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ID PMID Title PublicationDate abstract
12423770 Cyclooxygenase 2 activity modulates the severity of murine Lyme arthritis. 2002 Nov 15 Cyclooxygenase (Cox) is a key enzyme in the biosynthetic metabolism of prostaglandins. The inducible isoform of Cox-2 has been implicated in inflammation and its specific inhibition can be used to treat noninfectious inflammatory diseases, such as rheumatoid arthritis. Borrelia burgdorferi, the agent of Lyme disease, can induce joint inflammation. Here we show that B. burgdorferi induced the upregulation of cox-2 gene expression in murine joints at the onset of arthritis in infected mice. The level of mRNA expression correlated with the degree of inflammation. The specific inhibition of Cox-2 diminished the degree of joint inflammation, without affecting B. burgdorferi-specific antibody or cytokine responses. Cox-2 activity is therefore associated with the genesis of infectious arthritis caused by B. burgdorferi.
12682268 Essential role of Fc gamma receptors in anti-type II collagen antibody-induced arthritis. 2003 Apr 15 Anti-type II collagen (anti-CII) Ab is a well-known autoantibody observed in patients with rheumatoid arthritis. Injection of anti-CII Ab and LPS induces arthritis in mice in which anti-CII Ab as well as inflammatory cytokines, IL-1beta and TNF-alpha, play critical roles. We investigated the involvement of IgG FcRs (FcgammaRs) in this arthritis model. BALB/c mice injected with the F(ab')(2) of anti-CII Ab showed no signs of arthritis. Arthritis development was not observed in FcRgamma(-/-) mice and was partially suppressed in FcgammaRIII(-/-) mice despite the binding of anti-CII Ab and C3 to cartilage surface. Surprisingly, BALB/c mice lacking FcgammaRIIB, which is known as an inhibitory FcgammaR, developed arthritis with no exacerbation in arthritis score compared with wild-type (WT) mice, and only slight exacerbation was observed in the histopathological analysis. In contrast, aged FcgammaRIIB(-/-) BALB/c mice developed arthritis without LPS injection, suggesting an augmented susceptibility to arthritis in aged FcgammaRIIB(-/-) mice. No significant difference was observed among BALB/c-WT, -FcRgamma(-/-), and -FcgammaRIIB(-/-) mice on cytokine production induced by anti-CII Ab and LPS injection. Severe arthritis developed in BALB/c-WT and -FcgammaRIIB(-/-) mice, but not in BALB/c-FcRgamma(-/-) mice, after the injection of anti-CII Ab and inflammatory cytokines. These results suggest that the reason behind the nondevelopment of arthritis in FcRgamma(-/-) BALB/c mice is not due to a disorder in transient cytokine production, but to an irregularity downstream of cytokine production.
15113991 Using the Health Assessment Questionnaire and welfare benefits advice to help people disab 2004 Jul OBJECTIVES: To test, in a variety of health settings, the ability of the Health Assessment Questionnaire (HAQ) disability index to predict the eligibility of patients with moderate or severe arthritis for disability living allowance or attendance allowance. METHODS: The study included patients from 20 general practices and four hospital out-patient departments across four areas in the southwest of England. Adults with an established diagnosis of rheumatoid arthritis, or osteoarthritis of the hip or knee, and who were not in receipt of Disability Living Allowance (DLA) or Attendance Allowance (AA) were sent an HAQ. Those who scored 1.5 or more were offered an appointment with a welfare advice worker at which they completed an application for DLA or AA. After 3 months they were contacted by the advice worker and asked about the outcome of their applications. RESULTS: Over half of those who completed an HAQ scored 1.5 or over (moderate to severe disability as measured by the HAQ) and were offered advice from experienced welfare benefits advisors. Of these, 87% applied for DLA or AA. Sixty-nine per cent of the applicants were successful. Those scoring 1.75 and over were more likely to be awarded benefit (73% success CLs 67, 79) than people scoring between 1.5 and 1.625 where 55% (CLs 41,69) of applicants were successful. CONCLUSION: The HAQ was shown to be a good predictor of eligibility for AA or DLA. It can be used, in a variety of health settings, to indicate patients who, with help from an experienced advisor, are likely to gain increased financial help.
