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ID PMID Title PublicationDate abstract
15479888 Synovial tissue interleukin-18 expression and the response to treatment in patients with i 2004 Nov OBJECTIVE: To measure synovial tissue interleukin-18 (IL-18) expression in patients with inflammatory arthritis, and to identify associations with serum levels, disease activity, and response to treatment. METHODS: Synovial tissue biopsies and serum samples were obtained from patients with early, active, rheumatoid arthritis (RA) (n = 12), undifferentiated seronegative arthritis (SnA) (n = 9), psoriatic arthritis (PsA) (n = 5), and reactive arthritis (ReA) (n = 2) before and one year after introduction of disease modifying antirheumatic drug (DMARD) treatment. Osteoarthritis (OA) tissues were compared. Tissue IL-18 expression was determined after immunohistochemical staining using a semiquantitative scale. Serum IL-18 was measured by enzyme linked immunosorbent assay. RESULTS: Before treatment was started, tissue IL-18 expression was increased in each diagnostic group compared with OA (p<0.05). Tissue IL-18 expression was correlated with serum C reactive protein levels (r = 0.53, p = 0.003) but not with serum IL-18. After DMARD treatment, 12 patients (five RA, four SnA, three PsA) were re-evaluated. Decreases in tissue IL-18 expression were observed in eight, although the trend did not reach significance (p = 0.068). Changes in tissue IL-18 expression were correlated with changes in serum IL-18 (r = 0.62, p = 0.041) and C reactive protein (r = 0.72, p = 0.009). CONCLUSIONS: Synovial tissue IL-18 expression was correlated with disease activity in inflammatory arthritis. After treatment, tissue levels changed in parallel with changes in serum IL-18 and with changes in the acute phase response. These observations support a role for IL-18 in the pathophysiology of inflammatory arthritis.
12847274 IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leuk 2003 Jul 15 IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-alpha induction, which drives the production of leukotriene B(4) (LTB(4)), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB(4) and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB(4) synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB(4) production could also be blocked by a neutralizing anti-TNF-alpha Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55(-/-) mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB(4) that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.
11823125 Preparation and bioevaluation of 166Ho labelled hydroxyapatite (HA) particles for radiosyn 2002 Feb The preparation of 166Ho labeled hydroxy apatite (HA) particles for radiosynovectomy applications is described in this paper. 166Ho was prepared by the irradiation of Ho2O3 at a flux of 1.8 x 10(13) neutrons/cm2/s for about 7 days. The irradiation resulted in the production of approximately 17 GBq of 166Ho activity at the end of six hours post end of bombardment and the corresponding specific activity was approximately 3-4 GBq/mg of Ho. The irradiated target was dissolved in 0.1 N HCl solution. Radionuclidic purity was ascertained by high resolution gamma ray spectrometry. HA particles were synthesized and characterized by X-ray diffractometry. Labeling studies were carried out with and without citric acid as a transchelating agent. Radiochemical yield and purity of the 166Ho-HA particles were ascertained by paper chromatography and by paper electrophoresis techniques. Labeling yield of >98% could be achieved at pH 7, with 40 mg of HA particles and 8.6 microg of Ho. 166Ho-HA particles prepared were stable for 72 h. Bio-evaluation of the 166Ho -HA particles were carried out by injecting approximately 74 MBq dose in 200 microL (approximately 8 mg of 166Ho-HA particles) directly into the arthritis induced knee joints as well as into the healthy knee joints of white New Zealand rabbits. Images of the injected joints of the animals recorded using a gamma camera at regular intervals showed good retention. Blood samples were collected from the animals and activity assayed in a scintillation detector. Experiments were also carried out under identical conditions in normal rabbits. In both the cases, it was observed that there was no significant extra articular leakage of the injected activity over the study period of 96 h post injection.
