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ID PMID Title PublicationDate abstract
8834012 Adhesion molecules in autoimmune disease. 1996 Feb Leukocyte activation, circulation, and localization to inflammatory sites are dependent on adherence to molecules on other cells or to extracellular matrix ligands. Adhesion molecule expression and interactions are probably involved in initiation and propagation of autoimmune diseases. Adhesion molecules pertinent to the development of autoimmunity are the subject of this review. Material in this review was generated by a manual and a computerized search of medical literature pertaining to adhesion molecules and specific autoimmune diseases. Topics covered include adhesion molecule classification, regulation of adhesion, and characterization of adhesion receptors in specific autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren's syndrome, autoimmune thyroid disease, multiple sclerosis, and diabetes mellitus. Adhesion molecules are classified into selectin, integrin, and immunoglobulin supergene family groups. Increased adhesion molecule expression and avidity changes occurring with cellular activation are the principal methods regulating leukocyte adhesion. Tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN-gamma), and interleukin-1 (IL-1) stimulate adhesion receptor expression on lymphoid and nonlymphoid tissues. Although differences between specific autoimmune diseases exist, key interactions facilitating the development of autoimmune inflammation appear to include L-selectin/P-selectin/E-selectin, lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1), very late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1), and alpha 4B7/MadCAM or VCAM-1 adhesion. Administration of anti-adhesion molecule antibodies in experimental animal models of autoimmunity and in a preliminary trial with RA patients has been successful in preventing or reducing autoimmune disease severity. A vast array of adhesive interactions occurs between immunocompetent cells, endothelium, extracellular matrix, and target tissues during the evolution of an autoimmune disease. Further characterization of leukocyte migration patterns and adherence should clarify pathogenic processes in specific autoimmune diseases and identify potential therapeutic targets for their treatment.
8912503 Low-dose corticosteroids in rheumatoid arthritis. A meta-analysis of their moderate-term e 1996 Nov OBJECTIVE: To perform a systematic literature review and meta-analysis of the effectiveness of low-dose corticosteroids in the treatment of rheumatoid arthritis (RA). METHODS: After identifying all relevant studies meeting preselected inclusion criteria, we performed 2 meta-analyses. First, we compared the effectiveness of prednisone to placebo and active drug controls (aspirin, chloroquine, or deflazacort) using standard meta-analysis methods for continuous data. Then, to compare the relative effectiveness of prednisone to second-line agents, we used methods similar to prior meta-analyses of second-line agents for RA treatment. Outcomes assessed were the number of tender and swollen joints, grip strength, and the erythrocyte sedimentation rate (ESR). RESULTS: Very few studies directly assessed the effectiveness of corticosteroids for RA treatment, and many were of poor methodologic quality. Only 9 of 34 studies identified by our search met criteria for inclusion. The results of our standard meta-analysis indicated that corticosteroids appeared to be more effective than either placebo or active drug controls in improving most conventional outcome measures (effect size 0.90 for the number of tender joints, 1.05 for the number of swollen joints, and 1.20 for the ESR). In our second comparative meta-analysis, corticosteroids were nearly equivalent to second-line agents previously examined in meta-analyses (combined effect size 0.82). CONCLUSION: Based on the limited data available, during moderate-term treatment periods averaging slightly over 7 months, corticosteroids appeared to be as effective or more effective than alternative therapies in improving several common RA disease activity measures.
