Clinical relevance of the risk factors for coronary artery inflammation in Kawasaki disease.

The objective of this study was to determine predictive factors in children with Kawasaki disease (KD) with which we could distinguish the patients with KD who are either at very low risk or at very high risk for coronary artery inflammation (i.e., either patients who do not need intravenous immunoglobulin treatment or patients in whom more aggressive or even experimental therapies should be considered). Prospectively collected demographic, clinical, and laboratory data on 344 patients treated for KD were correlated with the patients' echocardiographic findings. The parameters studied were age, sex, duration of the fever, erythrocyte sedimentation rate, hemoglobin, white blood cell count, platelet count, and serum albumin. These were examined both in bivariable comparisons and in multiple logistic regression models. Low serum albumin, age <1 year, and the duration of the fever prior to treatment were risk factors for coronary arteritis. In the multivariable models, their combined predictive value for coronary lesions was poor, especially when identifying the patients at a low risk for coronary artery lesions (CALs). In fact, 44 of 98 patients with CALs were falsely classified to the low-risk group. Ten of 14 patients younger than 1 year of age, who also had low serum albumin (<30 g/L), had echocardiographically verified CALs, and 7 (50%) had a definite coronary artery aneurysm. We could not distinguish a group at such a low risk that these patients could be left untreated. Young patients with low albumin run a very high risk for CALs.

A three-stage clinical trial design for rare disorders.

Many clinical trials of uncommon diseases are underpowered because of the difficulty of recruiting adequate numbers of subjects. We propose a clinical trial design with improved statistical power compared to the traditional randomized trial for use in clinical trials of rare diseases. The three-stage clinical trial design consists of an initial randomized placebo-controlled stage, a randomized withdrawal stage for subjects who responded, and a third randomized stage for placebo non-responders who subsequently respond to treatment. Test level and power were assessed by computer-intensive exact calculations. The three-stage clinical trial design was found to be consistently superior to the traditional randomized trial design in all cases examined, with sample sizes typically reduced by 20 per cent to 30 per cent while maintaining comparable power. When a treatment clearly superior to placebo was considered, our design reached a power of 75 per cent with a sample of 21 patients compared with the 52 needed to attain this power when only a randomized controlled trial was used. In situations where patient numbers are limited, a three-stage clinical trial design may be a more powerful design than the traditional randomized trial for detecting clinical benefits.

Alpha-linolenic acid in the treatment of rheumatoid arthritis. A double-blind, placebo-controlled and randomized study: flaxseed vs. safflower seed.

In rheumatoid arthritis various pro-inflammatory metabolites of arachidonic acid (AA), such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), contribute to tissue destruction and pain. In contrast to AA, which is an omega-6 fatty acid, the omega-3 fatty acids, after having been liberated from the cell membrane phospholipids, are further converted into the non- or anti-inflammatory eicosanoids LTB5 and PGI3. AA concentration is an important regulatory step in the synthesis of both prostanoids and leukotriens. Dietary supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has therefore been used to decrease the ratio of AA to EPA or DHA to obtain beneficial clinical effects. EPA and DHA are found in animal fat and are quite expensive compared to their precursor alpha-linolenic acid (alpha-LNA) found in flaxseed oil. We, therefore, performed a placebo-controlled trial with alpha-LNA in 22 patients with rheumatoid arthritis, using a linoleic acid preparation as a placebo. After a 3-month follow-up, the treatment group showed an increased bleeding time, but the clinical, subjective (global assessment, classification of functional status, joint score index, visual analogue scale, pain tenderness score) and laboratory parameters (haemoglobin, erythrocyte sedimentation rate, C-reactive protein) did not show any statistical alterations. AA, EPA and DHA did not change either in spite of a significant increase in alpha-LNA in the treatment group. Thus, 3-month's supplementation with alpha-LNA did not prove to be beneficial in rheumatoid arthritis.