15242784 PAF is involved in the Mycoplasma arthritidis superantigen-triggering pathway for iNOS and 2004 Aug 1 We investigated the capacity of Mycoplasma arthritidis mitogen (MAM) to induce (a) expression of the inducible enzymes cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS), (b) production of prostaglandin E2 (PGE2) and nitric oxide (NO), and (c) involvement of platelet-activating factor (PAF) in the MAM-induced activation pathway. Resident peritoneal cells from C3H/HePas mice were incubated with MAM in the presence or absence of a PAF-antagonist (WEB2170) or COX-2 inhibitors (nimesulide or NS398). Enzyme expression was evaluated by immunoblotting, PGE2 by EIA, and NO by Griess reaction. Following MAM-stimulation of peritoneal cells, expression of COX-2 was detected at 3 h (peak levels at 12 h) and of iNOS at 6 h (peak levels at 20 h). PGE2 increased till 20 h, decreasing thereafter, whereas NO increased with time. WEB2170 (5 x 10(-5) M) treatment caused 44% inhibition of NO output and reduced iNOS expression (48% at the peak of expression). Concomitant treatment with WEB2170 and nimesulide (10(-5) M) reversed these inhibitory effects. WEB2170 reduced COX-2 expression (43% at the peak of expression) and prevented the decline in PGE2 levels after 20 h. These results suggest the involvement of PAF in the signaling pathway triggered by MAM that leads to expression of iNOS and COX-2, and show that PAF regulates the production of NO, possibly by controlling levels of PGE2.
14619096 [Membranous constriction of the colon caused by non-steroidal anti-inflammatory drugs--cas 2003 Aug A 79-year-old female patient with rheumatoid arthritis treated with NSAIDs on long-term developed iron-deficiency anaemia and subsequently subacute intestinal obstruction. Barium enema showed multiple diaphragm-like strictures. At colonoscopy the lumen of the ascending colon was divided into compartments by multiple thin circumferential mucosal membranes. Right hemicolectomy was carried out. The histology of the resected specimen confirmed diaphragm disease of the large bowel. Diagnosis is usually difficult, even at laparotomy, due to the poor external presence of the disease. Such lesions are rare (about 10 cases have been reported in the world literature) and are similar to those previously described in the small bowel. With the increasing world-wide use of NSAIDs, clinicians must be aware of this rare gastrointestinal complication, which may require emergency surgical intervention.
15170921 The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthri 2004 Jun OBJECTIVE: To describe the degree of clinical benefit in patients with rheumatoid arthritis (RA) who receive infliximab therapy after lack of efficacy with etanercept. METHODS: In a retrospective study among 6 centers primarily designed to assess the safety of infliximab in combination with leflunomide, a standardized chart review form was used to collect data on 93 patients with RA. During that study, it was noted that some of these patients had switched from etanercept to infliximab. In this study, we compared the response of subjects switching from etanercept to infliximab (n = 20) to that of subjects receiving infliximab with no prior tumor necrosis factor (TNF) therapy (n = 73). RESULTS: The swollen and tender joint count, patient and physician global assessments, morning stiffness, and C-reactive protein all improved substantially in both groups, with no statistical difference in the degree of benefit between the groups. At the time of chart review, switchers had received a statistically higher dose of infliximab than controls (4.4 vs 3.19 mg/kg; p = 0.006) with a total of 5.7 and 5 infusions, respectively. CONCLUSION: In this retrospective study, previous lack of efficacy with etanercept did not predict lack of efficacy with infliximab. Indeed, the degree of clinical improvement was similar in both groups, although switchers were receiving a higher dose of infliximab at the time of chart review. Our findings suggest that clinical response may differ between anti-TNF agents, and lack of response to one agent may not predict a lack of response to another.
