[Gene therapy as a treatment for rheumatoid arthritis]
JAMES M. Woods
JANUARY 10, 2004
Hungarian Immunology - 2004;3(01)
JAMES M. Woods
JANUARY 10, 2004
Hungarian Immunology - 2004;3(01)
[A clear understanding of the pathogenic events and/or environmental conditions that lead to the development of rheumatoid arthritis has not been accomplished. In recent years, some of the most capable therapies have targeted individual proteins, such as proinflammatory cytokines, which contribute to persistent inflammation. The success of these therapies in some patients underscores the importance of having a solid pathophysiologic knowledge of the mechanisms at play in the diseased joint. Targeting the joint therapeutically with proteins or other agents has presented many challenges in the treatment of rheumatoid arthritis. To circumvent these obstacles, the idea of providing transgenes to cells of the synovial lining was born. This use of gene therapy, as a delivery vehicle rather than replacement of a genetic deficit, has had many successes in preclinical animal studies. Preliminary results of the first Phase I clinical trial in humans suggests that an ex vivo approach can be safe and enable transgene expression. This review provides a consolidated overview of many of the successful gene therapy strategies undertaken for the treatment of animal models of arthritis. The focus is on: 1. joint targeting strategies, including discussion on the local and systemic approaches as well as the contralateral joint; 2. the applicability of viral vectors, including comparison of adenoviral, retroviral, adeno-associated, and herpes simplex viruses; 3. timing and dosage of treatment; and 4. targets and candidate proteins that have been examined, including targeting proinflammatory cytokines or the use of anti-inflammatory cytokines.]
[OBJECTIVE - To investigate the intracellular and soluble cytokine levels in peripheral blood of patients with active and inactive dermatomyositis (DM). Methods The frequency of the intracellular IFN-g, IL- 4 and IL-10 expression of CD4+ or CD8+ cells were determined by flow cytometry. We measured the concentrations of soluble cytokines with commercial ELISAs. RESULTS - In active DM we observed decreased IFNg expression of CD4+ and CD8+ cells. These prominent changes disappeared in the inactive stage of the disease. In DM we could not detect a significant change in the intracellular IL-4 cytokine expression either in the active or in the inactive form. The IL-10 expression was elevated in the inactive state of the patients. CONCLUSION - We can state that a difference between aDM and iDM seems to exist in the level of peripheral blood lymphocytes and their intracellular cytokine content.]
[We conducted the first Hungarian open-label study using infliximab (Remicade) in 62 rheumatoid arthritis (RA) patients. The mean disease duration was 8.7 years. Patients receiving methotrexate for at least 3 months with active RA were included in the study. All patients received concomittant methotrexate treatment. Results indicated a 61%, 35% and 18% improvement in ACR20, ACR50 and ACR70, respectively. In most patients, dramatic improvement was seen as soon as after the first or second infusion.]
[INTRODUCTION - In chronic idiopathic urticaria the etiology is unknown in spite of extensive investigations. In 27-50% of these cases autoimmune mechanisms are detected in the background. CASE REPORT - The authors demonstrate the case of an autoimmune urticaria patient with positive autologous serum skintest, who responded well to cyclosporin A therapy. CONCLUSION - According to the observation and the relevant literature, the authors also found small dose cyclosporin A therapy useful and safe in treating therapy resistant chronic urticaria.]
[The research of pathomechanism of rheumatoid arthritis resulted in remarkable pragmatic results beyond the important theoretical knowledge. These observations led to the development of new effective agents, which were named as biological therapy and introduced in clinical praxis. The key factor of pathomechanism of rheumatoid arthritis is the proinflammatoric citokin TNF-α. It can be found on the top of the inflammation cascade where regulates many other inflammatory mediators and also plays an important role in the defence against infections and tumours. The author describes the TNF-α blocking agents used in clinical practice, their chemical and pharmacological feature, as well as their mode of action and the consequence of inhibition of TNF-α. He reviews the main results of the major clinical tests with infliximab, etanercet, and adalimumab. The results of these clinical studies demonstrate that the TNF-α blocking therapy gives clinical improvement in case of therapy resistant patients, decreases the number of swollen and tender joints, the pain, ESR and CRP, decreases the radiological progression, furthermore improves the quality of life. There are also some data about the favourable impacts observed during the early arthritis treatment. The TNF-α blocking therapy can be used effectively and safely in rheumatoid arthritis. In most cases the infusion reaction and the injection site reaction are not reasons for withdrawal from the study. The sideeffects, however, developed in increasing numbers during widespread applications. Among these the most important ones are the opportunist infection and the tuberculosis. In addition the sporadic occurrence of lupus-like symptoms, demyelinating disease, and aplastic anemia were reported. The fundamental requirements of the safety of the biological therapy are the professional indication and the careful monitoring during the treatment, the principle of which has been already prepared by the Professional College of the Rheumatology and Physiotherapy based on the international experience.]
