Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis

OBJECTIVE: Reactive oxygen species are thought to play a role in rheumatoid arthritis (RA) in humans. We postulated that antioxidant treatment could have a beneficial effect in this disease. We therefore investigated the effects of vitamin E in the transgenic KRN/NOD mouse model of RA. METHODS: Mice were treated by gavage with oral vitamin E (alpha-tocopherol). Clinical, histologic, and biochemical parameters were assessed for 6 weeks. RESULTS: Vitamin E treatment did not modify the clinical features of the disease (date of onset or disease intensity, as measured by the articular index), but it did prevent joint destruction, as measured by qualitative and semiquantitative analyses. Redox status did not differ between treated and control mice. White blood cell chemiluminescence was higher in transgenic KRN/NOD mice than in controls, but vitamin E treatment attenuated this difference. Vitamin E treatment of the transgenic animals led to a significant decrease in the levels of interleukin-(IL-1beta) but not tumor necrosis factor alpha. CONCLUSION: Vitamin E seems to uncouple joint inflammation and joint destruction in this model of RA, with a beneficial effect on joint destruction. Since many investigations are currently in progress to evaluate the benefit of interventions targeted toward anti-IL-1beta, our findings suggest opportunities of therapeutic interest in human RA.     

Role of early synovectomy of the knee joint in rheumatoid arthritis

The prospective study of 32 knees in 26 patients with rheumatoid arthritis was carried out with an average followup of 3 years. Relief of pain and control of inflammation locally were obtained in 22 of 32 knees (69%). Articular cartilage was preserved in 20 of 28 knees (71%) and the synovitis recurred in 9 knees (28%), 7 of which showed progressive loss of cartilage. Therefore, it appears that synovectomy, if performed at a stage in which articular cartilage is still normal and after medical therapy has failed, is a very effective method for preserving articular cartilage and controlling inflammation locally. However, with a longer followup the disease with loss of articular cartilage will recur in a large number of cases. In patients whose disease progresses rapidly, no form of therapy effectively controls joint destruction.     

Listeria monocytogenes infection in a prosthetic knee joint in rheumatoid arthritis.

The prosthetic knee joint of a 64 year old woman with severe rheumatoid arthritis was found to be infected with Listeria monocytogenes. After treatment with intravenous antibiotics, symptoms gradually resolved. She subsequently received prolonged treatment with oral co-trimoxazole and 18 months later remained well.     

Predictors of rheumatoid arthritis in patients who have monoarthritis in a knee joint

To determine the predictive factors for rheumatoid arthritis (RA), 79 patients (11 men, 68 women; average age at onset of symptoms 37.1 years) with fixed joint effusion of one knee joint, of minimum 6 months' duration, were divided into three groups: group I, 11 patients (14%) who progressed to RA; group II, 8 patients (10%) with the correct diagnosis, except that RA became apparent during the subsequent follow-up; group III, 60 patients (76%) whose joint effusion resolved. In group I, the degree of joint effusion and the serological values of interleukin (IL)-1β, IgG-RF, and rheumatoid factor (RF) tended to be higher than those in the other groups at the time of our initial examination. The synovial fluid concentrations of IL-1β and IgG-RF in group I were significantly higher than those in the other groups. Magnetic resonance imaging (MRI)-determined stage and histological assessment of synovial inflammation also tended to be higher in group I than in the other groups. This study revealed that it might be possible to predict the outcome of cases of monoarthritis by examining IL-1β and IgG-RF levels in the synovial fluid, in addition to various elevated inflammation signs in the knee joint. Received: July 10, 2000 / Accepted: October 18, 2000     

Assessment of rheumatoid inflammation in the knee joint. A reappraisal.

Subjective pain score, clinical assessment, 99m technetium joint uptake, infrared thermography, and thermistor skin temperature measurements were evaluated and compared in patients with rheumatoid knee treated with intra-articular hydrocortisone. In 11 patients with definite and classical rheumatoid arthritis, 10 of whom had unilateral knee involvement, the affected knee joints were assessed by the above techniques before and at intervals after treatment of up to 14 days. The anti-inflammatory property of the steroid therapy was shown by all the assessment parameters, values having decreased significantly from the pretreatment values. However, the only parameter still showing a statistically significant decrease on the 14th post-treatment day was 99mTc joint uptake. Correlations were obtained between the two clinical measurements assessed by a physician i.e. pain score and index of joint inflammation. Both of these also correlated with the 99mTc joint uptake but not with skin temperature measurements. Using the clinical assessments as a yardstick, 99mTc joint uptake seemed to provide a useful index of changes in disease activity in the group as a whole. However, skin temperature measurements by infrared thermography and by the thermistor were of considerably less value.     

