Successful treatment of rheumatoid arthritis is associated with a reduction in synovial membrane cytokines and cell adhesion molecule expression

OBJECTIVE: To investigate the change in synovial membrane cytokine content and cell adhesion molecule expression in sequential biopsies from the same knee joint of patients with rheumatoid arthritis, before and following anti-rheumatic drug treatment and to assess the relationship of these changes with clinical responses to the drug treatment. METHODS: A selected group of patients with rheumatoid arthritis, some of whom had achieved a disease remission based on American College of Rheumatology (ACR) criteria, were included in this study. Sequential synovial biopsies obtained before and throughout the treatment period were studied by immunohistochemical labelling techniques for the cellular content, production of a range of pro- and anti-inflammatory cytokines and the expression of cell adhesion molecules. The staining was quantitated using computer-assisted digital image analysis. RESULTS: There was a decrease in tumour necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) production in the synovial membrane lining and sublining of all patients who responded to treatment. The changes in IL-1 receptor antagonist production were variable. Paradoxically, there was a trend to decreased synovial membrane production of the anti-inflammatory cytokines, IL-10 and transforming growth factor-beta (TGFbeta), while IL-4 was not detectable in any of the synovial membrane biopsies. A significant reduction in the density and total amount of E-selectin expression in the synovial membrane was seen. Similarly, intercellular adhesion molecule-1 (ICAM-1) expression in the lining and sublining was decreased in those patients who had a significant clinical response to drug treatment or attained disease remission. There were no consistent or significant changes seen in the expression of other cell adhesion molecules in the synovial membranes of these patients. CONCLUSIONS: Successful drug treatment of rheumatoid arthritis patients is characterized at the synovial membrane level by a decrease in TNFalpha, IL-10 and TGFbeta production. Some (E-selectin and ICAM-1) but not all (P-selectin, VCAM-1, PECAM-1) cell adhesion molecules are modulated in patients who respond clinically to drug treatment. E-selectin and ICAM-1 may be important targets for the development of future drug treatments for rheumatoid arthritis.     

The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis

BACKGROUND: Small intestinal bacterial overgrowth may contribute to the development of non-alcoholic steatohepatitis, perhaps by increasing intestinal permeability and promoting the absorption of endotoxin or other enteric bacterial products. AIMS: To investigate the prevalence of small intestinal bacterial overgrowth, increased intestinal permeability, elevated endotoxin, and tumour necrosis factor alpha (TNF-alpha) levels in patients with non-alcoholic steatohepatitis and in control subjects. PATIENTS AND METHODS: Twenty two patients with non-alcoholic steatohepatitis and 23 control subjects were studied. Small intestinal bacterial overgrowth was assessed by a combined (14)C-D-xylose and lactulose breath test. Intestinal permeability was assessed by a dual lactulose-rhamnose sugar test. Serum endotoxin levels were determined using the limulus amoebocyte lysate assay and TNF-alpha levels using an ELISA. RESULTS: Small intestinal bacterial overgrowth was present in 50% of patients with non-alcoholic steatosis and 22% of control subjects (p=0.048). Mean TNF-alpha levels in non-alcoholic steatohepatitis patients and control subjects were 14.2 and 7.5 pg/ml, respectively (p=0.001). Intestinal permeability and serum endotoxin levels were similar in the two groups. CONCLUSIONS: Patients with non-alcoholic steatohepatitis have a higher prevalence of small intestinal bacterial overgrowth, as assessed by the (14)C-D-xylose-lactulose breath test, and higher TNF-alpha levels in comparison with control subjects. This is not accompanied by increased intestinal permeability or elevated endotoxin levels.     