Intra-articular glucocorticoids in early juvenile chronic arthritis.

The efficacy of intra-articular glucocorticoid injections in the early phase of knee joint synovitis was studied in 79 children with juvenile chronic arthritis (42 girls and 37 boys). Half of the injections were given within the first six months from the onset of the disease. The probability of a patient staying in remission was much higher in triamcinolone-treated patients than in patients receiving methylprednisolone (p < 0.0005, Breslow statistics). Using multivariate analysis there was a significant association between the length of remission and the synovial fluid polymorphonuclear leucocyte proportion (SF-PMN%). Patients with a high SF-PMN% tended to have shorter remissions than those with a low SF-PMN% (improvement of the fit in stepwise model: chi-square = 8.81, p < 0.005). The difference between triamcinolone and methylprednisolone groups was still clearly evident two years after injection.

The relation of extraarticular tenderness to inflammatory joint disease and personality in patients with rheumatoid arthritis.

We measured the pain tenderness threshold at 16 fibrositic tender points in 44 consecutive patients with rheumatoid arthritis (RA) attending the outpatient rheumatology clinic of a university hospital. Pressure threshold measurements were transformed to z units to equalize the weights of the values at different anatomic sites and were then summed. This pain tenderness score correlated with the joint score index (p less than 0.02, r = -0.363), signifying a low pain threshold in the patients with a high joint score index. In contrast to this, the pain tenderness score was not explained by either personality factors or the generalized disease activity measuring variables (erythrocyte sedimentation rate, C-reactive protein). Our results show that the fibrositic point tenderness is real in RA, and that the tenderness is augmented near the active joints. The pain tenderness score of patients with RA is not affected by the subject's personality but may relate to sensitization of the pain fibers in arthritic joints.

Plasma zinc and copper concentrations in rheumatoid arthritis: influence of dietary factors and disease activity.

Forty patients with rheumatoid arthritis performed a thorough 7-d diet recording. The food diaries were analyzed together with clinical and laboratory data by means of stepwise multiple linear regression to clarify the effects of both diet and the inflammatory disorder on the plasma concentrations of zinc and copper. The patients' daily dietary intakes of zinc and copper (24.3 +/- 7.54 and 3.48 +/- 1.55 mg/MJ) were comparable to the corresponding intakes in the ordinary Finnish diet (24.0 and 3.68 mg/MJ). In multivariate analyses the best predictors of plasma trace elements were the measures of disease activity and not the dietary factors. As an exception to this, there was a strong correlation between plasma copper-copper intake ratio and zinc intake both in univariate (r = -0.638, P less than 0.001) and multivariate analysis. This suggests that zinc depresses copper absorption with intakes in normal, physiological ranges.

The factors affecting plasma glutathione peroxidase and selenium in rheumatoid arthritis: a multiple linear regression analysis.

The reactive oxygen radicals are trapped by anti-oxidants, such as selenium containing glutathione peroxidase (GSHpx), which also can inhibit the oxygenation of arachidonic acid to pro-inflammatory prostaglandins and leukotrienes. We studied the levels of anti-oxidant glutathione peroxidase and selenium (in plasma) in 48 patients with rheumatoid arthritis (RA). In the multiple regression model, joint score had the highest explanatory value for serum selenium, and sulphasalazine treatment was the most significant variable contributing to GSHpx activity. The plasma GSHpx activity was not increased in RA patients in general, but was high in those taking sulphasalazine as compared with those not doing so (342.4 +/- 48.2 vs. 298.9 +/- 34.7 U/l, 95% confidence interval of difference from 17.9 to 69.1, p less than 0.002). The serum selenium levels correlated with clinical activity of the joint, disease measuring joint score.

Serum baseline hyaluronate and disease activity in rheumatoid arthritis.

