Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
23180035 Genetics of ANCA-associated vasculitis in Japan: a role for HLA-DRB1*09:01 haplotype. 2013 Oct The epidemiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is considerably different between European and Asian populations. Whereas granulomatosis with polyangiitis is the most common form of AAV in northern European populations, microscopic polyangiitis (MPA) accounts for the majority of AAV in Japan. This difference may at least in part derive from the difference in genetic background. In this review, I focus on our observation on HLA, an obvious candidate gene for immune disorders, and discuss its potential implication. In Japanese AAV, significant association was detected with HLA-DRB1*09:01, the carrier frequency of which was increased in MPA [P=0.0087, odds ratio (OR) 1.90, 95% confidence interval (CI) 1.17-3.08] and in myeloperoxidase (MPO)-ANCA-positive AAV (P=0.0016, OR 2.05, 95% CI 1.31-3.23) when compared with healthy Japanese controls. HLA-DRB1*09:01 is one of the most common HLA-DRB1 alleles in Asians but is rare in Caucasian populations. Interestingly, HLA-DRB1*09:01 has been shown to be associated with multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus, suggesting that either HLA-DRB1*09:01 itself or other genes in tight linkage disequilibrium may play a role in a molecular pathway shared by various autoimmune diseases in Japanese and possibly in other Asian populations.
23164706 Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protei 2013 Jan 1 Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvβ3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were constructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.
23152079 Zinc oxide nanoflowers make new blood vessels. 2012 Dec 21 It is well established that angiogenesis is the process of formation of new capillaries from pre-existing blood vessels. It is a complex process, involving both pro- and anti-angiogenic factors, and plays a significant role in physiological and pathophysiological processes such as embryonic development, atherosclerosis, post-ischemic vascularization of the myocardium, tumor growth and metastasis, rheumatoid arthritis etc. This is the first report of zinc oxide (ZnO) nanoflowers that show significant pro-angiogenic properties (formation of new capillaries from pre-existing blood vessels), observed by in vitro and in vivo angiogenesis assays. The egg yolk angiogenesis assay using ZnO nanoflowers indicates the presence of matured blood vessels formation. Additionally, it helps to promote endothelial cell (EA.hy926 cells) migration in wound healing assays. Formation of reactive oxygen species (ROS), especially hydrogen peroxide (H(2)O(2))-a redox signaling molecule, might be the plausible mechanism for nanoflower-based angiogenesis. Angiogenesis by nanoflowers may provide the basis for the future development of new alternative therapeutic treatment strategies for cardiovascular and ischemic diseases, where angiogenesis plays a significant role.
23138975 Socio-demographic and clinical profile of chronic pain with neuropathic characteristics in 2013 Jul Data on characteristics of neuropathic pain (NP) in sub-Saharan Africa are scarce, especially in the elderly. We conducted this study to appreciate the socio-demographic and clinical profile of chronic pain (CP) with neuropathic characteristics in sub-Saharan African elderly with musculoskeletal pain. From January to December 2011, we performed a cross-sectional study in all Rheumatology outpatients over 60 years at the Center for Gerontology and Geriatrics, Dakar, Senegal. In this study, we included patients who experienced musculoskeletal pain for 3 months or longer (CP) and with a DN4 score ≥ 4 (NP). A complete clinical examination was performed to make the diagnosis of NP 'definite' or 'probable', and to identify the aetiologies of NP. During the study period, 698 outpatients were examined. There were 394 out of the 549 patients over 60 years who reported CP. Among them, 28 patients (7.1%) scored ≥4 on the DN4 questionnaire. Female patients, low educational attainment, manual professions, non-workers and diabetes were associated with NP (p < 0.05). The symptoms described by patients with NP, often intricate, were lumboradiculalgia (n = 9), cervico-brachial neuralgia (n = 3), polyneuropathy (n = 12) and mononeuropathy (n = 6). The presumed aetiologies in patients with NP were: chronic spine diseases (n = 14), painful diabetic peripheral neuropathy (n = 8), Sjögren's syndrome (n = 1), tarsal tunnel syndrome in rheumatoid arthritis (n = 1) and bone metastasis (n = 1). No aetiology was identified among three patients. Chronic spine diseases associated with radiculopathies and diabetic neuropathy are the main causes of NP, well detected by DN4 questionnaire and clinical examination in Senegalese sub-Saharan African elderly.
