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ID PMID Title PublicationDate abstract
18452607 Fatigue in osteoarthritis: a qualitative study. 2008 May 1 BACKGROUND: Fatigue is recognized as a disabling symptom in many chronic conditions including rheumatic disorders such as rheumatoid arthritis (RA) and lupus. Fatigue in osteoarthritis (OA) is not routinely evaluated and has only been considered in a very limited number of studies. To date, these studies have focused primarily on patients with OA under rheumatological care, which represent the minority of people living with OA. The purpose of this study was to increase our understanding of the fatigue experience in community dwelling people with OA. METHODS: In 2004, 8 focus groups were conducted with 28 men and 18 women (mean age 72.3) with symptomatic hip or knee OA recruited from a population-based cohort. Participants completed a self-administered questionnaire, which included demographics, measures of OA severity (WOMAC), depression (CES-D) and fatigue (FACIT). Sessions were audio taped and transcribed verbatim. Two researchers independently reviewed the transcripts to identify themes. Findings were compared and consensus reached. RESULTS: Mean pain, disability, depression and fatigue scores were 8.7/20, 27.8/68, 15.4/60, and 30.9/52, respectively. Participants described their fatigue as exhaustion, being tired and "coming up against a brick wall". Participants generally perceived fatigue as different from sleepiness and distinguished physical from mental fatigue. Factors believed to increase fatigue included OA pain and pain medications, aging, various types of weather and poor sleep. Mental health was identified as both affecting fatigue and being affected by fatigue. Participants described fatigue as impacting physical function, and their ability to participate in social activities and to do household chores. Rest, exercise, and avoiding or getting assistance with activities were cited as ways of coping. Participants generally did not discuss their fatigue with anyone except their spouses. CONCLUSION: Participants with OA described experiencing notable amounts of fatigue and indicated that it had a substantial impact on their lives. Further research is required to better understand the role of fatigue in OA in order to identify strategies to reduce its impact.
18420815 TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserv 2008 Apr 22 The newly identified tripartite motif (TRIM) family of proteins mediate innate immunity and other critical cellular functions. Here we show that TRIM21, which mediates the autoimmune diseases rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome, is a previously undescribed IgG receptor with a binding mechanism unlike known mammalian Fcgamma receptors. TRIM21 simultaneously targets conserved hot-spot residues on both Ig domains of the Fc fragment using a PRYSPRY domain with a preformed multisite interface. The binding sites on both TRIM21 and Fc are highly conserved to the extent that the proteins are functionally interchangeable through murine, canine, primate, and human species. Pre-steady-state analysis exposes mechanistic conservation at the level of individual residues, which make the same energetic and kinetic contributions to binding despite varying in sequence. Together, our results reveal that TRIM21 is a previously undescribed type of IgG receptor based on a non-Ig scaffold whose interaction at the fundamental level-structural, thermodynamic, and kinetic-is evolutionarily conserved.
18343027 Celastrol inhibits the growth of human glioma xenografts in nude mice through suppressing 2008 Jun 8 Celastrol, a compound purified from Tripterygium wilfordii whose preparations have been used for clinical treatment for rheumatoid arthritis, has been demonstrated to have antiangiogenic activity, and be inhibitory against mice tumor growth by a few recent studies. However, whether its antiangiogenic activity plays a role in the celastrol-mediated suppression of tumor growth and the molecular basis of anti-tumor activity are poorly understood. In this study, we found that celastrol inhibited the growth of human glioma xenografts in mice, which concurred with the suppression of angiogenesis. Interestingly, while celastrol had no effect on either the expression of VEGF or its mRNA levels, celastrol treatment lowered the expression levels of its receptors (VEGFR-1 and VEGFR-2) and their mRNA levels. These findings suggest that celastrol have potential to be used as an antiangiogenesis drug through its role in suppressing VEGF receptors expression that might consequently reduce the signal transduction between VEGF and VEGFR.