Effects of pulse methylprednisolone on inflammatory mediators in peripheral blood,synovial fluid,and synovial membrane in rheumatoid arthritis

Objective. To establish whether the clinical efficacy of pulse methylprednisolone (MP; 1,000 mg intravenously) is related to the modulation of proinflammatory cytokines within the peripheral blood, synovial membrane, or synovial fluid compartments. Methods. Eighteen patients with active rheumatoid arthritis (RA) were studied. Peripheral blood (11 patients) and knee synovial fluid (9 patients, 10 knees) were obtained before and at 4 and 24 hours after MP therapy. Interleukin-1β (IL-1β), IL-8, and tumor necrosis factor α (TNFα) were measured by enzyme-linked immunosorbent assay and biologic assays; prostaglandin E₂ (PGE₂) was measured by competitive radioimmunoassay. In 10 patients, arthroscopically directed synovial biopsies were obtained before and at 24 hours after treatment, at disease relapse (4 patients), and after retreatment (1 patient). Membranes were stained by immunohistochemical techniques with monoclonal antibodies against TNFα, IL-8, IL-1β, and the IL-1 receptor antagonist protein (IL-1Ra). Results. MP therapy was associated with a rapid (within 24 hours) and substantial decrease in the expression of TNFα in the lining and sublining regions of the synovial membrane, as well as substantial decreases in the levels of TNFα in serum and synovial fluid. There was also reduced IL-8 expression in the synovial lining, as well as reduced synovial fluid IL-8 levels. No effect on synovial membrane IL-1β and IL-1Ra or synovial fluid IL-1β and PGE₂ was found. Conclusion. MP therapy rapidly reduces IL-8 and TNFα levels in the synovial compartment, with cytokine changes in the serum and synovial fluid reflecting the changes in the synovial membrane. Alterations in TNFα expression in the synovial membrane correlated with clinical response to, and subsequent relapse after, MP therapy.     

Elective re‐intubation to treat complete left lung collapse following Tetralogy of Fallot repair in a very young child

An 18‐month‐old boy weighing 6 kilograms developed complete collapse of left lung following total correction of Tetralogy of Fallot on the next day of extubation. He received extensive chest physiotherapy, along with lung recruitment maneuver by using bubble CPAP, which failed to show any improvement in lung expansion in 2 days. He was then electively intubated on 3rd postoperative day (POD3) for the purpose of suctioning tracheobronchial secretions and maintaining positive airway pressure to open up the left lung. Good results were obtained immediately after intubation, and he was extubated 9 h later. His lung showed complete aeration afterward. He was transferred out of ICU on POD5 and discharged home on POD10.     

Neutrophil trafficking into inflamed joints in patients with rheumatoid arthritis,and the effects of methylprednisolone

Objective. To investigate the trafficking of circulating blood neutrophils and synovial fluid neutrophils in rheumatoid arthritis (RA) patients and the influence of a 1,000-mg intravenous pulse of methylprednisolone succinate (MP). Methods. Neutrophils were isolated from the circulation and from the knee synovial compartments of subjects with RA. Circulating neutrophils were labeled with technetium-99m hexametazime (^99mTc-HMPAO) and reinjected intravenously. Synovial fluid neutrophils were labeled with indium-111 oxine and reinjected into the knee from which they were isolated. Gamma camera images were obtained at intervals up to 24 hours post MP. Each patient had a baseline study (no MP) and a study in which MP was administered either 4 hours before (2 patients), 10 minutes before (1 patient), or 30 minutes to 1.5 hours after (6 patients) injection of the radiolabeled neutrophils. Subsequent analysis allowed quantitation of the neutrophil uptake into and clearance from the knee as a function of time. Results. Nine patients who had not received glucocorticoids in the previous 3 months were studied. MP significantly decreased neutrophil ingress in 13 of the 16 knees studied (almost total inhibition in 5 knees), and this occurred within 1.5 hours of MP administration in all except 1 knee. At 24 hours after MP administration, there was a significant increase in visual analog scale (VAS) scores for well-being and significant decreases in scores on the modified Health Assessment Questionnaire (P < 0.05), tender joints (P < 0.005), VAS for pain (P < 0.005), and generalized stiffness (P < 0.005), as well as a decrease in the C-reactive protein level (P < 0.05). MP had no effect on neutrophil egress (2 patients). Two additional patients who were receiving oral glucocorticoids were studied. One of them was clinically unresponsive to oral prednisolone, and MP had no effect on neutrophil ingress. The other patient showed no neutrophil ingress during the baseline study. This was confirmed by the presence of a noninflammatory synovial fluid at arthrocentesis. Conclusion. Neutrophil ingress into and egress from inflamed joints can be accurately monitored using radiolabeled neutrophils and quantitative gamma camera imaging. MP rapidly and substantially decreases neutrophil ingress into inflamed joints. In contrast, MP has no effect on neutrophil egress from the joint.