23128254 [Doctors, lawyers and pharmaceutical industry on health lawsuits in Minas Gerais, Southeas 2012 Oct OBJECTIVE: To describe the relationship between the prescribing doctor, lawyer and pharmaceutical industry in lawsuits against the state. METHODS: Retrospective descriptive study based on data from administrative files, relating to lawsuits involving medicine demands, in the state of Minas Gerais, Southeastern Brazil, from October 1999 to October 2009. RESULTS: A total of 2,412 lawsuits were analyzed with 2,880 medicine requests, including 18 different drugs, 12 of them provided through Pharmaceutical Policies of the Brazilian National Health System (SUS). The most frequent medicines requested included were adalimumab, etanercept, infliximab, insulin glargine and tiotropium bromide. The main diseases were rheumatoid arthritis, ankylosing spondylitis, diabetes mellitus, and chronic obstructive pulmonary disease. Private lawyers and doctors were predominant. The results revealed the association between doctors and law offices on drug requests. Among the lawsuits filed by the office A, 43.6% had a single prescriber to adalimumab, while 29 doctors were responsible for 40.2% of the same drug prescriptions. A single doctor was responsible for 16.5% of the adalimumab prescriptions, being requested through lawsuits filed by a single private law office in 44.8% of legal proceedings. CONCLUSIONS: A greater representation of doctors and lawyers from the private sector can hinder equity in health. The results revealed the association between doctors and law offices on drug requests. This is an indication that justice and medical practice have been used, at certain times, to serve the interests of the pharmaceutical industry.
23095275 Neuromyelitis optica spectrum disorder: 2-deoxy-2-[18F]fluoro-D-glucose positron emission 2012 A 51-year-old female with a history of rheumatoid arthritis rapidly developed anterior neck pain and paresis in the left upper and lower extremities and right lower extremity, sensory disturbance in the left upper and lower extremities, and bladder and rectal disorder. Adduction of the left eye and abduction of the right eye were also disturbed. Spinal magnetic resonance imaging demonstrated severe edema in the C1-T5 levels, which then deteriorated rapidly over 3 days, and lesions enhanced with gadolinium in the C1-C3 and C5-T3 levels. 2-Deoxy-2-[18F]fluoro-D-glucose positron emission tomography study demonstrated the inflammatory sites as segmental enhanced accumulation in the C1-C3, C5-C6, and T1 levels. The serum anti-aquaporin 4 antibody level was positive and she was diagnosed with neuromyelitis optica spectrum disorder. Marked improvement in the neurological conditions, concomitant with reduced spinal cord edema, was obtained by steroid pulse therapy.
22949320 IL-17-producing γδ T cells and innate lymphoid cells. 2012 Sep The inflammatory cytokine IL-17 plays a critical role in immunity to infection and is involved in the inflammatory pathology associated with certain autoimmune diseases, such as psoriasis and rheumatoid arthritis. While CD4(+) and CD8(+) T cells are important sources of this cytokine, recent evidence has suggested that γδ T cells and a number of families of innate lymphoid cells (ILCs) can secrete IL-17 and related cytokines. The production of IL-17 by γδ T cells appears to be largely independent of T-cell receptor activation and is promoted through cytokine signalling, in particular by IL-23 in combination with IL-1β or IL-18. Therefore IL-17-secreting γδ T cells can be categorised as a family of cells similar to innate-like lymphoid cells. IL-17-secreting γδ T cells function as a part of mucosal defence against infection, with most studies to date focusing on their response to bacterial pathogens. γδ T cells also play a pathological role in certain autoimmune diseases, where they provide an early source of IL-17 and IL-21, which initiate responses mediated by conventional IL-17-secreting CD4(+) T cells (Th17 cells). ILCs lack an antigen receptor or other lineage markers, and ILC subsets that express the transcriptional factor RORγt have been found to secrete IL-17. Evidence is emerging that these newly recognised sources of IL-17 play both pathological and protective roles in inflammatory diseases as discussed in this article.