18289868 Unique expression of a small IL-32 protein in the Jurkat leukemic T cell line. 2008 Apr Interleukin (IL)-32 was recently identified as a new cytokine which induces various proinflammatory cytokines in human monocytes and macrophages. Therefore, IL-32 has been primarily studied in inflammatory models such as rheumatoid arthritis and inflammatory bowel diseases. The regulation of endogenous IL-32 in other immune cells remains unknown. In the present study, we stimulated Jurkat T cells with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) and examined IL-32 expression at both the mRNA and protein levels. All mRNAs of the four IL-32 isoforms and the 12-15 kDa IL-32 protein were independent of PHA and PMA stimulation, however a 9 kDa molecular weight IL-32 protein in the cell culture supernatant was induced by PHA and PMA after 16 h of stimulation. Compared to other human cell lines, the Jurkat cell line constitutively expressed a 12-15 kDa molecule of IL-32, which is smaller than the known IL-32 isoforms. We used IL-32 shRNA to examine the specificity of the 12-15 kDa molecule. Upon IL-32 shRNA transfection, the 12-15 kDa band was decreased specifically as compared to the control scrambled clone. Thus, the constitutive expression of IL-32 mRNA as well as the predominant production of a smaller sized IL-32 isoform in Jurkat cells may implicate a role for IL-32 in human T cell leukemia.
18252224 Simple and efficient analysis of disease association with missing genotype data. 2008 Feb Missing genotype data arise in association studies when the single-nucleotide polymorphisms (SNPs) on the genotyping platform are not assayed successfully, when the SNPs of interest are not on the platform, or when total sequence variation is determined only on a small fraction of individuals. We present a simple and flexible likelihood framework to study SNP-disease associations with such missing genotype data. Our likelihood makes full use of all available data in case-control studies and reference panels (e.g., the HapMap), and it properly accounts for the biased nature of the case-control sampling as well as the uncertainty in inferring unknown variants. The corresponding maximum-likelihood estimators for genetic effects and gene-environment interactions are unbiased and statistically efficient. We developed fast and stable numerical algorithms to calculate the maximum-likelihood estimators and their variances, and we implemented these algorithms in a freely available computer program. Simulation studies demonstrated that the new approach is more powerful than existing methods while providing accurate control of the type I error. An application to a case-control study on rheumatoid arthritis revealed several loci that deserve further investigations.
18240988 Burden of premenstrual dysphoric disorder on health-related quality of life. 2008 Jan OBJECTIVE: The purpose of this study was to document the burden of premenstrual dysphoric disorder (PMDD) on health-related quality of life (HRQoL) in comparison to the U.S. general population and specific chronic health conditions. METHODS: The disease burden that PMDD placed on HRQoL was estimated by comparing SF-12v2 scores between women who were identified as being at risk for PMDD with those observed in the general U.S. female population. Additional comparisons were made to several chronic health conditions. Regression methods were used to estimate SF-12v2 normative values from the general population sample and statistically adjust them to match age and the presence of disease comorbidity of the PMDD patient group. Significance tests were used to compare the means across samples. RESULTS: After adjusting for multiple comparisons, six SF-12v2 scales and two summary measures of PMDD were significantly below the adjusted U.S. general population norms. Both summary measures of PMDD had mean differences greater than 3 points below the norm (threshold for clinical meaningful difference). The burden of PMDD was greater on mental/emotional HRQoL domains than on physical HRQoL. The HRQoL burden of PMDD was (1) greater than that of chronic back pain in bodily pain and mental health (MH) scales and greater than type 2 diabetes and hypertension in bodily pain scale while comparable in all other scales of the three conditions, (2) comparable to osteoarthritis and rheumatoid arthritis in all scales, and (3) less burden than depression in vitality and MH scales and mental component summary measure while comparable in other scales. CONCLUSIONS: PMDD is associated with substantial burden on both physical and mental aspects of HRQoL.
18085733 Prevalence of ankylosing spondylitis and related spondyloarthritides in an urban area of I 2008 Feb OBJECTIVE: To determine the prevalence of ankylosing spondylitis (AS) and related spondyloarthritides (SpA) in an adult urban population of Izmir, Turkey. METHODS: A survey was conducted of 2887 subjects aged 20 years or over, selected by cluster sampling. Those who responded positively to the screening questions were contacted by 2 rheumatologists and evaluated in detail to establish presence of AS (modified New York criteria) or related SpA (ESSG criteria). RESULTS: In the initial screening, 2835 subjects participated; 422 were considered screening-positive and a telephone interview was done with 328 (78%). Based on their clinical history, 145 subjects were invited to the hospital and 120 (83%) agreed to do so. After detailed evaluation, 31 subjects were classified as having SpA (including 14 with AS). The age- and sex-adjusted prevalence was estimated to be 0.49% for AS (95% CI 0.26-0.85), and 1.05% for SpA (95% CI 0.70-1.50). The prevalence of AS was 0.54% in men (95% CI 0.19-1.20) and 0.44% in women (95% CI 0.19-0.88), and that of SpA was 0.88% in men (95% CI 0.42-1.59) and 1.22% in women (95% CI 0.73-1.89). CONCLUSION: This epidemiological study suggests a high prevalence (0.49%) of AS in an adult urban population from western Turkey, which equals that of rheumatoid arthritis in the same population. The overall prevalence of SpA, including AS, was 1.05%. A minimal male predominance was noted among AS patients, which disappeared among the whole group of patients with SpA.