12707691 [In vivo assessment of mobility of meniscal bearings with ultrasound]. 2003 Apr Clinical scores and fluoroscopically guided standard X-rays are still the golden standard for evaluating the outcome of total knee arthroplasty, but up to now there was no way to evaluate the function of mobile inlays except with digital fluoroscopy. We describe a new method using a flat 8-MHz ultrasound for the in vivo measurement of meniscal bearings (MB) with an accuracy and precision of 0.7 mm and 0.4 mm, respectively. In 73 knees with LCS classic total knee replacement, all of the medial (100%) and 71 of the lateral (97%) MB could be analyzed. The MB moved unhindered with an average total shift of 4.5 mm (range: 0.2-12.1) on the medial and 4.2 mm (range: 0.8-13.2) on the lateral side. A significant correlation was found between the active range of motion (ROM) of the knee joint and the medial MB's shift ( p=0.004) but not for the lateral MB ( p=0.114). Three knees had to be revised due to aseptic loosening (2) or excessive PE wear (1). No single parameter of the ultrasound analysis could be detected to be predictive for the MB's failure. Conventional ultrasound allows the analysis of MB function at low cost with an accuracy better than 1 mm. This method is an alternative to radiological methods and suitable for studies with larger numbers of patients followed over longer periods.
14637151 Akt is an endogenous inhibitor toward tumor necrosis factor-related apoptosis inducing lig 2003 Dec 12 Akt is known to be activated in the rheumatoid synovial tissues. We examined here functional role of Akt during tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis in rheumatoid synovial cells. Rheumatoid synovial cells in vitro were rapidly committed to apoptosis in response to TRAIL in mitochondria-dependent manner whereas Akt and extracellular signal-regulated kinase (ERK) were also phosphorylated. TRAIL-mediated apoptosis in synovial cells was significantly increased through inactivation of Akt by LY294002, however, that process was not so changed by adding ERK inhibitor, PD98059. Platelet-derived growth factor (PDGF) clearly phosphorylated both Akt and ERK in synovial cells, and PDGF pretreatment markedly suppressed TRAIL-mediated synovial cell apoptosis. The use of not PD98059 but LY294002 abrogated PDGF-mediated inhibitory effect toward TRAIL-induced apoptosis in synovial cells. The above protective effect of Akt was confirmed by the use of short interfering RNA (siRNA)-directed inhibition of Akt. Our data suggest that Akt is an endogenous inhibitor during TRAIL-mediated synovial cell apoptotic pathway, which may explain that synovial cells in situ of the rheumatoid synovial tissues are resistant toward apoptotic cell death in spite of death receptor expression.
12716448 Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis. 2003 Urokinase plasminogen activator (uPA) is an important regulator of fibrinolysis in synovial fluid. An increase of uPA activity and expression of its receptor have been reported in joints of patients with rheumatoid arthritis (RA). The aim of the present study was to assess the arthritogenic capacity of uPA and the mechanisms by which this effect is mediated. uPA was injected into the knee joints of healthy mice, and morphological signs of arthritis were assessed 4 days after the injection. The prerequisite of different leukocyte populations for the development of uPA-triggered arthritis was assessed by selective cell depletion. The inflammatory capacity of uPA was assessed in vitro. Finally, levels of uPA were measured in 67 paired blood and synovial fluid samples from RA patients. The synovial fluid from RA patients displayed higher levels of uPA compared with blood samples. Morphological signs of arthritis were found in 72% of uPA-injected joints compared with in only 18% of joints injected with PBS (P < 0.05). Synovitis was characterised by infiltration of CD4-Mac-1+ mononuclear cells, by the formation of pannus and by occasional cartilage destruction. The absence of monocytes and lymphocytes diminished the frequency of synovitis (P < 0.01), indicating an arthritogenic role of both these leukocyte populations. Synthetic uPA inhibitor downregulated the incidence of uPA-triggered arthritis by 50%. uPA induced arthritis, stimulating the release of proinflammatory cytokines IL-6, IL-1beta and tumour necrosis factor alpha. Accumulation of uPA locally in the joint cavity is a typical finding in erosive RA. uPA exerts potent arthritogenic properties and thus may be viewed as one of the essential mediators of joint inflammation.