12728284 Etanercept, a TNF antagonist for treatment for psoriatic arthritis and psoriasis. 2003 Jan Etanercept (Enbrel, Amgen and Wyeth), a tumor necrosis factor (TNF) antagonist, was approved in January 2002, for the treatment of psoriatic arthritis (PsA). The anti-inflammatory effects of etanercept are due to its ability to bind to the pro-inflammatory cytokine TNF, preventing it from interacting with cell-surface receptors and rendering it biologically inactive. Etanercept was evaluated for the treatment of PsA and psoriasis in a preliminary study of 60 patients and in a confirmatory phase III study of 205 patients. In both studies, etanercept was shown to be significantly superior to placebo for the treatment of PsA, evaluated by Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) criteria. It also was superior to placebo in improving psoriatic skin lesions, evaluated by the Psoriasis Area and Severity Index (PASI) and target lesion scores. Side-effects were minimal; mild injection site reactions, which resolved during continued therapy, were experienced by approximately one-quarter of the patients. Overall, etanercept is highly effective and well tolerated by patients with PsA, with a safety profile similar to that seen in rheumatoid arthritis.
12557619 [Diagnosis of the Mikulicz-Sjogren syndrome using biopsy of the minor salivary glands]. 2002 Nov BACKGROUND: Sjögren's syndrome (SS) represents autoimmune disease characterized by chronic inflammation, destruction and insufficiency of exocrine glands, particularly salivary and lacrimal glands, accompanied by dryness of mouths and eyes. Diagnostic work-up involves clinical laboratory tests, radiography, scintigraphy and bioptic histopathological examination. Examination of small salivary glands in the biopsy of the lower lip represents a "golden standard" of diagnosis of SS, concerning the fact that the growth and the disfunction of salivary and lacrimal glands occurs in different pathologic states. METHODS: Resected specimens of the lower lip were obtained from 47 patients with clinical diagnosis of SS. After standard histopathological treatment, slices were hematoxylin and eosin stained. Immunohistochemistry against smooth muscle actin was performed using LSAB+ method (AHSMA-M7558, DAKO 1:50). On the basis of generally accepted histopathological diagnostic criteria the results were categorized as: findings suspicious for SS; findings compatible with the diagnosis of SS (mild, moderate and high degree of inflammation); nonspecific inflammatory reaction and nonrepresentative biopsy samples. RESULTS: Diagnosis of SS was confirmed in 32% of cases. In 2% of cases findings were suspected for SS, in 36% of cases findings were compatible with the diagnosis of nonspecific inflammation, and in 30% of cases material was not representative. CONCLUSIONS: By the biopsy of salivary glands of the lower lip the diagnosis of SS was confirmed in 50-60% of cases. Upon the precise diagnostic criteria it was also possible to determine the intensity of inflammation and tissue destruction in SS and identify other pathological conditions, which justified the biopsy. Surgical technique had to be adequate in order to obtain representative number of small salivary glands. In the presented material 30% of specimens were nonrepresentative which was very high percentage compared with literature data. This was most probably the reason why the diagnosis of SS was confirmed in only 32% of cases, i.e., in every third patient.
12972485 Randomised controlled study of postinjection immobilisation after intra-articular glucocor 2003 Oct BACKGROUND: Intra-articular glucocorticoid treatment is frequently used in arthritic disorders. Postinjection rest has been shown to improve the outcome of knee injections. OBJECTIVE: To investigate whether better treatment results might also be achieved by a similar postinjection regimen for the wrist, which is non-weightbearing. METHODS: 117 patients with rheumatoid arthritis and wrist synovitis were treated with intra-articular glucocorticoid injections. The patients were randomly allocated to 48 hour postinjection immobilisation in elastic wrist orthoses (n=58) or to normal postinjection activity (n=59). The primary end point was relapse of synovitis. In addition, joint circumference, pain, function, range of movement, and grip strength were followed up during six months. RESULTS: 24 relapses occurred in the orthoses group and 14 in the active group (p=0.056). The secondary measure showed no statistically significant differences between the groups. CONCLUSION: The use of elastic wrist orthoses as a postinjection regimen does not improve the outcome of intra-articular glucocorticoid treatment for wrist synovitis. Results achieved in studies on knees should not be generalised to other joints, and postinjection recommendations should differ depending on the joint treated.