18077767 Myosin IXB gene region and gluten intolerance: linkage to coeliac disease and a putative d 2008 Apr BACKGROUND: Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders. METHODS: In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls. RESULTS AND CONCLUSION: The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.
17928069 Graft-versus-host-like disease complicating thymoma: lack of AIRE expression as a cause of 2007 Nov 30 Three patients with graft-versus-host-like enterocolonopathy are reported. Their history was remarkable for thymoma and other autoimmune manifestations such as thrombocytopenia, red cell aplasia, interface dermatitis, Sjogren sialadenits, vanishing bile ducts and rheumatoid arthritis. In all patients, microsatellite analysis showed the autologous nature of the lymphocytes in the affected organs ruling out GVHD. In search for mechanisms that could mediate loss of tolerance to self-antigens we found in a panel of thymomas, including those of the three patients, a complete lack of autoimmune regulator (AIRE) and minimal expression of the transcription factor FOXP3 in the intra-tumoral T cells. AIRE is a recently discovered transcription factor which plays a key role in the maintenance of central tolerance and is mutated in the autosomal recessive autoimmune polyendocrinopathy syndrome APS-1. Our observations indicate that thymoma-related autoimmunity can potentially be elicited by an incomplete deletion of 'self'-specific T cells in concert with an insufficient formation of natural Tregs.
17911448 Anti-IL-17A autovaccination prevents clinical and histological manifestations of experimen 2007 Sep Excessive or inappropriate production of IL-17A has been reported in diseases such as rheumatoid arthritis, asthma, and multiple sclerosis. The potential clinical relevance of these correlations was suggested by the protective effects of anti-IL-17A monoclonal antibodies in various mouse disease models. However, the chronic nature of the corresponding human afflictions raises great challenges for Ab-based therapies. An alternative to passive Ab therapy is autovaccination. Covalent association of self-cytokines with foreign proteins has been reported to induce the production of antibodies capable of neutralizing the biological activity of the target cytokine. We recently reported that cross-linking of IL-17A to ovalbumin produced highly immunogenic complexes that induced long-lasting IL-17A-neutralizing antibodies. Vaccinated SJL mice were completely protected against experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein peptide (PLP 139-151), and a monoclonal anti-IL-17A Ab (MM17F3), derived from C57Bl/6 mice vaccinated against IL-17A-OVA, also prevented disease development. Here we report that this Ab also protects C57Bl/6 mice from myelin oligdendrocyte glycoprotein (MOG)-induced EAE. Histological analysis of brain sections of C57Bl/6 mice treated with MM17F3 showed a complete absence of inflammatory infiltrates and evidence for a marked inhibition of chemokine and cytokine messages in the spinal cord. These results further extend the analytical and therapeutic potential of the autovaccine procedure.
17910154 Periodontal disease severity and systemic diseases prevalent in a Caribbean catchment area 2007 Mar OBJECTIVE: To describe associations between the prevalence of periodontal disease severity and co-existence of systemic disease(s) and a smoking habit amongst periodontal referrals in a Caribbean catchment area of patients. METHODS: A total of 100 patients completed a medical history questionnaire and were categorized for periodontal disease severity, using clinical and radiographic parameters for association with the prevalence of systemic diseases. RESULTS: Twenty-two per cent presented with moderate periodontal disease (M/F ratio: 1:2.7). 68% of patients examined presented with severe periodontal disease (M/F ratio: 1:1.35). Amongst patients of the same mean age of 48 years presenting with moderate or severe periodontal disease, there was a two-fold increase in the number of missing teeth, amongst patients with severe periodontal disease. In this category there was twice the proportion of smokers and twice the number of mobile teeth, compared with those with moderate periodontal disease. In addition, there was twice the prevalence of diabetics and three times the proportion of patients with combined systemic diseases amongst those with severe periodontal disease, compared with those presenting with moderate periodontal disease, who were predominantly hypertensive or had rheumatoid arthritis. A history of smoking, diabetes mellitus and a combined manifestation of systemic diseases appeared to be more prevalent amongst those with severe periodontal disease. All these findings were significant (p < 0.001). CONCLUSION: An association between severity of periodontal disease and co-existence of systemic diseases may have implications for a unified therapeutic strategy for health.