12957697 Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low dise 2003 Sep OBJECTIVE: Cardiovascular mortality is excessive in patients with rheumatoid arthritis (RA). It has been proposed that the chronic inflammatory state of RA contributes to accelerated atherosclerosis. The aim of this study was to determine whether endothelial dysfunction, an early sign of arteriosclerosis, is present in young, long-term RA patients receiving standard methotrexate (MTX) therapy. Furthermore, we tested whether etanercept (ENC), a TNF-alpha receptor blocker, resulted in improved endothelial function compared to MTX in the same patients. METHODS: We studied eight RA patients twice: (1) on MTX and (2) after MTX washout and receiving ENC. Eight healthy volunteers matching for age, gender, height, weight and conventional cardiovascular risk factors served as control (C). All participants received intrabrachial infusions of increasing doses of acetylcholine (ACh, endothelium-dependent vasodilator) and glyceryl-trinitrate (GTN, endothelium-independent vasodilator). Forearm blood flow (FBF) was measured by bilateral venous occlusion plethysmography. RESULTS: Disease activity of RA was comparably low during both MTX and ENC (DAS 28 3.9+/-0.3 and 3.5+/-0.3). FBF in response to ACh was reduced in RA compared to C (P<0.01). Switching from MTX to ENC failed to improve vascular responsiveness to ACh. GTN comparably increased FBF in all groups. CONCLUSIONS: Our study for the first time demonstrates that long-term RA is associated with manifested endothelial dysfunction. Switching from MTX to ENC in stable RA patients has no beneficial effect on endothelial function.
14968383 [Early postoperative functional differences between total knee arthroplasties supplied wit 2004 Jan AIM: The goal of this study was to analyze differences of gait patterns among patients with total knee arthroplasty supplied with mobile-bearing platform in contrast to patients supplied with fixed-bearing knee systems. METHOD: For that reason 17 patients with mobile-bearing knee systems and two groups of 15 patients each with fixed-bearing knee systems have been examined clinically, radiologically, and by means of gait analysis up to 6 months postoperatively. Additionally 20 knee-healthy control subjects have been gait-analyzed for comparison. RESULTS: There existed no different developments of gait characteristics between the groups of patients in the preoperative status. After the operation an increase of the ground reaction force of the operated leg was observed in all groups. The functional range of motion in the operated knee joint improved among patients postoperatively. Besides, in the group with the mobile-bearing knee a significantly stronger flection of the operated leg during the stance phase under load could be proven. Between the groups of patients the average values of the respective radiological alignments did not exhibit statistically significant differences. No severe complications have been observed. CONCLUSION: For the group of patients with fixed-bearing knee course samples have been registered, which approximate the reference values of healthy control subjects more strongly. The entire course sample is characterized by an increased range of motion of the opposite side and the adjacent joints. The parameters measurable in the gait analysis point to a better biomechanical situation after implantation of the mobile-bearing system.
15218566 Effect of various stress models on lidocaine pharmacokinetic properties in the mandible af 2004 Jul PURPOSE: The aim of this study was to investigate the role of stress (trauma, cold swimming, and adjuvant rheumatoid arthritis) on lidocaine concentrations as well as lidocaine's protein binding in the mandible. MATERIALS AND METHODS: Forty male Wistar rats were used. The animals were divided into four groups. Group A served as control. Group B underwent mandible osteotomy. Group C was submitted to cold swimming stress. Group D was subjected to experimental arthritis. Additionally, all the groups received 5 doses of lidocaine, 1 dose of lidocaine (3 mg/kg) intramuscularly every 2 hours. Two hours after the last dose, the animals were killed. Lidocaine concentrations were estimated in plasma. Furthermore, the mandible was isolated, and both lidocaine concentrations and lidocaine protein binding were assessed. RESULTS: In groups under stress, lidocaine concentrations in serum showed a marked elevation. In addition, these animals demonstrated a significant decrease in the percent of lidocaine binding in the mandible. CONCLUSIONS: Stress can modify local anesthetics pharmacokinetic properties, resulting in alterations both in their concentration in serum and their protein binding in mandibular bone.