12716440 Elucidation of the potential roles of matrix metalloproteinases in skeletal biology. 2003 Irreversible destruction of joint structures is a major feature of osteoarthritis and rheumatoid arthritis. Fibrillar collagens in bone, cartilage and other soft tissues are critical for optimal joint form and function. Several approaches can be used to ascertain the role of collagenases, matrix metalloproteinases, in proteolysis of joint collagens in arthritis. These approaches include identifying spontaneous genetic disorders of the enzymes and substrates in humans and animals, as well as engineering mutations in the genes that encode these proteins in mice. Insights gained from such studies can be used to design new therapies to interrupt these catabolic events.
12020227 The effectiveness of tumor necrosis factor alpha antibody (infliximab) in treating recalci 2002 May BACKGROUND: Psoriasis is being recognized as an autoimmune disease in which immunocyte-derived cytokines are thought to drive the development of the altered keratinocyte phenotype. Although the role of tumor necrosis factor alpha (TNF-alpha) in psoriasis is not completely understood, it may underlie many of the key steps that lead to induction and maintenance of the disease. Infliximab is an immunoglobulin monoclonal antibody that binds and inactivates TNF-alpha and has been successfully used in the management of TNF-alpha-mediated diseases, such as Crohn disease and rheumatoid arthritis. OBSERVATIONS: Two patients with recalcitrant psoriasis that was unresponsive to multiple skin-directed and systemic therapies were treated with a single infusion of infliximab. The treatments resulted in rapid and complete clearing of psoriatic erythroderma and resolution of symptoms of arthritis in one case and complete clearing of widespread psoriatic plaques and improvement of symptoms of arthritis and inflammatory bowel disease in the other. The single treatments with infliximab were well tolerated with no immediate or long-term adverse effects noted. CONCLUSION: A single infusion of infliximab at 5 to 10 mg/kg resulted in the rapid and complete clearing of recalcitrant psoriatic plaques and erythroderma with a disease-free interval of 3 to 4 months in these 2 patients and improved the symptoms of psoriatic arthritis.
15228620 Expanding the armamentarium for the spondyloarthropathies. 2004 Ankylosing spondylitis (AS) is a member of the family of spondyloarthropathies, which are inflammatory arthritides largely involving the axial skeleton and commonly accompanied by peripheral arthritis. Genetic factors, particularly the presence of HLA-B27, are major contributors to the susceptibility for AS. Despite some therapeutic advances, the treatment options for patients with AS and related disorders have been limited. Several lines of evidence have led to the hypothesis that patients with AS might benefit from treatment with tumor necrosis factor (TNF). Specifically, TNF concentrations are known to be significantly elevated in the synovium of patients with rheumatoid arthritis (RA), in the inflamed gut of patients with inflammatory bowel disease, and in the inflamed sacroiliac joints of patients with AS. The anti-TNF agents have been shown to be of benefit in, and currently have indications for, RA (etanercept, infliximab, adalimumab), Crohn's disease (infliximab), and psoriatic arthritis (etanercept). Because the spondyloarthropathies share pathogenetic mechanisms with the above-specified disease states, studies have been conducted to evaluate the effectiveness of anti-TNF agents in several disorders, including AS. Data from clinical trials so far with infliximab and etanercept show that patients with AS and related disorders achieve significant improvement in clinical signs and symptoms based on validated outcomes measures. Computed tomography and magnetic resonance imaging (MRI) can facilitate the early diagnosis of AS. Studies with infliximab using MRI together with updated scoring methods demonstrated significant decreases in associated spinal inflammation. TNF antagonist therapy is well tolerated in patients with AS, with a side effect profile consistent with the prior experience of patients with RA.