1569728 [A case of gold lung with positive lymphocyte stimulation test to gold, using bronchoalveo 1992 Mar Gold lung, a gold-induced pneumonitis, is considered to be caused by hypersensitivity reaction to gold. We performed lymphocyte stimulation test (LST) to determine the response to gold, using lymphocytes obtained by bronchoalveolar lavage (BAL) from a patient with gold lung. A 57-year-old man was admitted with progressive shortness of breath following a skin eruption. He had been receiving weekly sodium gold thiomalate (Shiosol) for rheumatoid arthritis, with a cumulative dose of 485 mg. Chest roentgenogram showed diffuse interstitial infiltrates. LST for the response to gold, using peripheral lymphocytes, was positive. T cell lymphocytosis was observed in BAL, and transbronchial lung biopsy showed lymphocytic alveolitis and granulation tissue in alveolar ducts. From these findings, we diagnosed gold lung. Prednisolone (PSL) was started with an initial dose of 30 mg/day and resulted in a rapid improvement. As the dose of PSL was tapered, the patient's condition deteriorated and he was treated with a maintenance dose of 10 mg PSL. The second BAL revealed persistent lymphocytosis, and LST using bronchoalveolar lymphocytes for response to gold was positive. LST using peripheral lymphocytes was also positive, but was weaker than that using bronchoalveolar lymphocytes. This is the first report in Japan of a positive LST for response to gold, using bronchoalveolar lymphocytes from a patient with gold lung. This case suggests that the presence of activated lymphocytes against gold in the lung is cumulative, and that cell-mediated hypersensitivity is related to gold lung.
1516258 Prevalence of anti-Fab antibodies in patients with autoimmune and infectious diseases. 1992 Sep Sensitive ELISA were devised to examine the specificity of circulating IgM and IgA autoantibodies for whole human IgG, Fc and Fab fragments of human IgG. Sera from patients with autoimmune and infectious conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), tuberculosis (TB), infectious mononucleosis (IM) and cystic fibrosis (CF) were studied. Results of the ELISA assays using whole human IgG as antigen revealed that a proportion of patients in each of the groups studied had circulating IgM and IgA rheumatoid factors (RF). Fifteen normal individuals studied were negative. In the latex positive RA group, IgM RF and IgA RF had primarily anti-Fc reactivity (100% and 93% respectively), although 3/15 patients also showed IgM anti-Fab reactivity and one patient had high IgA anti-Fab activity. Patients with SLE and TB who had detectable RF levels also revealed predominantly anti-Fc specificity. In contrast, examination of 25 patients with IM showed positivity for IgM RF activity in 8% of patients using whole IgG as antigen, 24% positivity using purified Fc fragments as antigen and 45% positivity when plates were coated with Fab fragments. Similarly, a large number of CF patients (54%) also showed predominantly IgM anti-Fab activity. Of interest, 69% of the CF patients who were all studied at the time of bacterial infection had detectable IgA RF levels, with 46% of these patients showing both IgA anti-Fc and anti-Fab activity. These findings suggest that autoantibody specificities in autoimmune and infectious diseases are different.
1339266 A systematic approach to defining the germline gene counterparts of a mutated autoantibody 1992 Mar OBJECTIVE: To define the germline counterparts of potentially highly mutated autoantibodies in disease states. METHODS: We developed a systematic approach by first characterizing a rearranged Ig gene and its upstream flank, and then designing suitable primers to amplify specifically the putative germline counterpart. RESULTS: We identified and characterized the germline counterpart of a rheumatoid factor heavy chain variable region. CONCLUSION: We showed unequivocally that the heavy chain of a rheumatoid factor, derived from synovial tissue, has 4 replacement mutations from the corresponding germline gene. The technique allows quick assessment of the degree of somatic mutation in many autoantibodies, and thus can help to elucidate the underlying mechanisms for the induction and sustained production of such antibodies in patients.
7473483 A Grip Ability Test for use in rheumatology practice. 1995 Aug OBJECTIVE: To develop and evaluate a Grip Ability Test (GAT) for clinical evaluation of hand function in patients with rheumatoid arthritis (RA) by modifying a general test for hand function based entirely on activities of daily living, the Grip Function Test (GFT). METHODS: The GAT items were selected from those in the GFT that were sensitive to change in a hand training program of patients with RA. Based on a multivariate analysis, 3 items were chosen with an optimal representation of different grip types. RESULTS: The reliability was high: intraobserver test r = 0.985, p < 0.001; interobserver test r = 0.948, p < 0.001; internal consistency (Cronbach's alpha) 0.65. All items discriminated (p < 0.001) between patients with RA and healthy controls. The sensitivity to change in a hand training program in 24 patients with RA was significant for the total GAT (p < 0.001), as well as for the 3 items separately (p < 0.01, 0.01, and 0.05, respectively). CONCLUSION: The GAT for patients with RA was reliable, valid, and sensitive to change. It does not require sophisticated equipment and takes 5 min to perform.