12399886 [Technique and diagnostic value of musculoskelatal ultrasonography in rheumatology. Part 5 2002 Oct Shoulder-related symptoms are very common in rheumatic diseases. For the evaluation of the diagnosis as well as for therapy and prognosis, an anatomic assignment is essential. Clinical investigations alone are often not capable to do this. Ultrasonography is a method to delineate bony surfaces as well as the soft tissues around the shoulder joints statically and even dynamically. For the purpose of rheumatic diseases, ultrasound standard scans help to detect the lesions at the biceps tendon, the bursae, the rotator cuff, the humeral head as well as in the acromial and sternoclavicular joints. Considering the limitations of the method (obesity, frozen shoulder, no findings under bony structures) and knowing the pitfalls and errors of the method, ultrasonography is a reliable, quick and low cost method for the diagnosis of rheumatic shoulder joint pathology. Compared to computer tomography and magnetic resonance imaging, ultrasonography should be used as a screening method. The following standard scans are suggested for sonographic evaluation of the shoulder: 1) anterior transverse scan and 2) anterior longitudinal scan at the bicipal groove to detect synovitis and tenosynovitis, 3) anterior transverse scan at the coracoacromiale window in the neutral position, 4) at maximal external rotation and 5) at maximal internal rotation to evaluate the rotator cuff, bursitis, synovitis and erosions, 6) anterior longitudinal scan at 90 degrees to the coracoacomiale window at maximal internal rotation to describe these findings in an additional dimension, 7) anterior-lateral longitudinal scan at the anterior lateral acromion to tuberculum majus to evaluate the distal part of the supraspinatus muscle, 8) posterior transverse scan at the fossa infraspinata lateral under the spina scapulae, 9) axillary longitudinal scan to evaluate synovitis, synovial proliferation, erosions at the humeral head, lesions at the glenoidale labrum, 10) anterior transverse scan at the acromioclavicular joint and 11) anterior oblique scan at the sternoclavicular joint to detect synovitis, synovial proliferation, erosion, osteophytes.
14718605 Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2- 2004 Apr Tumor necrosis factor (TNF)-alpha is a well validated therapeutic target for the treatment of rheumatoid arthritis. TNF-alpha is initially synthesized as a 26-kDa membrane-bound form (pro-TNF) that is cleaved by a Zn-metalloprotease named TNF-alpha-converting enzyme (TACE) to generate the 17-kDa, soluble, mature TNF-alpha. TACE inhibitors that prevent the secretion of soluble TNF-alpha may be effective in treating rheumatoid arthritis (RA) patients. Using a structure-based design approach, we have identified a novel dual TACE/matrix metalloprotease (MMP) inhibitor 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1). This molecule inhibits TACE and several MMPs with nanomolar IC(50) values in vitro. In cell-based assays such as monocyte cell lines, human primary monocytes, and human whole blood, it inhibits lipopolysaccharide (LPS)-induced TNF-alpha secretion at submicromolar concentrations, whereas there is no effect on the TNF-alpha mRNA level as judged by RNase protection assay. The inhibition of LPS-induced TNF-alpha secretion is selective because TMI-1 has no effect on the secretion of other proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and IL-8. Importantly, TMI-1 potently inhibits TNF-alpha secretion by human synovium tissue explants of RA patients. In vivo, TMI-1 is highly effective in reducing clinical severity scores in mouse prophylactic collagen-induced arthritis (CIA) at 5, 10, and 20 mg/kg p.o. b.i.d. and therapeutic CIA model at 100 mg/kg p.o. b.i.d. In summary, TMI-1, a dual TACE/MMP inhibitor, represents a unique class of orally bioavailable small molecule TNF inhibitors that may be effective and beneficial for treating RA.