14677193 Total incidence and distribution of inflammatory joint diseases in a defined population: r 2003 Nov OBJECTIVE: To study the incidence of inflammatory joint diseases in a defined population in Finland. METHODS: We collected data for the year 2000 on a population of 87,000 inhabitants of Kuopio, Finland, of whom 20% were < 16 years of age. Information about the study was given through a local newspaper, and subjects attended one health center and 2 local hospitals for study. Inclusion criteria were that subjects have at least one peripheral joint with synovitis or signs of inflammation in sacroiliac, glenohumeral, or hip joints on the first visit. Incidence rates were calculated according to the diagnosis on the first visit, except for children, for whom diagnoses were established after 3 months' followup. RESULTS: A total of 188 adult incident cases (138 women, 50 men) and 11 children (8 girls, 3 boys) satisfied the inclusion criteria. The incidence of all arthritides was 230/100,000 (95% confidence interval 198.9-263.9) for the whole population; 271/100,000 (95% CI 233.7-312.7) for adults and 64/100,000 (95% CI 31.7-113.8) for children. Among adults the annual incidence of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), other spondyloarthropathies (SpA), connective tissue disease (CTD), crystalline arthritis, viral arthritis, and undifferentiated arthritis were 36, 7, 23, 10, 13, 9, 19, 7, and 149/100,000, respectively. The mean age at diagnosis was 49.4 +/- 16.3 years for all cases of arthritis among adults, about the same for both women and men. The mean age at diagnosis was 59.7 years in RA, 31.5 years in AS, 48.7 years in PsA, 38.0 years in ReA, 36.5 years in other SpA, 36.1 years in CTD, 65.0 years in crystalline arthritis, 53.3 years in viral arthritis, and 48.3 years in undifferentiated arthritis. Four of 11 children had juvenile idiopathic arthritis (JIA). The incidence of JIA was 23/100,000 in the population < 16 years of age. Of the remaining cases, 3 children had antibodies against Sindbis (Pogosta) virus and 4 had a transient monoarthritis. CONCLUSION: The overall incidence of arthritides among adults was slightly higher than previously reported from Finland. The incidence rates in the child population are in agreement with previous figures. These data are useful in planning the provision of health care.
11914926 RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse. 2002 Mar Rheumatoid arthritis (RA) is a systemic disorder characterized by synovial inflammation and subsequent destruction and deformity of synovial joints. The articular lesions start with synovitis, focal erosion of unmineralized cartilage, and then culminate in the destruction of subarticular bone by pannus tissue. Periarticular osteopenia and systemic osteoporosis follow as late complications of RA. Osteoclasts, specialized cells that resorb bone, play a central role in developing these osteolytic lesions. To elucidate the mechanism of osteoclastogenesis and bone destruction in autoimmune arthritis, we investigated the expression of RANK ligand (RANKL), RANK, and osteoprotegerin (OPG) mRNA in a mouse type II collagen-induced arthritis (CIA) model by in situ hybridization. The results indicated that most of the TRAP-positive mono- and multinucleated cells in the inflamed and proliferating synovium and in the pannus were RANK-positive authentic osteoclasts and their precursors. In the inflamed synovium and pannus of the mouse CIA model, synovial fibroblastic cells around these RANK-positive cells were strongly positive for RANKL. Moreover, RANKL-positive osteoblasts on the endosteal bone surface, at a distance from the affected synovial joints, increased significantly in the mouse CIA model prior to periarticular osteopenia and systemic osteoporosis. These data indicated that the RANKL-RANK system plays an important role for osteoclastogenesis in both local and systemic osteolytic lesions in autoimmune arthritis, and can therefore be a good target for therapeutic intervention.
