Saaeha Rauz

Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study

Objective: Primary Sjögren syndrome (pSS) causes significant systemic symptoms including fatigue as well as glandular dysfunction. There are currently no effective systemic therapies; however, open label series have suggested that rituximab may be beneficial for systemic and glandular manifestations. Therefore, we performed a double blind, placebo-controlled, randomised pilot study of the efficacy of rituximab in reducing fatigue in pSS. Methods: A total of 17 patients with pSS and a score on fatigue visual analogue scale (VAS) >50 were randomised to receive either 2 infusions of rituximab 1 g or placebo; patients also received oral and intravenous steroids. Outcome measures included: the proportion of patients with >20% reduction in fatigue VAS, changes in pSS related symptoms, health related quality of life and immunological parameters of pSS. These were measured 6 months after therapy. Results: There was significant improvement from baseline in fatigue VAS in the rituximab group (p<0.001) in contrast to the placebo group (p = 0.147). There was a significant difference between the groups at 6 months in the social functioning score of SF-36 (p = 0.01) and a trend to significant difference in the mental health domain score of SF-36 (p = 0.06). There was one episode of serum sickness in the rituximab treated group. Conclusions: This is the first double blind study of rituximab in pSS to show benefit; further studies are justified.

Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study

Objective To observe intracranial pressure in women with idiopathic intracranial hypertension who follow a low energy diet. Design Prospective cohort study. Setting Outpatient department and the clinical research facility based at two separate hospitals within the United Kingdom. Participants 25 women with body mass index (BMI) >25, with active (papilloedema and intracranial pressure >25 cm H2O), chronic (over three months) idiopathic intracranial hypertension. Women who had undergone surgery to treat idiopathic intracranial hypertension were excluded. Intervention Stage 1: no new intervention; stage 2: nutritionally complete low energy (calorie) diet (1777 kJ/day (425 kcal/day)); stage 3: follow-up period after the diet. Each stage lasted three months. Main outcome measure The primary outcome was reduction in intracranial pressure after the diet. Secondary measures included score on headache impact test-6, papilloedema (as measured by ultrasonography of the elevation of the optic disc and diameter of the nerve sheath, together with thickness of the peripapillary retina measured by optical coherence tomography), mean deviation of Humphrey visual field, LogMAR visual acuity, and symptoms. Outcome measures were assessed at baseline and three, six, and nine months. Lumbar puncture, to quantify intracranial pressure, was measured at baseline and three and six months. Results All variables remained stable over stage 1. During stage 2, there were significant reductions in weight (mean 15.7 (SD 8.0) kg, P<0.001), intracranial pressure (mean 8.0 (SD 4.2) cm H2O, P<0.001), score on headache impact test (7.6 (SD 10.1), P=0.004), and papilloedema (optic disc elevation (mean 0.15 (SD 0.23) mm, P=0.002), diameter of the nerve sheath (mean 0.7 (SD 0.8) mm, P=0.004), and thickness of the peripapillary retina (mean 25.7 (SD 36.1) µ, P=0.001)). Mean deviation of the Humphrey visual field remained stable, and in only five patients, the LogMAR visual acuity improved by one line. Fewer women reported symptoms including tinnitus, diplopia, and obscurations (10 v 4, P=0.004; 7 v 0, P=0.008; and 4 v 0, P=0.025, respectively). Re-evaluation at three months after the diet showed no significant change in weight (0.21 (SD 6.8) kg), and all outcome measures were maintained. Conclusion Women with idiopathic intracranial hypertension who followed a low energy diet for three months had significantly reduced intracranial pressure compared with pressure measured in the three months before the diet, as well as improved symptoms and reduced papilloedema. These reductions persisted for three months after they stopped the diet.

NMR‐based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases – a diagnostic tool?

We sought to evaluate the diagnostic accuracy of metabolomic biomarker profiles in neurological conditions (idiopathic intracranial hypertension (IIH), multiple sclerosis (MS) and cerebrovascular disease (CVD) compared to controls with either no neurological disease or mixed neurological diseases).

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common γ-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