15588074 Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estroge 2004 Dec 16 Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
12473245 Polyreactivity of human IgG Fc-binding phage antibodies constructed from synovial fluid CD 2002 Dec Recent data indicate that rheumatoid factors (RFs) that occur in patients with rheumatoid arthritis (RA) are derived from Ig-producing terminally differentiated CD20-, CD38+ plasma cells present in synovial fluids (SFs). Phage antibody display libraries were constructed using CD38+ plasma cells isolated from SFs of two RF-seropositive RA patients. The libraries were enriched for phage antibodies (Phabs) binding to human IgG (HuIgG) Fc fragments and the sequences of their V genes were analysed. These data provided further evidence for an Ag-driven immune response in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a germinal center reaction. In the present study, the functional characteristics of these HuIgG Fc-binding monoclonal (mo) Phabs were further analysed in order to provide more insight into the specificity of HuIgG Fc-binding Phabs. Remarkably, all HuIgG Fc-binding moPhabs tested (n=48; derived from four different libraries) displayed polyreactivity. Structural analysis of the CDR3 regions revealed characteristic features of polyreactive Igs. Most H chain CDR3 regions harboured tryptophan/tyrosine-rich parts and approximately 60% of the L chain CDR3 regions of both RA patients displayed an identical stretch of amino acids (W/Y-D-S-S). Supportive for a dominant role of VH in specificity, exchange of VL regions with a single VH region yielded moPhabs with similar specificities. All together, the data suggest the presence of an Ag-driven process in the joints of patients with RA, including somatic mutation and clonal selection entailing isotype switching, resulting in the differentiation of B cells into polyreactive RF-secreting plasma cells.
11937933 [Phenylbutazone-induced sialadenitis fever simulating angioedema]. 2002 Jan BACKGROUND: Drug-induced sialadenitis is uncommon and unrecognized. Drugs such as nitrofurantoïn, nifedipine and methimazole have been reported to induce sialadenitis. However, phenylbutazone and oxyphenbutazone are the most frequently implicated agents. We describe a case of phenylbutazone-induced parotitis and submaxillitis with cutaneous and hepatic involvement. CASE REPORT: A 51 year-old woman who had received phenylbutazone for the past 6 days was hospitalized for diagnosis of Quincke's oedema. Clinical examination in fact revealed bilateral parotitis and submaxillitis. The patient had contracted mumps in infancy. Improvement was noticed 8 days after stopping the drug and treatment by glucocorticosteroid. Nevertheless a pruritic eruption with fever appeared. Laboratory data showed leukocytosis with neutrophilia, ESR of 75 mm/hr, hepatic cholestasis and cytolysis. Infectious and autoimmune causes were ruled out. The eruption spontaneously disappeared after 5 days. Laboratory studies 3 weeks later were normal. DISCUSSION: Quincke's edema diagnosis had been established too fast on "allergic past history" and patient interrogation. Complete clinical examination revealed the correct diagnosis of sialadenitis. This observation shows similarities with other publications: unbearable xerostomia appearing before sialadenitis and with a long course, parotitis with sub-maxillitis, 6 days delay after the first administration of phenylbutazone before fever, local evolution without complication, inflammatory biological syndrome with neutrophilia and absence of infectious cause. Pruritic maculo-papulous eruption and biological hepatic abnormalities are however rare. An hypersensibility mechanism is discussed.
12848626 Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn's di 2003 Jul 1 BACKGROUND: Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter. AIM: : To determine the relative bioavailability of oral low-dose methotrexate administered with and without concomitant folic acid vs. subcutaneous administration in patients with stable Crohn's disease. METHODS: Ten patients were randomized to receive their regular maintenance dose of methotrexate (15-25 mg) for three consecutive weeks: orally, orally with 5 mg folic acid or subcutaneously. Blood samples were drawn at specified intervals during 24 h, and methotrexate levels were determined by fluorescence immunoassay. Areas under the curve extrapolated to infinity (AUC infinity ) were compared between the three routes. RESULTS: The geometric mean AUC infinity values (95% confidence intervals) were 360 nmol x h/L (301-430 nmol x h/L), 261 nmol x h/L (214-318 nmol x h/L) and 281 nmol x h/L (209-377 nmol x h/L) per milligram of methotrexate administered for subcutaneous, oral and oral with folic acid administration, respectively (P < 0.05 and P < 0.01 for oral with folic acid and oral vs. subcutaneous administration, respectively). The geometric mean relative bioavailabilities (95% confidence intervals) were 0.73 (0.62-0.86) and 0.77 (0.60-0.99) for oral and oral with folic acid administration, respectively (difference not significant). CONCLUSIONS: In patients with stable Crohn's disease, the oral bioavailability of methotrexate is highly variable and averages 73% of that of subcutaneous administration. Concomitant folic acid has no significant effect on the bioavailability. Dose adjustments based on individual pharmacokinetic assessment should be considered when switching patients from parenteral to oral therapy.