22946654 Targeting T-cell migration in inflammatory bowel disease. 2012 Nov Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract and are collectively referred to as inflammatory bowel disease (IBD). IBD is a major cause of lifetime morbidity, has a severe impact on quality of life of patients (equivalent to that of rheumatoid arthritis, asthma, migraine or diabetes) and constitutes a substantial economic burden to the healthcare system. The introduction of anti-tumour necrosis factor (TNF) antibodies has dramatically improved the treatment of IBD, but approximately one-third of patients are nonresponders and another 30-50% will eventually lose the therapeutic effect or become intolerant to these antibodies. Thus, there is an urgent and unmet need for new therapies. The aetiologies of the different forms of IBD have not been fully elucidated but there is strong evidence implicating T cells and T-cell migration to the gut in initiating and perpetuating the intestinal inflammatory process and tissue destruction. In recent years, progress in basic science has shed light on the mechanisms regulating T-cell migration to the gut and new therapeutics targeting these pathways have been developed. It is interesting that some of the factors directing the localization of T cells to the gut have been shown to be relatively organ specific, potentially enabling new T-cell-targeted treatments to demonstrate improved safety whilst preserving therapeutic efficacy. Here, fundamental aspects of the gut immune system, the generation of tissue-tropic effector T cells and the mechanisms of T-cell trafficking to the gut mucosa will be reviewed. In addition, the role of these processes in IBD and how they have been exploited for the development of novel therapies for IBD will be discussed.
22801948 B-cell depletion in the treatment of lupus nephritis. 2012 Sep Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients.
22785497 Radiosynoviorthesis for treating recurrent joint effusions after endoprosthetic knee repla 2012 Aug PURPOSE: Radiosynoviorthesis (RSO) has been established as a treatment modality for rheumatoid arthritis. Other forms of joint diseases like recurrent joint effusions after knee arthroplasties are under investigation. The aim of this study was to examine whether RSO therapy is effective in the application of an endoprosthesis and whether there are common causes of failure. MATERIALS AND METHODS: Between 1998 and 2005, 55 patients received RSO treatment (90Y colloid) for recurrent joint effusions after endoprosthetic knee replacement. A total of 46 patients were followed up and questioned anonymously according to a modified Knee Society Knee Scoring System (KSS) and Hospital for Special Surgery score. On the basis of patient records, a subgroup analysis of patients with revision surgery after RSO (subgroup A) and without further operative interventions (subgroup B) was performed. RESULTS: Subgroup A comprised 46% (21/46) and subgroup B comprised 54% (25/46) of all patients. Most patients from subgroup A did not benefit from RSO. Of these 21 patients, 7 presented with low-grade infection, 7 presented with signs of endoprosthetic loosening, 2 presented with metal allergy, and 2 had undergone revision because of trauma.Patients in subgroup B experienced a significant improvement in pain (KSS score, from 22.5 to 34 points) and function (KSS score, from 62.9 to 77.3 points; Hospital for Special Surgery score, from 30.2 to 38.7) after RSO. CONCLUSIONS: Radiosynoviorthesis resulted in an improvement in pain and function in ∼50% of patients with knee endoprostheses. In 85% of all patients, in whom RSO treatment failed, endoprosthetic complications like infection, loosening, allergy, and trauma were detected. In conclusion, RSO is a valid therapeutic option for joint effusions after knee arthroplasties. However, if RSO fails, a thorough exclusion of endoprosthetic complications should be performed.
22688775 Central nervous system distribution of the poxviral proteins after intranasal administrati 2012 Poxviral proteins are known to interact with the immune system of the host. Some of them interact with the transcription factors of the host, whereas others interact with the components of the immune system. Vaccinia virus secretes a 28.8-kDa complement control protein (VCP), which is known to regulate the complement system. This protein helps the virus to evade the immune response of the host. Such viral proteins might also prove beneficial in the treatment and prevention of the progression of the disorders, where up-regulation of the complement system is evident. VCP has been shown experimentally to be effective in protecting tissues from inflammatory damage in the rodent models of Alzheimer's diseases (AD), spinal cord injury, traumatic brain injury, and rheumatoid arthritis. Not only VCP, but also other poxviral proteins could be used therapeutically to treat or prevent the progression of the brain disorders, where the immune system is inadequately controlled. However, being a protein that cannot traverse the brain barrier because of its size, delivery of such proteins to the central nervous system (CNS) could be a limiting factor in their usefulness as CNS therapeutics. In this chapter, we show methods for the intranasal route of administration of a protein and show ways to detect its distribution in the cerebrospinal fluid (CSF) and to the different parts of the brain. These protocols can be extended to examine the distribution of viral antigens in the brain. A protocol is also included to quantitate vaccinia virus in different segments of the brain after intracranial administration of the virus.