Evaluation of foldable intraocular lenses in patients with uveitis

OBJECTIVE To evaluate various foldable posterior chamber intraocular lenses (IOLs) after phacoemulsification in patients with uveitis. DESIGN A prospective, noncomparative, interventional case series. PARTICIPANTS Forty-nine consecutive patients (60 eyes) with various types of uveitis (anterior, n = 20; posterior, n = 1; panuveitis, n = 37, intermediate, n = 2). INTERVENTION All patients underwent phacoemulsification with foldable posterior chamber IOL implantation. All eyes were free of active inflammation at the time of surgery. A variety of IOL biomaterials were implanted: acrylic (n = 30), silicone (n = 17), and hydrogel (n = 13). MAIN OUTCOME MEASURES Detailed examination was performed by one masked observer. Several parameters were compared for each implant biomaterial, including level of best corrected Snellen visual acuity at final follow-up, presence of posterior synechiae, anterior capsular phimosis, posterior capsule opacification, and the degree of cellular deposits on the IOL optic. RESULTS There were 26 males and 23 females, aged 9 to 83 years (mean, 48 years). Follow-up ranged from 1 to 33 months (mean, 17.03 months). At final follow-up, 56 eyes (93.3%) had an improvement in visual acuity compared with preoperative levels as follows: 34 eyes (56.6%) achieved an improvement of four or more Snellen lines, and 44 eyes (73.3%) achieved 20/30 or better. Giant cells, observed on the IOL optic in 19 eyes (31.7%), were most often seen on the acrylic biomaterial at the 1-month follow-up, although this was not found to be statistically significant. Scratch marks produced by the lens-introducing forceps were seen in 24 eyes (40.0%), mainly on the acrylic and hydrogel optics. Posterior capsule opacification (PCO) occurred in 49 eyes (81.7%), with only 5 eyes requiring laser capsulotomy. There was no association between PCO and the various lens biomaterials. Other causes for reduced visual acuity included glaucomatous optic neuropathy (n = 5) and cystoid macular edema (n = 8). CONCLUSIONS The use of foldable IOLs in eyes with uveitis is safe, but the optimal biomaterial has yet to be found.

Exploring the pathogenesis of IIH: An inflammatory perspective

Idiopathic intracranial hypertension (IIH) is a common blinding condition amongst the young obese female population (20 per 100,000) characterised by elevated intracranial pressure (ICP). The aetiology of IIH is not known. In this review we explore the literature investigating the pathogenesis of IIH and suggest additional hypotheses. Chronic inflammation is emerging as an aetiological factor in the pathogenesis of obesity and we propose that this may be a feature of IIH. Obesity is also related to dysregulation of cortisol production by the pre-receptor enzyme, 11beta-hydroxysteroid dehydrogenase, and we speculate that this may have a role in the pathogenesis of obesity and raised ICP seen in IIH.

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

Objective  The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well‐recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH.

Cerebrospinal Fluid Corticosteroid Levels and Cortisol Metabolism in Patients with Idiopathic Intracranial Hypertension: A Link between 11β-HSD1 and Intracranial Pressure Regulation?

CONTEXT The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. OBJECTIVE The aim was to characterize 11β-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11β-HSD1 activity after therapeutic weight loss in IIH. DESIGN AND SETTING We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. PATIENTS OR OTHER PARTICIPANTS Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. INTERVENTION Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. MAIN OUTCOME MEASURES Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. RESULTS 11β-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2±7.8 kg; P<0.001), global 11β-HSD1 activity decreased (P=0.001) and correlated with reduction in intracranial pressure (r=0.504; P=0.028). CSF and serum glucocorticoids remained stable, although the change in CSF cortisone levels correlated with weight loss (r=-0.512; P=0.018). CONCLUSIONS Therapeutic weight loss in IIH is associated with a reduction in global 11β-HSD1 activity. Elevated 11β-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11β-HSD1 in IIH is needed, our results suggest that 11β-HSD1 inhibition may have therapeutic potential in IIH.

Patient-reported outcomes in primary Sjögren's syndrome: comparison of the long and short versions of the Profile of Fatigue and Discomfort—Sicca Symptoms Inventory

OBJECTIVES The long-form 64-item Profile of Fatigue and Discomfort--Sicca Symptoms Inventory (PROFAD-SSI) questionnaire was developed as a patient-reported assessment tool for use in primary SS (PSS) and other rheumatic disorders. In this study, we assess whether the (shorter and more practical) 19-item PROFAD-SSI-SF (short form) gives similar results and whether a still briefer version using visual analogue scales (VASs) is feasible. METHODS Questionnaire surveys comprising the long and short versions of the PROFAD-SSI were mailed to 43 patients with PSS and 50 patients with RA, who were asked to complete these contemporaneously as well as repeating the process 1 month later. PSS patients also completed a series of VASs comprising fatigue and sicca domains of the SSI. RESULTS Surveys were returned from 35 PSS patients and 35 RA patients. All domains of the long- and short-form PROFAD-SSI showed strong correlations (Spearman rho between 0.779 and 0.996, P < 0.01). Factor analysis generally confirmed the previously validated domain structure with Cronbachs alpha = 0.99. The PROFAD-SF somatic fatigue domain correlated more strongly with a fatigue VAS than did the mental fatigue domain. The SSI-SF domain scores correlated with equivalent VAS scores. CONCLUSION The long- and short-form PROFAD-SSI questionnaires correlate closely suggesting that the PROFAD-SF is valid as an outcome tool. Preliminary data also suggest that an even briefer form with compression of the domains into single VAS is also feasible.

The TRACTISS Protocol: a randomised double blind placebo controlled clinical TRial of Anti-B-Cell Therapy In patients with primary Sjögren's Syndrome

BackgroundPrimary Sjögren’s Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 – 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.Methods/designTRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.DiscussionThe TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.Trial registrationUKCRN Portfolio ID:9809 ISRCTN65360827.