12571296 Patellar resurfacing in total knee arthroplasty. A prospective, randomized study. 2003 Feb BACKGROUND: Anterior knee pain following total knee arthroplasty is a common complaint and typically is attributed to the patellofemoral joint. The purpose of the present study was to compare the outcome of resurfacing and nonresurfacing of the patella, particularly with regard to anterior knee pain, and to clarify the indications for patellar resurfacing at the time of total knee arthroplasty. METHODS: We performed a prospective, randomized study of 514 consecutive primary press-fit condylar total knee replacements. The patients were randomized to either resurfacing or retention of the patella. They were also randomized to either a cruciate-substituting or a cruciate-retaining prosthesis as part of a separate trial. The mean duration of follow-up was 5.3 years (range, two to 8.5 years), and the patients were assessed with use of the Knee Society rating, a clinical anterior knee pain score, and the British Orthopaedic Association patient-satisfaction score. The assessment was performed without the examiner knowing whether the patella had been resurfaced. At the time of follow-up, there were 474 knees. Thirty-five patients who had a bilateral knee replacement underwent resurfacing on one side only. RESULTS: The overall prevalence of anterior knee pain was 25.1% (fifty-eight of 231 knees) in the nonresurfacing group, compared with 5.3% (thirteen of 243 knees) in the resurfacing group (p < 0.0001). There was one case of component loosening. Ten of eleven patients who underwent secondary resurfacing had complete relief of anterior knee pain. The overall postoperative knee scores were lower in the nonresurfacing group, and the difference was significant among patients with osteoarthritis (p < 0.01). There was no significant difference between the resurfacing and nonresurfacing groups with regard to the postoperative function score. Patients who had a bilateral knee replacement were more likely to prefer the resurfaced side. CONCLUSIONS: As the present study showed a significantly higher rate of anterior knee pain following arthroplasty without patellar resurfacing, we recommend patellar resurfacing at the time of total knee replacement when technically possible.
12355481 Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is sha 2002 Sep OBJECTIVE: To analyze the fine specificity of IgG autoantibodies in sera from rheumatoid arthritis (RA) patients for type II collagen (CII) epitopes that are arthritogenic in collagen-induced arthritis (CIA), a relevant murine model of RA. METHODS: For enzyme-linked immunosorbent assay (ELISA) analysis of conformation-dependent autoantibody binding, recombinant chimeric collagens that harbor the respective CII epitopes as an insertion within the frame of a constant type X collagen triple helix were constructed. In addition, synthetic peptides mimicking the native collagen structures were applied for the first time in the ELISA assessment of humoral CII autoimmunity. RESULTS: The pathogenicity of IgG responses to certain CII determinants in CIA was demonstrated by arthritis development in BALB/c mice upon the combined transfer of 2 mouse monoclonal antibodies specific for precisely mapped conformational CII epitopes (amino acid residues 359-369 [C1(III)] and 551-564 [J1]), whereas antibodies to another epitope (F4) were not arthritogenic. To test whether human autoimmune responses are similarly directed to these conserved CII determinants, serum IgG was analyzed. The prevalence of sera with increased IgG binding to the C1(III) epitope was significantly higher in RA compared with sera from healthy donors or from patients with other rheumatic conditions, e.g., osteoarthritis (OA), systemic lupus erythematosus (SLE), or relapsing polychondritis (RP), whereas levels of antibodies specific for the nonarthritogenic F4 epitope were associated with OA rather than RA. CONCLUSION: Autoimmunity to CII, although detectable in different rheumatic conditions, differs in fine specificity between distinct disease entities. In RA, in contrast to degenerative joint disease, RP, and SLE, autoantibody responses are directed to an evolutionary conserved CII structure that is also targeted by pathogenic autoimmune responses in murine models of arthritis.