12051397 Evaluation of amplicor chlamydia PCR and LCX chlamydia LCR to detect Chlamydia trachomatis 2002 Mar OBJECTIVES: PCR has been successfully used in research for the detection of C. trachomatis DNA in synovial samples. However, each research laboratory has developed its own PCR, making inter-laboratory comparisons difficult. To allow for standardization we evaluated two commercially available amplification systems originally designed for the examination of urogenital samples (Roche Amplicor Chlamydia PCR and Abbott LCX Chlamydia LCR), using them to analyse spiked and clinical synovial fluid (SF) samples from reactive arthritis (ReA), undifferentiated arthritis (UA), and rheumatoid arthritis (RA) patients. We compared their sensitivity in assays of clinical SF samples with our in-house developed C. trachomatis specific nested PCR. METHODS: SF was spiked with purified C. trachomatis elementary bodies (EB) and analyzed by the commercial assays. Clinical SF samplesfrom ReA (n=21), UA (n=79) and RA (n=50) patients were examined by the two commercial assays and our in-house PCR. RESULTS: Using SF samples spiked with defined numbers of C. trachomatis EB, the sensitivity of the commercial tests was high and similar to published PCR sensitivity. In clinical SF specimens the commercial assays was also able to detect CT; however, the in-house PCR was more sensitive. Out of 10 PCR-positive SF samples Amplicor tested positive in only 4/10 and LCX in only 3/10. The in-house PCR detected chlamydial DNA in synovialfluidfrom 5/21 ReA (24%), 5/79 UA (6%) and in none of the 50 RA patients. CONCLUSION: Commercial amplification assays allow the detection of C. trachomatis in clinical specimens, although with a lower sensitivity than optimized PCR. Potential explanations are discussed.
11860705 Interleukin-13 gene therapy reduces inflammation, vascularization, and bony destruction in 2002 Feb 10 Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovial pannus formation, leukocyte infiltration, and angiogenesis. Adenoviral production of interleukin-13 (IL-13) reduces levels of proinflammatory mediators in an explant model of RA synovial tissue in vitro. To assess this approach in an animal model of arthritis, we compared intra-articular injections of an adenovirus producing rat IL-13 (AxCArIL-13), a control virus, and rat ankles receiving phosphate-buffered saline (PBS) in rat adjuvant-induced arthritis (AIA). We demonstrate that IL-13 levels are normally low in ankles throughout the course of rat AIA. We show that administration of AxCArIL-13 before arthritis onset significantly reduces ankle circumference, paw volume, bony destruction, the number of polymorphonuclear cells (PMNs), the quantity of blood vessels, and levels of monocyte chemoattractant protein (MCP)-1 in ankles. When administered as a treatment to inflamed ankles, AxCArIL-13 decreases articular index scores, paw volumes, bony destruction, vascularization, tumor necrosis factor-alpha (TNF-alpha) levels, and the quantity of monocytes, lymphocytes, and PMNs. Thus, increasing IL-13 levels significantly ameliorates the course of rat AIA, suggesting that similar strategies for the treatment of human RA are worthy of further study.
15496642 Absence of a clinically relevant interaction between etanercept and digoxin. 2004 Nov Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr), is effective and well tolerated in the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between digoxin and etanercept at steady state. In a crossover, open-label, nonrandomized, 3-period study, 12 healthy male subjects received loading oral doses of digoxin 0.5 mg every 12 hours on day 1 and 0.25 mg every 12 hours on day 2, followed by a daily maintenance dose of 0.25 mg for a total of 27 days. Etanercept was administered as a twice-weekly 25-mg subcutaneous dose beginning on day 9 and continuing up to day 37 for a total of 9 doses. All ratios of maximum plasma concentration (C(max)) and area under the plasma concentration versus time curve (AUC) for pharmacokinetics of digoxin fell within the confidence interval of 0.8 to 1.25. Although not considered clinically relevant, the mean C(max) and AUC of etanercept were 4.2% and 12.5% lower, respectively, when etanercept was given with digoxin than when administered alone. There were no clinically relevant changes in the electrocardiogram (ECG) parameters, and adverse events did not increase when both drugs were combined. In conclusion, there is no clinically relevant interaction between etanercept and digoxin, and both drugs can be safely coadministered without the need for a dosage adjustment.