17889336 Quantitative analysis of dynamic contrast-enhanced MRI datasets of the metacarpophalangeal 2007 Oct RATIONALE AND OBJECTIVES: In this article, we propose an alternative approach to voxel-by-voxel analysis, which overcomes problems associated with heuristic methods currently used for dynamic contrast-enhanced MRI (DCE-MRI) data assessment. We aim to allow fully automated extraction of various heuristic parameters via robust preprocessing methods and a new technique for classification of temporal patterns of contrast agent uptake, making full use of all available dynamic frames of the datasets. We also demonstrate that application of efficient preprocessing methods permits more accurate analysis of the dynamic data. MATERIAL AND METHODS: Ten DCE-MRI datasets enhanced by gadolinium diethylene triamine pentacetic acid were acquired from patients with rheumatoid arthritis using a 1.5-T MRI scanner. Fully automated voxel-by-voxel analysis of DCE-MRI signal intensity curves from 60 temporal slices was performed using a new method. Qualitative evaluation of the degree of inflammation was done via constructing parametric maps and quantitative by computing various heuristics such as maximum rate of enhancement, initial rate of enhancement, and time of onset of enhancement. RESULTS: Quantitative and qualitative evaluation obtained for 10 DCE-MRI datasets is presented. We demonstrate that preprocessing techniques compensate for patient movement, contribute to data fidelity and therefore permit more robust estimation of various heuristics such as maximum rate of enhancement, initial rate of enhancement, and time of onset of enhancement. Automatically generated parametric maps of these heuristics show favorable characteristics, permitting easier differentiation of structures of interest. These results are free from the subjective input and therefore easily reproducible. Furthermore, the proposed classification scheme provides information on the pattern of contrast uptake previously unavailable. CONCLUSION: Our preliminary results demonstrate the potential of the proposed method for providing objective quantitative and qualitative assessment of DCE-MRI in the metacarpophalangeal joints. Further evaluation within a clinical setting is needed to examine the method's diagnostic utility.
17729038 Apoptotic signal transduction and T cell tolerance. 2007 Sep The healthy immune system makes use of a variety of surveillance mechanisms at different stages of lymphoid development to prevent the occurrence and expansion of potentially harmful autoreactive T cell clones. Disruption of these mechanisms may lead to inappropriate activation of T cells and the development of autoimmune and lymphoproliferative diseases [such as multiple sclerosis, rheumatoid arthritis, lupus erythematosus, diabetes and autoimmune lymphoproliferative syndrome (ALPS)]. Clonal deletion of T cells with high affinities for self-peptide-MHC via programmed cell death (apoptosis) is an essential mechanism leading to self-tolerance. Referred to as negative selection, central tolerance in the thymus serves as the first checkpoint for the developing T cell repertoire and involves the apoptotic elimination of potentially autoreactive T cells clones bearing high affinity T cell receptors (TCR) that recognize autoantigens presented by thymic epithelial cells. Autoreactive T cells that escape negative selection are held in check in the periphery by either functional inactivation ("anergy") or extrathymic clonal deletion, both of which are dependent on the strength and frequency of the TCR signal and the costimulatory context, or by regulatory T cells. This review provides an overview of the different molecular executioners of cell death programs that are vital to intrathymic or extrathymic clonal deletion of T cells. Further, the potential involvement of various apoptotic signaling paradigms are discussed with respect to the genesis and pathophysiology of autoimmune disease.
17728288 Dyspepsia in general practice: incidence, risk factors, comorbidity and mortality. 2007 Oct BACKGROUND: Many individuals consulting their GP with upper abdominal symptoms are initially classified as having dyspepsia. Few studies have described the incidence of dyspepsia or the comorbidities, risk factors or prognosis associated with this diagnosis. METHODS: We used the UK General Practice Research Database to find patients with a new diagnosis of dyspepsia in 1996 (n = 6,913) and a control cohort (n = 11,036). We determined the incidence of dyspepsia, potential risk factors and comorbidity, and the risk of new onset morbidity in the year following the index date. RESULTS: The incidence of dyspepsia was 15.3 per 1,000 person-years. An increased probability of a dyspepsia diagnosis was associated with chest pain [odds ratio (OR): 2.4], general pain (OR: 1.8), sleep disorders (OR: 1.5), angina (OR: 1.5), osteoarthritis/rheumatoid arthritis (OR: 1.4) and smoking (OR: 1.2). There was only a borderline association with obesity (OR: 1.1). Patients with dyspepsia had an increased likelihood of a diagnosis of irritable bowel syndrome (IBS) (OR: 264), gastroesophageal reflux disease (GERD) (OR: 62.8) or peptic ulcer disease (PUD) (OR: 27.2) during the following year. CONCLUSIONS: The commonest diagnosis to emerge after an initial consultation for dyspepsia was IBS, followed by GERD and PUD.