22591402 Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors. 2012 Jun 28 A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
22575417 The expression of BAFF in the muscles of patients with dermatomyositis. 2012 Aug 15 A B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF) plays a crucial role in B-cell survival and maturation. An elevated serum BAFF level has been linked to several autoimmune diseases such as Sjögren syndrome, systemic lupus erythematosus and rheumatoid arthritis. Dermatomyositis (DM), one of autoimmune inflammatory myopathies, is characterized by inflammatory cell infiltration (CD4(+) T cells and B cells) in skeletal muscle. Serum BAFF level was significantly high in DM, but the role of BAFF is not well understood. We investigated the role of BAFF in the immunopathogenesis of DM. To examine the transcriptional increase of BAFF gene expression, we performed RT-PCR analysis with skeletal muscle tissue that contained 4 controls and 9 patients with DM. Next, in order to detect BAFF expression and cellular localization in DM, we executed immunostaining in cryosection of biopsied muscle tissue with 4 controls and 8 patients and we adopted to double immunostaining to find which inflammatory cells expressed BAFF-receptor (BAFF-R). BAFF mRNA level was increased in DM patients compared with normal controls. BAFF expression was markedly increased at muscle fibers in the perifascicular area but not blood vessels. BAFF-R was expressed in inflammatory cells in skeletal muscle tissues of DM patients. We found that BAFF expression in muscle tissue may be associated with an increased number of CD4(+) T cells and CD19(+) B cells in DM. Our study results suggest that BAFF might play an important role in the pathogenesis of DM.
22563780 Nonstandard drugs and feasible new interventions for autoimmune hepatitis: part II. 2012 Oct Molecular, cellular, and genetic interventions are now feasible for autoimmune hepatitis because of improved understanding of pathogenic mechanisms, advances in recombinant technology, and previous successes in animal models and humans with other immune-mediated inflammatory diseases. Non-mitogenic monoclonal antibodies to CD3 promote apoptosis of cytotoxic T lymphocytes, inhibit production of pro-inflammatory cytokines, improve the function of regulatory T cells, and induce a durable remission in mouse models and humans with autoimmune diabetes. Monoclonal antibodies to CD20 deplete B lymphocytes, modify antibody-dependent and cell-mediated cytotoxic pathways, enhance regulatory T cell function, and improve isolated cases of autoimmune hepatitis with B-cell disorders. Recombinant cytotoxic T lymphocyte antigen-4 fused with immunoglobulin can block the second co-stimulatory signal required for lymphocyte activation, and it has been licensed for use in rheumatoid arthritis but not tried in autoimmune hepatitis. Other considerations on the distant horizon are monoclonal antibodies against inhibitory receptors on regulatory T cells, adoptive transfer of fresh regulatory T cells, tailored glycolipids that strengthen the immunosuppressive activity of natural killer T cells, small inhibitory ribonucleic acid molecules that silence promoter genes supporting disease activity, and mesenchymal stem cell transplantation to re-constitute immune homeostasis and support the damaged liver. Development of these feasible new interventions for autoimmune hepatitis requires therapeutic animal models, societal support, and a collaborative network of investigators to conduct rigorous clinical trials.
22398212 Detection of allantoin in clinical samples using hydrophilic liquid chromatography with st 2012 Apr 1 Allantoin is the major oxidation product of urate in humans and is a potential biomarker of oxidative stress. Several methods are used to measure allantoin in biological samples but they have inherent issues that can include lack of specificity and sensitivity, difficulty in sample preparation, or artefactual generation of allantoin. We have developed a method for measuring allantoin using hydrophilic liquid chromatography with stable isotope dilution tandem mass spectrometry (HILIC-MS/MS). It was validated for measuring allantoin in plasma, synovial fluid and urine from human subjects. The limit of quantification was determined to be 10 fmol and the assay displayed excellent linearity for the wide range of concentrations found in clinical samples. Relative standard deviations were <5% for between-day and <7% for within-day variation. Accuracy was between 100% and 104%. Concentrations of allantoin in plasma of healthy controls (2.0 μM; interquartile range 1.4-3.6 μM, n=35) was significantly lower (p<0.001) than that in plasma from patients with rheumatoid arthritis (3.7 μM; IQR 3.0-5.6 μM, n=43) and in synovial fluid of patients with gout (3.3 μM; IQR 2.8-5.8 μM, n=10). This newer HILIC-MS/MS method is a simple and highly sensitive assay for detection of allantoin. It can be used to assess the level of oxidative stress in human pathologies.
