheme returned to the previous one. The results of our study indicate that a consistent percentage (72%) of subjects with PsA, achieving a sustained remission with ETN 25 mg biweekly, maintains a remission, after a year of starting therapy, despite a progressive dose reduction by an increase in the dosing interval, 21% with a weekly regimen and 51% with an every-other-week regimen. Our results show that the main reasons that hinder the dosing interval increase in ETN in PsA patients in sustained clinical remission at standard doses are peripheral polyarthritis pattern and exacerbation of cutaneous manifestations.

Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients

In chronic kidney disease (CKD) patients, the ability to excrete a phosphate load is impaired. Compensatory increase in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) promote phosphaturia. Serum FGF23 concentration is considered an early biomarker of excess phosphate load and high levels of FGF23 have been associated with increased mortality. In the present study, we have evaluated the changes in plasma FGF23 after treatment with the phosphate binder lanthanum carbonate in patients with CKD-3 and a normal serum phosphate concentration. Eighteen Caucasian CKD Stage 3a/3b patients with serum phosphate <4.5 mg/dL were recruited in a prospective longitudinal open-label study. Patients received a 4-week period of standardized phosphorus-restricted diet containing 0.8 g/Kg/day protein. Thereafter, the same diet was maintained and patients received lanthanum carbonate (750 mg with the three main meals) for 4 weeks. No significant changes were observed in serum phosphate, however, lanthanum carbonate significantly decreased urinary excretion of phosphate and fractional excretion of phosphate (P < 0.004). This was accompanied by a significant decrease in carboxyterminal FGF23 (median percent change from baseline -21.8% (interquartile range -4.5, -30%), P = 0.025). No changes were observed in PTH. In conclusion, lanthanum carbonate reduced phosphate load, as assessed by urinary phosphate excretion, and also reduced plasma FGF23 in CKD-3 patients. This occurs in the presence of unchanged normal serum phosphate levels.

Open-Label, Longitudinal Study of Tamsulosin for Functional Bladder Outlet Obstruction in Women

Objectives: To investigate the clinical effect of tamsulosin for the treatment of functional bladder outlet obstruction (BOO) in adult women. Methods: In a prospective, longitudinal open-label study, 63 women affected by functional BOO were treated with tamsulosin. Inclusion criteria were: age >18 years, reporting voiding symptoms (intermittent stream, hesitancy, straining and/or a feeling of incomplete emptying), uroflowmetry maximum flow rate (Q_max) under 12 ml and/or presence of postvoid residual greater than 50% of the voiding volume. Exclusion criteria were: patients suffering from any other anatomical or functional disorder such as urethral stenosis, pelvic organ prolapse, neurological disturbances, or systemic diseases that could impact upon bladder voiding. Tamsulosin was administered in a single daily dose of 0.4 mg for at least 30 days. Primary outcomes were clinical efficacy and Q_max improvement; secondary outcomes were tolerability and safety. Voiding and storage symptoms and uroflowmetry results were assessed before and at the end of the α-blocker therapy. Results: Tamsulosin therapy was well tolerated. After therapy voiding symptoms improved in 71.4% of patients (45/63; p < 0.0001), and if associated with storage symptoms in 66.67% (26/39; p < 0.00001). Recurrent infections were reduced by 50% in 81% (21/26) of patients. Uroflowmetry parameters improved in 36/63 patients (57.1%). Postvoiding residue improved in 62.5% (10/16) and disappeared in 25% (4/16) with no significant changes in voided volume. An improvement was observed in 66% (16/24) of patients with isolated voiding symptoms, in 51.2% (20/39) with associated storage symptoms and in 65% (17/26) of women with associated recurrent urinary infections. Conclusions: These results suggest that α-blocker may be an effective treatment option in women with voiding dysfunction due to functional BOO.

Reliability of different Doppler ultrasound quantification methods and devices in the assessment of therapeutic response in arthritis

To evaluate the metric qualities of power Doppler ultrasound (PDUS) for different quantification methods and devices in the assessment of arthritis during anti-inflammatory treatment. Twenty-four patients with active arthritis and first-time treatment with the TNF-alpha inhibitor adalimumab underwent sequential clinical, laboratory and US examination at baseline, weeks 2, 6 and 12. 2D and 3D PDUS was performed by two independent investigators. The images and movies were scored from 0 to 3 and the amount of colour pixels and voxels was calculated. In addition, the resistance index of a synovial artery was measured. Thirteen patients were examined with a second US machine. Treatment response was already observed at week 2 with a significant reduction of 2D (P < 0.01) and 3D scores (P < 0.001). A moderate correlation to 28-joint disease activity score was found for 3D voxel count (r(s) = 0.35, P < 0.001). Interobserver agreement was kappa or ICC >or= 0.8 for all methods except the resistance index (ICC = 0.60). Intermachine agreement was kappa = 0.57 for 2D PDUS score. The study demonstrates good to excellent interobserver and moderate intermachine reliability of different PDUS assessment methods in a longitudinal open-label study.