17695525 Detrimental effects of an antibody directed against tumor necrosis factor alpha in experim 2007 Jul Antibodies directed against tumor necrosis factor (TNF)-alpha are clinically used for Crohn's disease, rheumatoid arthritis and psoriasis. TNF-alpha is also an important cytokine in radiotherapy because it mediates inflammatory responses in normal tissues. To study the influence of TNF-alpha inhibition on radiation toxicity, we used a well-established mouse model of kidney irradiation, where the portal also includes parts of the intestine. Mice were treated with single-fraction radiotherapy to the right kidney with doses of 8 or 10 Gy with or without the monoclonal TNF-alpha antibody infliximab injected i.v. in three doses. The kidney function was assessed by means of repeated 99mTc-dimercaptosuccinate scans during a maximum follow-up of 49 weeks. Treatment with infliximab significantly exacerbated radiation nephropathy at all time points, both in the 8 Gy and 10 Gy groups. The drug itself is not known to cause renal impairment. In the control group irradiated with 10 Gy, one mouse died from delayed radiation-induced intestinal toxicity. Skin reactions and general performance status were also similar across the groups. These data suggest that administration of infliximab concomitant to radiotherapy causes profound alterations in the development of kidney dysfunction. Importantly, other radiation-related toxicities were similar across all groups.
17535381 Vitamin D deficiency in general medical inpatients in summer and winter. 2007 Jun BACKGROUND: Vitamin D deficiency is common in various populations worldwide. Adverse effects of vitamin D deficiency are the development of bone disorders; however, other diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and certain cancers have also been linked to vitamin D deficiency. The general medical inpatient population is a group at increased risk of vitamin D deficiency. These patients often have coexistent risk factors for its consequences. This study aims to document a point prevalence of vitamin D deficiency in this population. METHODS: Two cross-sectional audits of patients admitted to general medicine units were carried out--the first in mid-November at the end of winter and the second in mid-April and May at the end of summer. Information regarding patients' comorbidities, medication usage, previous falls and fractures was obtained and serum 25-hydroxyvitamin D, parathyroid hormone and calcium levels were measured. RESULTS: A total of 129 patients was studied (65 in winter and 64 in summer). Ninety-four patients (74%) had 25-hydroxyvitamin D levels < or = 50 nmol/L. Seven patients had severe deficiency (levels < or = 12.5 nmol/L). Average vitamin D levels were lower at the end of winter (35 vs 43 nmol/L, P = 0.007). Of the 37 patients receiving vitamin D supplements, 20 (54%) had 25-hydroxyvitamin D levels < or = 50 nmol/L. CONCLUSION: Low vitamin D levels were common in this general medical inpatient population. The average vitamin D level was lower in the patient group tested in November following winter. Supplementation of vitamin D did not uniformly prevent deficiency.
17497940 Protein arginine deiminase 4: evidence for a reverse protonation mechanism. 2007 Jun 5 The presumed role of an overactive protein arginine deiminase 4 (PAD4) in the pathophysiology of rheumatoid arthritis (RA) suggests that PAD4 inhibitors could be used to treat an underlying cause of RA, potentially offering a mechanism to stop further disease progression. Thus, the development of such inhibitors is of paramount importance. Toward the goal of developing such inhibitors, we initiated efforts to characterize the catalytic mechanism of PAD4 and thereby identify important mechanistic features that can be exploited for inhibitor development. Herein we report the results of mutagenesis studies as well as our efforts to characterize the initial steps of the PAD4 reaction, in particular, the protonation status of Cys645 and His471 prior to substrate binding. The results indicate that Cys645, the active site nucleophile, exists as the thiolate in the active form of the free enzyme. pH studies on PAD4 further suggest that this enzyme utilizes a reverse protonation mechanism.