22364138 Adverse cardiovascular effects of antirheumatic drugs: implications for clinical practice 2012 Clinical manifestations of most rheumatic diseases have changed over the past few decades, largely due to advances in therapies targeting autoimmune and (auto)inflammatory pathways. Improvements in the management of rheumatic diseases have also now brought to the fore the issue of comorbidities. It has become evident that the burden of cardiovascular morbidity and mortality is increased in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the spondyloarthropathies, amongst other conditions. As a result, efforts have switched toward investigating the effects of conventional antirheumatic and new biologic agents on inflammationinduced atherothrombosis. Evidence is accumulating suggesting a beneficial cardiovascular profile of some antirheumatic drugs, such as methotrexate and hydroxychloroquine, but it also indicates the possibility of a variety of adverse events developing in the short- and long-term. The aim of this review is to highlight cardiovascular adverse effects of the drugs widely used in the treatment of rheumatic diseases. The literature search was performed through PubMed, the Cochrane Library, Scopus, and Web of Science databases using the following terms: "antirheumatic drugs", "inflammation", "rheumatic diseases", "cardiovascular diseases", "adverse events", "toxicity", "drug design", and "drug interactions". Adverse events ranging from infusion-related hypertension and myocardial ischemia, to restrictive cardiomyopathy and congestive heart failure have been reported in large trials and case series on most antirheumatic drugs. Clinicians should be alert of the wide variety of cardiovascular adverse effects of individual antirheumatic drugs, and should carefully monitor blood pressure and markers of inflammation, thrombosis, myocardial ischemia, electrolytes, and lipid disturbances while administering these drugs. Future prospective studies should specifically investigate the cardiovascular safety of most antirheumatic drugs as part of mono- or combination therapy in relation to different dosage regimens, duration of therapy, age, and gender.
22144022 A new optical imaging probe targeting αVβ3 integrin in glioblastoma xenografts. 2011 Nov α(V)β(3) Integrins are a widely recognized target for in vivo molecular imaging of pathological conditions such as inflammation, cancer and rheumatoid arthritis. We have evaluated the sensitivity of a new, near-infrared fluorescence (NIRF), RGD cyclic probe (DA364) in noninvasive detection of α(V) β(3) integrin-overexpressing tumors. DA364's binding affinity for α(V)β(3) integrin was first evaluated in vitro. Human α(V)β(3) integrin-positive, U-87 MG glioblastoma cells were then xenografted in nude mice, and DA364 was injected intravenously (i.v.) to evaluate its in vivo distribution, specificity and sensitivity in comparison with a commercially available probe. DA364 bound α(V)β(3) integrin on U-87 MG cells with high affinity and specificity, both in vitro and in vivo. This binding specificity was corroborated by the strong inhibition of its tumor uptake induced by nonfluorescent, cyclic-RGD peptides. Ex vivo analysis showed that DA364 accumulated at the tumor site, whereas very low levels were detected in liver and spleen. In conclusion, DA364 allows sensitive and specific detection of transplantable glioblastoma by NIRF imaging, and is thus a promising candidate for the elaboration of imaging and therapeutic probes for α(V)β(3) integrin-overexpressing tumors.