Acute and chronic neuroendocrine effects of interferon‐β 1a in multiple sclerosis

Treatment of multiple sclerosis with interferon-beta (IFN-beta) results in variable responses interindividually. Cytokine-hormone interactions may modulate the therapeutic effects of IFN-beta. Since hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis and other neuroendorine disturbances occur in multiple sclerosis, we determined the detailed neuroendocrine response of patients with multiple sclerosis to IFN-beta. Longitudinal open-label study. Eight patients with relapsing-remitting multiple sclerosis (four women, age 31.9 +/- 1.5 years, EDSS 1.5-2.5). Plasma ACTH, cortisol, prolactin, GH, TSH, LH and FSH were determined in 30-min intervals during 8 h on four occasions: after intramuscular injection of saline; after the first dose of IFN-beta 1a; after the second IFN-beta dose with oral indomethacin pretreatment; and after 3 months of IFN-beta therapy. Dexamethasone-corticotropin-releasing hormone test was performed before and at 3 months on IFN-beta. Compared to saline, IFN injection resulted in marked rise in plasma ACTH (mean, 370% of baseline), cortisol (214%), prolactin (253%) and GH (756%), between 2 and 6 h after injection. With indomethacin, hormone secretion occurred with reduced peak values. Endocrine response adapted partially after 3 months of treatment. HPA axis activity decreased in most patients, but increased in one patient with frequent relapses. Marked neuroendocrine effects occur in response to IFN-beta in multiple sclerosis. Upon prolonged treatment, these effects partially adapt, and HPA axis hyperactivity is reduced. Prospective studies to determine the relation to individual treatment response can be based on these findings.

First-line therapy with latanoprost 0.005% results in improved ocular circulation in newly diagnosed primary open-angle glaucoma patients: a prospective, 6-month, open-label study

To evaluate the effect of latanoprost 0.005% on the optic nerve head (ONH) and retinal circulation of newly diagnosed and previously untreated primary open-angle glaucoma (POAG) patients. Twenty-two newly diagnosed and previously untreated POAG patients (mean age+/-SD: 68.38+/-11.92 years) were included in this longitudinal open-label study. Patients were treated with latanoprost 0.005% once a day. Intraocular pressure (IOP), systemic blood pressure (BP), mean ocular perfusion pressure (MOPP), and ocular perfusion parameters 'volume', 'velocity', and 'flow' measured at the optic nerve head (ONH) and retina by means of Heidelberg Retina Flowmeter system were evaluated during a 6-month follow-up period. Treatment with latanoprost 0.005% resulted in a significant decrease in IOP (P<0.0001) and increase in MOPP (P<0.0001). After correcting for changes in MOPP, the blood velocity measured at the ONH level was significantly higher after 6 months of treatment than at baseline (P=0.0310). In addition, blood volume and flow measured at the peripapillary retina level improved after 3 and 6 months of treatment (P=0.0170; P=0.0260, and P=0.0170; P=0.0240 respectively). Previously untreated POAG patients exhibit reduced IOP, increased MOPP and improved ocular perfusion at the ONH and retina levels when treated with Latanoprost 0.005%. These effects could be beneficial for glaucoma patients suffering from ocular vascular dysregulation.

Cardiovascular Risk Factors in Acromegaly before and after Normalization of Serum IGF-I Levels with the GH Antagonist Pegvisomant

Acromegaly is associated with premature cardiovascular mortality. GH replacement therapy decreases inflammatory markers of cardiovascular risk, but little is known about these markers in patients with acromegaly. The GH receptor antagonist, pegvisomant, reduces IGF-I levels in 98% of patients treated. We investigated the effects of GH receptor blockade on inflammatory and other cardiovascular risk markers in active acromegaly. Forty-eight patients with acromegaly and 47 age- and body mass index-matched controls were included. The study consisted of 3 parts: a cross-sectional study, a prospective randomized 12-wk placebo-controlled study, and a longitudinal open-label study of up to 18 months of pegvisomant treatment. After baseline evaluation, patients with acromegaly were randomized to placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) daily pegvisomant for 12 wk. Subsequently, all patients received at least 10 mg pegvisomant daily for up to 18 months, with dose adjustments to achieve a normal IGF-I level. Anthropometry, GH, IGF-I, and pegvisomant levels were measured monthly. C-reactive protein (CRP), IL-6, homocysteine, lipoprotein(a), glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were determined at baseline, 4 and 12 wk in the placebo-controlled study and at 3-month intervals (during which IGF-I levels were normal) in the longitudinal study. In the cross-sectional study, patients had lower CRP than did controls [median, 0.3 (range, 0.2–0.8) vs. 2.0 (0.6–3.7) mg/liter; P < 0.0001] and had higher insulin [78.6 (55.8–130.2) vs. 54.5 (36.6–77.5) pm, P = 0.0051]. IL-6, homocysteine, triglycerides, lipoprotein(a), LDL cholesterol and HDL cholesterol were not different between groups. In the placebo-controlled study, CRP increased in patients treated with 20 mg pegvisomant, compared with placebo (mean ± sem, 13.7 ± 3.6 vs. 0.5 ± 3.3 mg/liter; P = 0.010). There were no significant differences in IL-6, homocysteine, glucose, insulin, triglyceride, total cholesterol, LDL cholesterol and HDL cholesterol levels. In the longitudinal open-label study (median duration, 15.6 months), CRP increased by 2.0 ± 0.5 mg/liter (P = 0.0002). Total cholesterol and triglycerides increased (0.22 ± 0.11 mm, P = 0.050; and 0.25 ± 0.09 mm, P = 0.007, respectively), whereas lipoprotein(a) decreased (−70 ± 33 mg/liter, P = 0.039). Glucose, insulin, homocysteine, HDL cholesterol, and IL-6 did not change. We conclude that patients with active acromegaly have lower CRP and higher insulin levels than healthy controls. Administration of pegvisomant increases CRP levels. We propose that GH secretory status is an important determinant of serum CRP levels, although additional studies are needed to determine the mechanism and significance of this finding.