1466597 Specificity of the proteus antibody response in rheumatoid arthritis. 1992 Nov Antibodies to proteus were determined by indirect immunofluorescence in 146 serum samples from patients with rheumatoid arthritis (RA). An autoantibody screen was performed in the same samples and in 52 of these antibody titres to the viruses influenza A, adenovirus, rubella, and parvovirus were determined. There was no significant correlation between proteus antibodies and any of the other antibodies tested. Dividing the samples into those from patients with active (C reactive protein > 10 mg/l) and inactive RA showed that the only antibodies to be significantly increased in active RA were the proteus antibodies. These observations suggest that the proteus antibody response in RA is specific.
8749584 Psychological impact of illness downturns: a comparison of new and chronic conditions. 1995 Dec Older adults (N = 166) who had chronic arthritis, a chronic vision problem, new arthritis symptoms, or a new vision problem were compared with older adult controls on psychological distress and well-being. The psychological impact of new versus chronic illness stressors, and stressors associated with arthritis versus vision loss, were examined. The chronic arthritis group had the greatest psychological distress, the least well-being and the greatest self-reported pain. Results supported an additivity theory approach to chronic illness and not an anticipatory coping approach. Differences in level of pain accounted in part for elevations in distress but did not explain differences between groups in psychological well-being. Positive affect was found to be the indicator of well-being that best differentiated groups.
1445377 Cell proliferation-related production of matrix metalloproteinases 1 (tissue collagenase) 1992 Sep We investigated the effects of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin on the cell proliferation of and the production of matrix metalloproteinases (MMPs) by rheumatoid synovial fibroblasts in order to determine the role of these agents in rheumatoid arthritis. PDGF stimulated rheumatoid synovial fibroblasts to increase DNA synthesis and the production of precursor forms of MMP-1 of M(r) = 53,000 and -3 of M(r) = 57,000. EGF and insulin also increased DNA synthesis and the production of these enzymes, but the amount of DNA or MMPs was smaller than that induced by PDGF. Since the production of matrix macromolecules and their degradation is essential for the remodelling of synovial tissue in rheumatoid arthritis, these data suggest that the production of MMP-1 and-3 by rheumatoid synovial fibroblasts in relation to cell proliferation plays an important role in the pathological process of rheumatoid arthritis.
8986897 Recurrent plantar ulceration following pan metatarsal head resection. 1996 Nov Although the pan metatarsal head resection, since it was originally described and performed by Hoffman in 1911, has proven to be an effective and viable procedure in treating many forefoot deformities, it is not without its own complications. The authors provide an historical perspective of the pan metatarsal head resection, a discussion on the complication of recurrent plantar ulceration after the pan metatarsal head resection, and a review of their own experience with this procedure. A retrospective review was performed of all patients having undergone pan metatarsal resections between August 1980 and April 1993. Twenty procedures were performed on 12 patients with diabetic neuropathy, and 21 procedures were performed on 15 patients with rheumatoid arthritis. The incidence of recurrent plantar ulceration after surgical correction was 25% and 28%, respectively. All 27 patients underwent primary healing. The authors, therefore, conclude that the complication of recurrent plantar ulceration after this procedure is a very likely and distinct possibility.