15380040 A proinflammatory role for Fas in joints of mice with collagen-induced arthritis. 2004 Collagen-induced arthritis (CIA) is a chronic inflammatory disease bearing all the hallmarks of rheumatoid arthritis, e.g. polyarthritis, synovitis, and subsequent cartilage/bone erosions. One feature of the disease contributing to joint damage is synovial hyperplasia. The factors responsible for the hyperplasia are unknown; however, an imbalance between rates of cell proliferation and cell death (apoptosis) has been suggested. To evaluate the role of a major pathway of cell death - Fas (CD95)/FasL - in the pathogenesis of CIA, DBA/1J mice with a mutation of the Fas gene (lpr) were generated. The susceptibility of the mutant DBA-lpr/lpr mice to arthritis induced by collagen type II was evaluated. Contrary to expectations, the DBA-lpr/lpr mice developed significantly milder disease than the control littermates. The incidence of disease was also significantly lower in the lpr/lpr mice than in the controls (40% versus 81%; P < 0.05). However DBA-lpr/lpr mice mounted a robust immune response to collagen, and the expression of local proinflammatory cytokines such as, e.g., tumor necrosis factor alpha (TNF-alpha) and IL-6 were increased at the onset of disease. Since the contribution of synovial fibroblasts to inflammation and joint destruction is crucial, the potential activating effect of Fas on mouse fibroblast cell line NIH3T3 was investigated. On treatment with anti-Fas in vitro, the cell death of NIH3T3 fibroblasts was reduced and the expression of proinflammatory cytokines TNF-alpha and IL-6 was increased. These findings suggest that impairment of immune tolerance by increased T-cell reactivity does not lead to enhanced susceptibility to CIA and point to a role of Fas in joint destruction.
14528319 Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in muri 2003 Nov The angiogenic factor VEGF promotes synovitis and bone erosion in rheumatoid arthritis (RA). Previously, we have demonstrated that VEGF expression correlates with disease severity in RA patients and in murine collagen-induced arthritis (CIA). In this study, we adopted an adenoviral gene delivery system expressing soluble VEGF receptor 1 (sFlt-1) to further study the role of VEGF in CIA. Arthritis was induced in DBA/1 mice by injection of bovine collagen. Adenoviruses expressing human soluble VEGF receptor 1 (AdvsFlt-1), or without transgene (Adv0), were injected intravenously on the first day of arthritis. We found that disease severity and paw swelling were significantly suppressed in mice receiving AdvsFlt-1, when compared to untreated or Adv0-treated mice. Expression of sFlt-1 peaked 24 h after injection, with protein detectable in the liver, synovial issue and serum, but rapidly decreased by 72 h. The effect of sFlt-1 expression on signs of disease was paralleled by reduced joint destruction and decreased expression of the vascular marker von Willebrand factor. In summary, adenoviral delivery of human soluble VEGF receptor type 1 significantly suppressed disease activity in CIA. The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA.
15557198 Inhibition of fractalkine ameliorates murine collagen-induced arthritis. 2004 Dec 1 Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive infiltration of inflammatory cells in the synovium of multiple joints. We and others have shown that fractalkine (FKN/CX3CL1), a chemokine expressed on fibroblast-like synoviocytes and endothelial cells in RA synovium, may contribute to the accumulation of T cells, macrophages, and dendritic cells, which express CX3CR1, the receptor for FKN. This interaction might be involved in adhesion of the inflammatory cells to endothelial cells, migration into the synovium, and cytokine production. In this study, we examined the effect of FKN inhibition on murine collagen-induced arthritis. Anti-FKN mAb significantly lowered clinical arthritis score compared with control Ab, and reduced infiltration of inflammatory cells and bone erosion in the synovium. However, anti-FKN mAb did not affect the production of either serum anti-collagen type II (CII) IgG or IFN-gamma by CII-stimulated splenic T cells. Furthermore, treatment with anti-FKN mAb inhibited migration of adoptively transferred splenic macrophages into the inflamed synovium. Our results suggest that anti-FKN mAb ameliorates arthritis by inhibiting infiltration of inflammatory cells into the synovium. Thus, FKN can be a new target molecule for the treatment of RA.