Impact of the CTLA‐4/CD28 axis on the processes of joint inflammation in rheumatoid arthritis

Objective

The importance of the costimulatory molecules CD28 and CTLA‐4 in the pathologic mechanism of rheumatoid arthritis (RA) has been demonstrated by genetic associations and the successful clinical application of CTLA‐4Ig for the treatment of RA. This study was undertaken to investigate the role of the CTLA‐4/CD28 axis in the local application of CTLA‐4Ig in the synovial fluid (SF) of RA patients.

Methods

Quantitative polymerase chain reaction was used to analyze the expression of proinflammatory and antiinflammatory cytokines in ex vivo fluorescence‐activated cell sorted CTLA‐4+ and CTLA‐4− T helper cells from the peripheral blood and SF of RA patients. T helper cells were also analyzed for cytokine expression in vitro after the blockade of CTLA‐4 by anti–CTLA‐4 Fab fragments or of B7 (CD80/CD86) molecules by CTLA‐4Ig.

Results

CTLA‐4+ T helper cells were unambiguously present in the SF of all RA patients examined, and they expressed increased amounts of interferon‐γ (IFNγ), interleukin‐17 (IL‐17), and IL‐10 as compared to CTLA‐4− T helper cells. The selective blockade of CTLA‐4 in T helper cells from the SF in vitro led to increased levels of IFNγ, IL‐2, and IL‐17. The concomitant blockade of CD28 and CTLA‐4 in T helper cells from RA SF by CTLA‐4Ig in vitro resulted in reduced levels of the proinflammatory cytokines IFNγ and IL‐2 and increased levels of the antiinflammatory cytokines IL‐10 and transforming growth factor β.

Conclusion

Our ex vivo and in vitro results demonstrate that the CTLA‐4/CD28 axis constitutes a drug target for not only the systemic, but potentially also the local, application of the costimulation blocking agent CTLA‐4Ig for the treatment of RA.

     

Intraarticular lymphoscintigraphy of the human knee joint: a preliminary study

Intraarticular (knee) lymphoscintigraphy using 99mTc-nanocoll was performed in five patients with chronic synovitis. Scintigrams from the anterior and lateral view of the knee and of the iliac region were taken 1, 2, 4, and 22 hours after injection. The inguinal and iliac lymph nodes uniformly visualized in about 2 hours. Based on radioactivity in regional lymph nodes measured at prescribed time intervals, we were able to quantify lymph drainage from the knee joint. Lymphoscintigraphy is without complication and discomfort and is potentially useful to study synovial fluid reabsorption in joint diseases.     

A double-blind randomized comparative study of triamcinolone hexacetonide and dexamethasone intra-articular injection for the treatment of knee joint arthritis in rheumatoid arthritis

Intra-articular glucocorticoid (GC) injection has been used for more than half a century in the treatment of refractory synovitis in patients with rheumatoid arthritis (RA). There are limited data about the efficacy of intra-articular injection of various preparations of GCs on inflamed joint. The aim of this study was to compare the efficacy and side effects of intra-articular injection of dexamethasone (DEX) and triamcinolone hexacetonide (TH) in the treatment of knee joint arthritis in RA. In a double-blind randomized clinical trial, 70 patients with RA and knee joint arthritis were recruited to the study. Swelled knee joints were injected with 40 mg TH or 8 mg DEX randomly. The primary outcome measures were reduction of knee joint swelling and pain 1 and 3 weeks after joint injection. The secondary outcome measures were relapse of knee arthritis at 2, 4, and 6 months after injection and side effects of intra-articular injection. Difference in the knee circumferences between DEX and TH groups at weeks 1 and 3 was not significant. The average times of pain reduction after injection were 3.4 ± 2.3 and 2.3 ± 1.8 days in TH and DEX, respectively. There were no differences of knee pain between the two groups. Relapse of knee arthritis was occurred in two (6.7 %) and three (9.4 %) patients in the DEX and TH groups, respectively. Intra-articular injection of DEX like TH causes rapid and long-term reduction of knee pain and swelling in patients with RA and is safe.