7603085 Does IgA-alpha1 antitrypsin complex correlate with IgM, IgG and IgA rheumatoid factor in e 1994 Jul This study was undertaken to determine whether the rheumatoid factor (RF) isotypes affect the level of IgA-AT complex in early rheumatoid arthritis. IgA-AT complex and IgM, IgG, and IgA RF were evaluated using a double antibody enzyme-linked immunosorbent assay (ELISA) in sera of 83 (61 women and 22 men) patients. The mean level of the complex was higher in RA patients as compared with the control group (0.60 +/- 0.41 U vs 0.19 +/- 0.11 U, p < 0.05). The IgA-AT complex values exceeding the norm were found in 19 of 83 RA cases (23%), mainly in patients non-treated with DMARDs. IgM RF values judged as positive were present in 53 (64%), IgG RF in 55 (66%), and IgA RF in 56 (67%) patients. Higher RF values of IgM and IgG, but not those of IgA class, were found more frequently in patients with elevated IgA-AT levels. A good correlation was established between IgA and IgM RF (r = 0.61, p < 0.01), but not between IgA and IgG, or IgM and IgG RF in the group of patients under study. However, we did not find any significant correlation between isotypes of RF and parameters of the disease activity.
8707338 Repopulation of blood lymphocyte sub-populations in rheumatoid arthritis patients treated 1996 May Patients with severe rheumatoid arthritis who had failed treatment with conventional therapies were treated with a course of five or 10 daily intravenous infusions of CAMPATH-1H, a humanized antibody against the CD52 antigen, resulting in profound depletion of peripheral blood mononuclear cells. During the subsequent 18 months, lymphocytes were analysed for sub-populations by fluorescence-activated cell sorter (FACS) and for proliferation in response to polyclonal T-cell stimulation with anti-CD3 or staphylococcal enterotoxin B (SEB). Treatment resulted in almost complete depletion of lymphocytes from the blood followed by gradual repopulation. CD16+ natural killer (NK) cells and CD14+ monocytes returned to pretreatment levels within 1-2 months. CD19+ B cells returned to within 50% of pre-treatment levels by day 66 and to within normal range by day 150, whereas CD8+ T cells recovered to 50% of pretreatment levels by day 66, but did not show any further increase during the rest of the study period. The most profound effects were on the CD4+ T lymphocyte sub-population, as the mean CD4+ count did not increase above 20% of pre-treatment level at any time during the study period (550 days), at all the doses tested. The T cells which initially repopulated the blood 1-2 months after treatment, nearly all expressed the activation markers human leucocyte antigen (HLA)-DR and CD45RO, although the percentage of T cells expressing these molecules gradually declined to normal levels over time. Proliferative responses to polyclonal T-cell stimulation (anti-CD3 and SEB) were also significantly reduced in the first few months after treatment, but recovered to pre-treatment levels by day 250. The relationship between these observations and the clinical response is discussed.
8714431 A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 8 (neutrophil co 1996 Jan 31 A one-step sandwich enzyme immunoassay (EIA) system for human matrix metalloproteinase 8 (MMP-8, neutrophil collagenase, EC 3.4.24.7) has been established with a pair of monoclonal antibodies prepared against the zymogen of MMP-8 purified from human neutrophils. MMP-8 in samples simultaneously reacted with both solid-phase and peroxidase-labeled antibodies. Sensitivity of this EIA system was 0.34 micrograms/l (5.7 pg/assay) and linearity was obtained between 0.5 and 500 micrograms/l (8.3-8300 pg/assay). The EIA system recognized both precursor and active forms of MMP-8 but not MMP-8 complexed with tissue inhibitors of metalloproteinases. There was no difference in the MMP-8 levels between the plasma samples from patients with rheumatoid arthritis or osteoarthritis and those from healthy subjects (median 6.2 micrograms/l, range 1.5-28 micrograms/l). However, the level in synovial fluids from patients with rheumatoid arthritis (median 345 micrograms/l, range 84-2860 micrograms/l) was shown to be higher than that from osteoarthritic patients. MMP-8 levels in human whole saliva from patients with periodontal diseases (median 282 micrograms/l, range 0-1420 micrograms/l) were also significantly higher than those from clinically healthy subjects (median 25 micrograms/l, range 0-100 micrograms/l). Immunoreactivity analyses showed that MMP-8 species in normal human plasma exists as a precursor but not as a complex form with tissue inhibitor of metalloproteinases (TIMP)-1 or TIMP-2.