12839866 Calcineurin inhibitors exert rapid reduction of inflammatory pain in rat adjuvant-induced 2003 Jul 1. FK506 and cyclosporin A (CsA) are immunosuppressive drugs, that specifically inhibit T-cell activation via calcineurin inhibition. This study was undertaken to investigate whether calcineurin inhibitors exert analgesic actions in rat adjuvant-induced arthritis (AIA), an animal model of rheumatoid arthritis (RA). 2. AIA was induced in female Lewis rats. Single doses of FK506 and CsA were orally administered to arthritic rats 17 days after arthritis induction. Intensity of hyperalgesia was assessed by measuring the pain threshold of hind paws. Tumor necrosis factor (TNF)-alpha, IL-1beta and PGE(2) levels in paw extracts were determined by ELISA. TNF activity was measured by L929 cell cytotoxicity assay. IL-1beta and cyclooxygenase (COX) mRNA expression in arthritic paws were measured by RT-PCR. 3. Single doses of FK506 and CsA markedly reduced joint hyperalgesia 24 h after drug administration, without affecting inflammation in an advanced stage of AIA. 4. The calcineurin inhibitors partially reduced the elevated level of TNF-alpha in arthritic paws, however, the analgesic effects of these drugs were not associated with the reduction in TNF-alpha level. 5. Moreover, treatment with anti-rat TNF-alpha antibody did not affect the hyperalgesia, when TNF-alpha activity was suppressed in arthritic paws by that treatment. 6. Both calcineurin inhibitors reduced the elevated level of IL-1beta in arthritic paws to a normal level, 24 h after drug administration. 7. FK506 reduced IL-1beta and COX-2 mRNA expression and PGE(2) level in arthritic paws. 8 In conclusion, calcineurin inhibitors rapidly reduce joint hyperalgesia probably by downregulating IL-1beta, but not TNF-alpha, in AIA. Our findings may provide a new strategy for the treatment of pain in RA.
15461871 Infliximab monotherapy for refractory psoriasis: preliminary results. 2004 Sep Tumour necrosis factor (TNF)-alpha plays an important role in the pathogenesis of psoriasis. Infliximab is an anti-TNF-alpha chimeric monoclonal antibody, which is licensed for the treatment of rheumatoid arthritis and Crohn's disease. Some reports have shown the efficacy of infliximab, either in monotherapy or in combination with methotrexate, for the treatment of psoriatic arthropathy and psoriasis. The efficacy and tolerability of infliximab monotherapy was evaluated in 29 patients with moderate to severe psoriasis, unresponsive to conventional treatments. Fourteen patients suffered from concomitant arthropathy. Patients received intravenous infliximab, 5mg/kg, at weeks 0, 2, and 6. After this 3-dose-induction regimen, patients were followed-up at monthly intervals and retreated with a single-dose infusion in case of relapse of signs and symptoms. Clinical assessment was performed using the psoriasis area and severity index (PASI) to monitor psoriasis activity; pruritus and joint pain were assessed on a scale of 0 to 3. A marked improvement of skin lesions and subjective symptoms was noted in the majority of patients; an excellent reduction of PASI score (> or =75%) was observed in 13.8% of cases at week 2, 71.4% at week 6 and 78.6% at week 10. During the follow-up period, some patients maintained satisfactory clinical results without requiring any additional infusions. In general, skin lesions showed a trend towards a more prolonged and sustained improvement as compared with subjective symptoms. Treatment was well tolerated and no serious adverse events occurred.
12000198 Ambulatory treatment with intravenous norepinephrine in a patient with end stage renal dis 2002 Mar A 35-year-old man with juvenile rheumatoid arthritis and generalized AA amyloidosis of 10 years duration developed end stage renal failure. Following appendectomy, the patient experienced progressive circulatory failure which required IV treatment with norepinephrine. All attempts to discontinue IV norepinephrine failed, each leading to recurrent life-threatening hypotension. Finally, a central venous port with a portable mechanical infusion pump system was implanted supplying a continuous norepinephrine infusion. The patient then became independently mobile and could be discharged. For three months, the patient was monitored as an outpatient and treated by ambulatory intermittent hemofiltration. Finally, the patient suffered from a hemorrhagic infarction of the small bowel due to postoperative adhesions and died shortly after surgery. At autopsy, advanced generalized AA amyloidosis was found. Amyloid deposits had almost entirely replaced the cortex and the medulla of the adrenal glands. It can be speculated that the requirement of exogenous norepinephrine may be in part due to an adrenal insufficiency whereas it was initially considered as being only related to cardiac involvement. A continuous ambulatory treatment with catecholamines could be a possible treatment - at least temporarily - in amyloid cases in which all other attempts have failed to prevent chronic life-threatening hypotension.