21938452 Safety of immunomodulatory therapy in patients with bronchiectasis associated with rheumat 2012 Feb Rheumatic diseases as well as inflammatory bowel disease (IBD) have been associated with the occurrence of non-cystic fibrosis bronchiectasis (NCFB). There are few data on NCFB and adverse events from immunosuppressive or biological response modifier therapy in patients with rheumatoid arthritis (RA) or IBD and NCFB. We identified 37 patients with NCFB and rheumatic disease, and nine patients with inflammatory bowel disease that received immunomodulatory treatment. We retrospectively analysed adverse pulmonary events. In nine patients with RA, the association between disease activity score (DAS) and spirometry was analysed in a small cohort study. Pulmonary side effects occurred in 50% of patients, most commonly respiratory infections, and resulted in a change of immunomodulatory treatment in 37% of patients. Spirometry and exacerbation rate was not different in NCFB patients with RA or IBD as compared with NFCB due to other causes. The incidence of pulmonary adverse events was highest in patients treated with conventional immunomodulatory treatment, especially methotrexate, as compared with patients with NCFB treated with newer biological therapies. Three patients were started on azithromycin because of recurrent bronchitis and had no events afterwards. Serial assessment of DAS and spirometry showed that a rise in DAS was associated with lung function decline and vice versa. Currently used immunosuppressive drugs can be used in NCFB albeit under close follow-up. The role of azithromycin for infection prevention needs further research. An association between DAS and lung function was shown.
21876398 Nuclear medicine techniques in the assessment of alkaptonuria. 2011 Oct Alkaptonuria is a rare autosomal recessive disorder due to a lack of the enzyme homogentisate dioxygenase, leading to ochronosis, a process of accumulation of a melanin-like polymer of homogentisic acid in cartilage and other collagenous structures. Patients develop severe osteoarthropathy that resembles osteoarthritis. Although the diagnosis of alkaptonuria is not particularly challenging in view of the blue-black discolouration of visible connective tissue and the presence of homogentisic acid in urine, the natural history of alkaptonuria remains poorly understood. Patients would benefit immensely from an objective assessment of their disease status and from a clearer understanding of the pathophysiology and associated physical changes. Isotope bone scans, which are commonly used to identify the extent of involvement of bones in cancerous processes, have also been increasingly used for characterizing the extent of arthropathy in conditions such as osteoarthritis and rheumatoid arthritis. Semiquantitative scores based on the extent of involvement of joints have been used to describe the involvement of large joints in the context of symptomatic treatment for osteoarthritis. A similar semiquantitative isotope bone scan score depending on the involvement of the number of large joints in patients with alkaptonuria can be formulated and validated in a suitable cohort of patients. Bone densitometry measurement using dual-energy X-ray absorptiometry scanning is an internationally accepted tool to assess the risk and extent of osteoporosis, and is increasingly used to assess the additional fracture risk in patients with arthropathy. We believe that, currently, nuclear medicine techniques can provide useful information, which can be incorporated into disease severity scores for alkaptonuria. Once the biological basis for alkaptonuria is better understood, it is feasible that nuclear medicine techniques of even greater sensitivity and specificity can be developed, thereby taking advantage of the vast advances in the fields of radiochemistry, radiopharmacy, positron emission tomography-computed tomography and positron emission tomography-magnetic resonance imaging scanning.
21771179 Rituximab for childhood refractory nephrotic syndrome. 2011 Oct Several therapies including immunosuppressive agents have been shown to be effective and safe for frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS) and steroid-resistant nephrotic syndrome in children. It is evident, however, that a substantial number of children are still refractory to treatment despite these therapies. Rituximab is a chimeric monoclonal antibody, which inhibits CD20-mediated B-cell proliferation and differentiation. It was first introduced for the treatment of B-cell non-Hodgkin's lymphoma and was subsequently administered to patients with autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, or immunocomplex glomerulonephritis. Recently, a number of case reports and non-controlled clinical trials have suggested that rituximab may be effective for children with refractory nephrotic syndrome. Controlled prospective trials, however, are required to establish the value of rituximab in refractory nephrotic syndrome. The purpose of the present study was therefore to evaluate the efficacy and safety of rituximab in childhood-onset refractory nephrotic syndrome. The Research Group of Childhood-onset Refractory Nephrotic Syndrome (RCRNS) conducted a randomized, double-blind, placebo-controlled, multi-center clinical trial (RCRNS-01) and an open-label, multi-center, pharmacokinetic clinical trial (RCRNS-02). These two trials were investigator-initiated, registration-directed clinical trials designed to apply Ministry of Health, Labour and Welfare approval for the use of rituximab for childhood-onset refractory FRNS/SDNS in Japan. RCRNS-01 could be the first study to clarify whether rituximab is effective and safe for childhood-onset refractory FRNS/SDNS.