8911651 Perturbations of hypothalamic-pituitary-gonadal (HPG) axis and adrenal androgen (AA) funct 1996 May The available evidence reviewed does not allow definitive response to the question of a primary versus secondary role of sex hormone perturbations in RA. However, this conclusion should not be discouraging in view of the relatively recent focus upon this facet of the physiopathogenesis of RA and the enormous complexities of sex hormone biology and this disease. Specifically, data on the incidence of RA as well as life cycle changes in serum androgenic-anabolic (A-A) and sex hormone levels suggest important risk correlations. Furthermore, HLA-susceptibility markers for RA, gender, menopause and older age are all factors which significantly relate to the risk of developing RA and each has been shown to associate with sex hormone status. Whether or not HPG-AA hormonal status may modulate RA risk (or its course) primarily and independently or merely be predictive markers of other biological mechanisms was critically considered and requires further study. Sex hormone influences on cellular and humoral immunological reactivity and vascular pathogenetic mechanisms in RA were summarized. Androgens generally suppress immunoreactivity and cartilage responses to inflammation-mediated injury processes and may enhance synovial macrophage-like lining cell apoptosis. Oestrogens generally enhance immunoreactivity, offer some protection to inflammation-mediated cartilage damage (but less than androgens) and may inhibit apoptosis in certain in vitro cell models. Scant information is available on the balance of sex hormones (and glucocorticoids) in RA or its presumed pathogenetic mechanisms. Data were reviewed which support the concept of a spectrum of androgenicity in the normal population, particularly among women. A simplified schema of trophic and tropic steroidogenic mechanisms was proposed which could influence androgenic-anabolic (A-A) status and might relate to RA. Serum concentrations of DHAS (mumol/l), T (nmol/l) and O2 (pmol/l) span several orders of magnitude in normal physiology. The effects of alterations in the individual levels of these sex hormones and deviations from their normal physiological balance are not well understood. Critical attention to their biological functions is needed in RA as well as in health and disease generally. Such focused clinical and experimental investigations of HPG-AA functions promise to clarify the complex physiopathology of RA and contribute to its improved long-term management.
7543347 Determination of the apparent synovial permeability in the knee joint of patients sufferin 1995 Jun The concentrations of alpha 1-acid glycoprotein (alpha 1-antitrypsin (alpha 1-AT), ceruloplasmin (Cp) and alpha 2-macroglobulin (alpha 2-MG) in serum and in knee joint synovial fluid of patients suffering from rheumatoid arthritis (RA) and osteoarthritis (OA) were determined and apparent synovial permeability (SP) to each protein calculated. The results showed that the rheumatoid synovia were significantly more permeable (P < 0.001) than the osteoarthritic synovia. Cp and alpha 2-MG showed the greatest average increase in apparent SP, about five times the values for OA joints. Apparent SP reflected disease activity rather well, since the patients with the more active disease had the highest values, six times that of the OA values. Although the values for the small proteins alpha 1-AGP and alpha 1-AT were greater in RA joints, more intense inflammation resulted in a greater increase in apparent SP to larger proteins, so that the apparent SP for alpha 2-MG and Cp are more reliable for evaluating disease activity. Apparent SP as determined by this and previous studies appeared to be a much more accurate and sensitive measure than the synovial fluid/plasma protein concentration ratio. Knowledge of the apparent SP could be a useful parameter in evaluating synovitis since the exudative flare-ups usually parallel the intensity of the inflammation.
8129787 Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. 1994 Mar Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.