The baseline serum hyaluronate (HA) concentration from samples obtained five to seven hours after mobilization of the patient was quantified using a radiometric 125I-HA binding method in 58 patients with rheumatoid arthritis and compared with several clinical and laboratory parameters by means of stepwise multiple linear regression. In the age- and sex-adjusted model, the variables with independent predictive value for serum hyaluronate concentration were the erythrocyte sedimentation rate (ESR) and the joint score index measuring the extent of the synovial inflammation. The estimated synovial mass index and C-reactive protein values did not improve the fit of the model after ESR and joint score were entered, and were left out from the multiple regression equation. When ESR and joint score were studied in univariate regression analysis with serum hyaluronate, the coefficients were r = 0.492 and r = 0.397, and the P values were P less than 0.001 and P less than 0.005, respectively. It was concluded that the baseline hyaluronate level in serum is closely related to the synovitic activity of the rheumatoid inflammation and that measurement of serum hyaluronate is of value when the activity and extent of synovial inflammation is being assessed in patients with rheumatoid arthritis.

Serum cholesterol and vitamins A and E in juvenile chronic arthritis.

Serum total cholesterol is decreased during acute infections and in adults with rheumatoid arthritis, probably partly because of enhanced lipid peroxidation. Oxidative stress also causes augmentation of inflammation and tissue damage in arthritic synovium. Therefore, concentrations of serum total cholesterol and the antioxidant vitamins A and E were studied in 125 children with juvenile chronic arthritis. Total serum cholesterol was significantly lower in the patients than in healthy children in most age groups and correlated with the markers of disease activity, haemoglobin and the erythrocyte sedimentation rate. In age- and sex-adjusted stepwise multiple linear regression, serum zinc had a significant predictive value for cholesterol. The vitamin A concentrations in the sera of the patients was virtually the same as in the healthy controls, though serum vitamin E concentrations were low (22.8 +/- 15.2 vs 30.5 +/- 4.3 mumol/l, p less than 0.001). The deficiency in vitamin E was not compensated for by another lipoperoxide antioxidant, glutathione peroxidase. Only serum cholesterol had an independent explanatory significance for vitamin E in multiple linear regression analysis (partial correlation 0.554, p less than 0.001). It is suggested that low vitamin E and impairment of the anti-oxidant protection further contribute to low serum cholesterol values in JCA.

Future trends in the treatment of rheumatoid arthritis in the light of current etiopathogenetic theories.

The current treatment of rheumatoid arthritis is based on the use of synthetic chemical compounds, the mechanism and action of which have been more or less unknown. Usually this therapeutic effectiveness was discovered accidentally. Often the initial use of such compounds was motivated on the basis of generally diffuse ideas about the eventual pathogenesis of rheumatoid arthritis. The main site of action of most of these drugs has recently been elucidated. Depending on their multiple sites of action the polypharmacy frequency relied upon at present seems also to be theoretically motivated. Many new possibilities for treatment which have appeared recently have resulted from the amission of page limitation. These include various thymic (46), steroid and other hormones (67) and various vehicles or new modes of application, e.g. percutaneous, for directing the effects of drugs selectively to the target tissue, organ and cells. The use of specific T cell clones in therapy (68) has been only briefly dealt with in this article, and the development of operative techniques, endoprosthesis technology and orthopedic devices have not been dealth with at all. Chemical synovectomies with 165Dy-FHMA and other agents (69) will be developed further etc. This overview mainly deals with future trends in the treatment of rheumatoid arthritis based on advances made in the evaluation of the etiopathogenesis. Due to advances in basic sciences and medicine, the pathogenetic mechanisms effective in rheumatoid arthritis are better known today than ever before. The same progress in science has for the first time in history provided us with a potential means of producing bioactive mediators and reagents in sufficient amounts to enable their use also for therapeutic trials and treatment. In addition to the need to develop better methods of treatment for the patients crippled by this chronic disease, studies on the pathogenesis will also be of great benefit to our ideas about exactly what is involved in the complex process clinically known as rheumatoid arthritis.