Introduction - Peripheral nerve injury (PNI) is a frequent problem among young adults. Hopefully, regeneration can occur in PNI unlike central nervous system. If nerve cut is complete, gold standard treatment is surgery, but incomplete cuts have been tried to be treated by medicines. The aim of the study was to evaluate and compare clinical and histopathological outcomes of independent treatment of each of Vitamin B12 (B12) and Vitamin D3 (D3) and their combination on sciatic nerve injury in an experimental rat model. Materials and methods - Experimental animal study was performed after the approval of BEH Ethics Committee No. 2015/10. 32 rats were grouped into four (n=8) according to treatment procedures, such as Group 1 (controls with no treatment), Group 2 (intraperitoneal 1 mg/kg/day B12), Group 3 (oral 3500 IU/kg/week D3), Group 4 (intraperitoneal 1 mg/kg/day B12+ oral 3500 IU/kg/week D3). Sciatic Functional Index (SFI) and histopathological analysis were performed. Results - SFIs of Group 2, 3, 4 were statistically significantly higher than controls. Group 2 and 3 were statistically not different, however Group 4 was statistically significantly higher than others according to SFI. Axonal degeneration (AD) in all treatment groups were statistically significantly lower than in Group 1. AD in Group 4 was significantly lower than in Group 2 and 3; there was no significant difference between Group 2 and 3. There was no significant difference between Group 1,2 and 3 in Axonolysis (A). But A of Group 4 was significantly very much lower than all others. Oedema- inflammation (OE-I) in all treatment groups were significantly lower than in Group 1; there was no significant difference between Group 2 and group 4. OE-I in Group 2 and 4 were significantly lower than in Group 3. There were no significant differences between Group 1, 2 and 3 in damage level scores; score of Group 4 was significantly lower than of Group 1. Conclusions - B12 and D3 were found effective with no statistically significant difference. But combined use of B12 and D3 improve nerve healing synergistically. We recommend combined use of B12 and D3 after PNI as soon as possible.
Evidence suggests that pathogen-associated pattern recognition receptors (Toll-like receptors, TLRs) are implicated in the pathophysiology of schizophrenia. TLRs are important in both peripheral immune responses and neuronal plasticity. However, the relationship between peripheral TLR expression and regional brain volumes is unknown in schizophrenia. We therefore assessed 30 drug-naïve, first-episode patients with schizophrenia. TLR4+/TLR1+ monocytes were measured using flow-cytometry. High resolution magnetic resonance images (T1 MRI) were obtained and analyzed with FreeSurfer. Results revealed significant negative correlations between the percentage of TLR4+ monocytes, mean fluorescent intensities, and brain volumes in frontal and anterior cingulate regions. The measures of TLR1+ monocytes did not show significant relationships with regional brain volumes. These results raise the possibility that abnormal TLR-activation is associated with decreased brain volumes in schizophrenia.
Background - Lumbar disc herniation (LDH) causes major disabilities worldwide. Several studies in the literature had reported the correlation between radiculopathy and inflammatory markers. Mean platelet volume (MPV), red cell distribution width (RDW) and neutrophil to lymphocyte (N/L) ratio are parameters of hemogram which have been found to be associated with inflammatory conditions. Purpose - Since inflammation has an important role in lumbar disc hernias, and RDW, MPV and N/L ratio are also known to be in correlation with inflammation, we have investigated these parameters of the patients with lumbar disc hernias and compared them with the results of the healthy subjects. Methods - Our study group was composed of patients with lumbar disc hernia, whereas the control group was consisted of healthy volunteers whom visited our outpatient clinics for a routine check-up. Patient characteristics and hemogram parameters of the study cohort were obtained from computerized database system of our institution. SPSS software (SPSS 15.0 for Windows, Chicago, IL, USA) was used for the analysis. Results - There was no significant difference between study and control groups in terms of WBC, neutrophil count, lymphocyte count, neu\lym ratio, Hb, Htc, MCV, and PLT levels (all p>0.05). RDW was significantly increased in study group [15.6 (12.3-22.5)] when compared to control group [14.5(11.9-16.3)] (p=0.004). And MPV in the study group [9.25 (6.38-14.5)] was also significantly increased in comparison to the control subjects [8.8 (6-10.1)] (p=0.013). Discussion - In this retrospective study, we found that, RDW and MPV values in hemograms were increased in patients with lumbar disc herniation when compared to the control group. Conclusions - We suggest that, elevated RDW and MPV may help physicians in decision taking to order radiological imagings in patients with symptoms which can be associated with possible LDH diagnosis. However, for the sake of precision, prospective studies with larger populations are needed.
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[Nitric oxide is a key molecule of the human body. Since its discovery, a library of books and papers have been published on its physiological and pathophysiological role. It is involved in almost all pathological processes. In healthy individuals nitric oxide plays a crucial role in the vascular regulation by protecting against atherosclerosis, myocardial infarction and stroke. In the central nervous system, nitric oxide in its function as a neurotransmitter is responsible for synaptic plasticity, long-term potentiation, memory and a number of neuroendocrine control mechanisms. Furthermore, during inflammation and host defense, macrophages and neutrophils produce nitric oxide that has antibacterial, antiviral, and tumour cell killing activity. In pathologic conditions, however, nitric oxide reacts with superoxide anion to form peroxynitrite that damages the enzymes of the mitochondrial respiratory chain, superoxide-dismutase, reduced glutathion and activates or inactivates signalling molecules. During ischaemia- reperfusion, nitric oxide and peroxynitrite contribute to nitrative/nitrosative stress, DNAfragmentation and consequent polyADP-ribosepolymerase- 1 enzyme activation both in coronary thrombosis and ischaemic stroke.]
[INTRODUCTION - The joints have been secured from rheumatoid arthritis by diminution of biomechanical effeciency. This effect was analyzed and named articular protective phenomenon three decades ago. CASE REPORT - A case of bilateral rheumatoid arthritis associated with unilateral developmental abnormality hand and bronchial asthma in a 35 year old female patient is presented. Her left 2nd, 3rd, 4th and 5th metacarpal bones moreover her fingers had not evolved. The patient has been treated by antiasthmatic steroid drugs for five years. Rheumatoid disorders of the affected left hand were more severe, than the abnormality of the normal upper limb. Eight years later the most severe bony lesions (ankylosis and mutilation) appeared on this side, only. CONCLUSION - The patient's hand was not saved by inborn bone defect in rheumatoid arthritis. The absence of articular protective phenomenon can be explained by the undisturbed innervation of limb, the motility of hypotrophic carpus besides to steroid-induced suppression.]
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