9679599 [Sesamoid osteoopathy of the foot]. 1996 Dec 1 Taking parts of sesamoids in several arthroosteopathies of 160 males and 156 females in the retrospective study were investigated. On the comparative dorsi-plantar, oblique, inversion and eversion pedal plain films could demonstrate bony hypotrophy and hypertrophy of sesamoids in 124 (39.55%) of 316 subjects. Until the dorsi-plantar radiographs were obtained with 15 degrees cephalic tube angulation, then the oblique, inversion and eversion ones were unangled. Radiographically the sesamoid osteopathies were divided into mild (grade 1, 36 of 124 cases), moderate (grade 2, 44 of 124 cases) and severe (grade 3, 44 of 124 cases) forms. The affictions involved the constant sesamoid bones of forefeet (1st and 5th metatarsophalangeal joints) exclusively. Sesamoid osteopathy was clinically specified by the serious locomotive pain of ball of the feet as well unfavourable chances against conservative treatment.
7904085 Protocol development for combination therapy with disease-modifying antirheumatic drugs. 1993 Oct To date, it has been exceptionally difficult to prove that any combination of disease-modifying antirheumatic drugs is more effective than its components used one at a time. However, only a few of many possible combinations have been evaluated in clinical trials. Careful attention to the details of patient selection, study design and duration, and choice of primary outcome measures is essential. A logical strategy for protocol development emphasizes the use of multiple small pilot studies to screen series of combinations and doses to identify a few that appear to show clinical benefit. The most promising combinations can then be evaluated in large, double-blind, randomized, pivotal studies with a higher probability of success.
7621589 Neutrophil expression of tumour necrosis factor receptors (TNF-R) and of activation marker 1995 Jul In vitro analysis of polymorphonuclear neutrophils (PMN) has allowed various stages of cell activation to be distinguished, characterized by the expression level of specific membrane markers and of functional receptors. Among those, TNF-alpha receptors (TNF-R) are modulated by various PMN activators, a mechanism which may be important to control cell responses to TNF in inflammatory reactions such as rheumatoid arthritis (RA). PMN, isolated from the blood of 36 RA patients and from the synovial fluid of 23 of them, were analysed for membrane expression of the two TNF-R (p55 and p75). Soluble p55 and p75 (sTNF-R) and TNF concentrations were measured in the plasma and synovial fluid by specific ELISA assays. Our results show that PMN from the blood of RA patients bear a normal number of TNF-R, with a normal p55/p75 ratio, compared with PMN from normal controls. Soluble TNF-R levels were similar in patients and normal plasma. In spite of high endogenous TNF concentration, patients' circulating PMN were not activated, as shown by a CD11b/CD18 expression similar to that of control resting cells. In contrast with blood neutrophils, PMN from RA patients' synovial fluids had an activated phenotype, characterized by increased expression of CD11b, decreased expression of leukosialin, CD43, and the appearance on the plasma membrane of an azurophil granule protein, CD63. High levels of soluble TNF-R were measured in RA synovial fluids. Nevertheless, membrane TNF-R levels and p55 and p75 proportions were similar to those of PMN from normal blood. These results suggest the existence of regulatory mechanisms which maintain a stable neutrophil expression of TNF-R as well as a balance between both types of receptors in inflammatory situations where neutrophils are strongly activated.
7488280 Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoi 1995 Nov OBJECTIVE: To assess the safety and effectiveness of leflunomide versus placebo in patients with active rheumatoid arthritis (RA) treated for 6 months. METHODS: Four hundred two patients were randomly assigned to receive placebo or leflunomide at 5 mg, 10 mg, or 25 mg daily. A washout period of 6-12 weeks from prior second-line therapy was required. RESULTS: Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10-mg and 25-mg dosage groups compared to placebo. Twenty-one patients (7.0%) in the active treatment groups withdrew due to adverse events (AEs). The incidence of AEs was higher with leflunomide than with placebo. Gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia were more common in the 10-mg and 25-mg dosage groups. The incidence of infections was similar between the treatment and placebo groups; no opportunistic infections were seen. Transient elevations in liver function studies were noted in a small number of patients. CONCLUSION: Leflunomide is effective in daily doses of 10 mg and 25 mg in patients with active RA. Improved efficacy at the 25-mg dose was associated with a higher incidence of AEs. Randomized, placebo-controlled trials using daily doses of 10 mg and 20 mg are under way in the US and Europe to confirm these positive results.