17474954 Use of nonsteroidal anti-inflammatory drugs in infants. A survey of members of the Associa 2007 May BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as perioperative analgesics. Many are currently used off label. Diclofenac is currently licensed for use in children over 1 year of age for the treatment of juvenile rheumatoid arthritis, while ibuprofen is licensed for use in children weighing over 7 kg. The dose and interval in children is currently extrapolated from adult studies, as the pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking in infants. METHODS: A postal questionnaire was sent to members of the Association of Paediatric Anaesthetist of Great Britain and Ireland seeking to clarify members' prescribing patterns of NSAIDs, especially in infants. Information regarding the choice of NSAIDS, route of administration, lower age limit, dose interval, dose and practice in two specific perioperative contexts (adenotonsillectomy and open heart surgery) was sought. RESULTS: The response rate was 80%. NSAIDs are used by 86% of responders in infants. Diclofenac is most commonly used intraoperatively (78%); while ibuprofen (73%) was used more frequently postoperatively. NSAIDs are used by 21% of respondents in ICU. Commonest routes of administration were oral (81%) and rectal (80%), rarely intravenously (9%). The commonest dose for diclofena is 1 mg x kg(-1) (59%); the dosing schedule employed being 8 hourly in 53% of cases. NSAIDs are used by 57% of responders as part of their analgesic regime for adenotonsillectomies. CONCLUSION: Members of the Association of Paediatric Anaesthetists of Great Britain and Ireland commonly prescribe NSAIDs in infants. This is despite the dearth of PK and PD data in this age group.
17454054 Cyclosporine A: a review of current oral and intravenous delivery systems. 2007 Mar As early as 1978, the immunosuppressive effect of cyclosporine A (CsA), a metabolite of the fungus Tolypocladium inflatum (Borel, 1989), was reported to be effective in inhibiting organ rejection in patients receiving kidney transplants from mismatched cadaver donors (Calne et al., 1978) and in the treatment of graft-versus-host disease in patients with acute leukemia following bone marrow transplants (Powles et al., 1978). Today, CsA is still indicated to prevent rejection following solid organ transplantations, prevent and treat graft-vs-host disease following bone marrow transplants, and has also been used in the treatment of autoimmune disease such as psoriasis, rheumatoid arthritis, and nephrotic syndrome (Canadian Pharmacists Association, 2006). The effectiveness of CsA is derived from its ability to specifically and reversibly inhibit immunocompetent lymphocytes in the G(0) and G(1) phase of the cell cycle. The T-helper cells are the main target, but suppression of the T-suppressor cells also occurs. The production and release of lymphokines, including interleukin-2 are also inhibited (Novartis, 2005a). CsA can be administered intravenously as well as orally in the form of a solution or a soft gelatin capsule. The following review will focus on the evolution of the emulsion-based oral formulations from the first generation as Sandimmune to the second generation Neoral, both products of Novartis Pharmaceutical, as well as on the Sandimmune commercial intravenous formulation. The potential of alternative delivery systems, including micelles, micro- and nanoparticles, and liposomes, will also be discussed.
17432111 Exploring new territory: considering the future. 2007 The European League Against Rheumatism (EULAR)'s guidelines for lupus state that mycophenolate mofetil has at least equivalent efficacy to and less toxicity than cyclophosphamide for the short-and medium-term treatment of lupus nephritis but that long-term data are available only for cyclophosphamide. New therapies are needed to reduce toxicity and the need for steroids and to offer the possibility of cure. Therapies under investigation include other immunosuppressive agents, anti-cellular therapies, drugs that modify cell-cell interactions, (anti-)cytokine therapy, hormone therapy and lupus-specific immunomodulation. Rituximab has shown promise in patients refractory to conventional immunosuppression, which suggests that targeting B cells may be successful. Other anti-cell therapies include epratuzumab, belimumab and alemtuzumab. Anti-cytokine approaches include tumour necrosis factor alpha blockade with infliximab, anti-interleukin 6-receptor therapy with tocilizumab and interferon-alpha blockade. As antidouble-stranded DNA antibodies correlate with flares of lupus nephritis, they may represent another therapeutic target--as do monocyte chemoattractant protein-1 and protein kinase CK2. Therapeutic options to prevent damage in lupus nephritis include non-immunosuppressive treatments aimed at reducing cardiovascular risk (such as statins, angiotensin-converting enzyme inhibitors and aspirin). As was the case with rheumatoid arthritis, a change in therapeutic aims--from survival through prevention of renal failure to induction of remission--may modify outcomes. EULAR's guidelines state that renal biopsy is the best monitor of clinical outcome in lupus nephritis, as immunological tests have limited predictive value. Measurement of urinary mRNA for cytokine and growth factor genes may provide a more sensitive, non-invasive method of monitoring therapeutic response.