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ID PMID Title PublicationDate abstract
11285377 The relationship between soft tissue swelling, joint space narrowing and erosive damage in 2001 Mar OBJECTIVES: To test the hypotheses that the progression of joint space narrowing behaves differently from the progression of erosions and that clinically and radiologically assessed soft tissue swelling relates more to diffuse cartilage loss than to erosive damage. METHODS: Radiographs and clinical data were obtained from 28 patients in a prospective, multicentre, randomized, placebo-controlled trial of prednisolone 7.5 mg daily over 2 yr. Radiographic scoring included the Larsen score, joint space narrowing and soft tissue swelling. Clinical joint inflammation in the hands was assessed every 3 months and cumulative synovitis score over the period of study was then calculated for each joint. The placebo-treated patients and the prednisolone-treated patients were analysed separately. The Larsen scores were compared after log transformation [transformed score=log(10) (original score+1)]. Changes in Larsen scores and joint space narrowing scores were compared with the cumulative presence of clinical synovitis and radiological soft tissue swelling using the correlation coefficient. RESULTS: There was a difference in the rate of progression in the Larsen score between placebo- and prednisolone-treated patients, but there was no significant difference in the rate of joint space loss. In placebo-treated patients, measures of synovitis correlated more strongly with progression of joint space narrowing than with changes in the Larsen score. In prednisolone-treated patients there was no correlation between clinical synovitis and change in Larsen score (r=0.029) and only a slight and non-significant correlation with joint space narrowing (r=0.127). Radiographic evidence of soft tissue swelling remained correlated with joint space narrowing (r=0.279, P:<0.001) but was not correlated with change in Larsen score (r=-0.113, P:<0.001 for difference between correlations). The correlation between Larsen score progression and joint space narrowing seen in the non-treated patients was completely abolished in the glucocorticoid-treated group (r=-0.003). CONCLUSIONS: The progression of joint space narrowing behaves differently from the progression of erosions. Prednisolone slows (or even stops) the progression of erosions (as assessed by the Larsen score) while making no difference to the progression of cartilage loss (as assessed by joint space narrowing). The results also suggest that synovitis, whether measured clinically or radiologically, is more closely related to diffuse cartilage loss than to erosion progression. Any link between synovitis and erosions is abolished by glucocorticoid therapy while the link between synovitis and cartilage loss is not, pointing to at least two different mechanisms for these observed radiological features.
9704647 Radiographic progression in rheumatoid arthritis: a long-term prospective study of 109 pat 1998 Aug OBJECTIVE: To investigate the long-term radiographic course as a mathematical function of disease duration in individual patients and in a group of patients with rheumatoid arthritis (RA). METHODS: In 109 patients with RA, radiographic examinations of 46 diarthrodial joints were performed at regular intervals of 1-3 years, for up to 30 years after disease onset. RESULTS: Five main types of progression were identified: 1) a rare type (<1%), with no radiographic progression at all; 2) a type with a slow or moderate onset, but an increasing progression rate (9% exponential growth type and 30% linear type); 3) a type with a moderate-to-fast onset and a stable progression rate (the square-root type; 11%); 4) a type with a fast onset, but a later decreasing progression rate (the first-order kinetics type, 30%); and 5) a type characterized by slow onset, then acceleration and later deceleration (the sigmoid type, 20%). CONCLUSION: The progression of radiographic damage in RA followed mathematical functions of time. The identification of progression type may be used in the prediction of outcome in patients with RA.
10027783 HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheu 1999 Feb We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.
11354349 Relationship between meniscal degeneration and element contents. 2001 Mar The purpose of this study is to investigate the relationship between meniscal degeneration and element contents. The contents of elements (calcium, phosphorus, sulfur, and magnesium) in the menisci from 17 patients with osteoarthritis (OA) of the knee, 6 with rheumatoid arthritis (RA), and 2 who underwent the surgical operation for malignant tumors (control) were analyzed by inductively coupled plasma-atomic emission spectrometry, and the menisci were divided into four stages (Stage 0-3) of histological degeneration. The calcium contents of the menisci were 0.26 +/- 0.16 in Stage 0, 0.50 +/- 0.37 in Stage 1, and 0.69 +/- 0.66 in Stage 2, respectively (the values represent mg elements/g dry tissue). They increased with the progression of the stage. This tendency was found in the menisci with OA, but was not clear in those with RA. The calcium content in the control group was 0.17 +/- 0.09 mg/g. There was no significant relationship between the stage of degeneration and the contents of phosphorus, sulfur, or magnesium. The calcium content of the meniscus might indicate the degree of meniscal degeneration.
10812057 Preferential inhibition of cyclooxygenase-2 by meloxicam in human rheumatoid synoviocytes. 2000 May 3 The aim of this study was to evaluate the anti-inflammatory effect of 4-hydroxy-2-methyl-N-[5-methyl-2-thiazolyl]-2H-1, 2-benzothiazine-3-carboxamide-1,1-dioxide (meloxicam) using cultured rheumatoid synovial fibroblast-like cells (synoviocytes). Synoviocytes were treated with meloxicam in the presence or absence of interleukin-1beta. Meloxicam had no effect on both cyclooxygenase-1 and -2 expression as determined by Western blot analysis, immunohistochemical staining, and reverse transcription polymerase chain reaction (RT-PCR). Even the lower doses of meloxicam inhibited cyclooxygenase-2 activity, but only the higher doses of meloxicam inhibited cyclooxygenase-1 activity as determined by prostaglandin E(2) synthesis assay. So meloxicam had a preferential inhibitory effect of cyclooxygenase-2 relative to cyclooxygenase-1 on cultured rheumatoid synoviocytes without affecting cyclooxygenase expression. On the other hand, indomethacin had no selectivity and dexamethasone inhibited the expression of cyclooxygenase-2. Our data indicate that clinical efficacy and safety of meloxicam for rheumatoid arthritis may result from its preferential inhibition of cyclooxygenase-2 activity relative to cyclooxygenase-1 on rheumatoid synoviocytes.
11407687 Specific overexpression of rheumatoid arthritis-associated HLA-DR alleles and presentation 2001 Jun OBJECTIVE: To compare levels of HLA-DR expression in rheumatoid arthritis (RA) patients and healthy controls for whom an ordered expression according to the DR alleles is demonstrated and to test the functional consequences of this expression on peptide presentation. METHODS: Using monoclonal antibodies that recognize different DRB1 alleles, DR molecules were quantitated at the surface of the peripheral blood B cells of 23 RA patients and 17 healthy subjects. The functional consequences of the level of DR surface expression was tested using a universal model of antigen presentation and mutated peptides with variable affinities for the T cell receptor. RESULTS: In healthy subjects, surface HLA-DR molecules were expressed at different levels according to allele (DR53, DR4, and DR11 less than DR1 less than DR7 less than DR15). In RA patients, this hierarchy was not conserved and, furthermore, the density of RA-associated DR4 and DR1 molecules was enhanced in patients compared with the basal density in healthy individuals. We demonstrated that an increased expression of DR molecules at the surface of antigen-presenting cells allowed a noteworthy presentation of low-affinity peptides that under normal conditions are not efficient in generating a T cell response at physiologic surface density of the DR molecules. CONCLUSION: Our results suggest that the specific overexpression of RA-associated HLA molecules could be responsible for the presentation of low-affinity autopeptides and therefore the activation of peripheral autoreactive T cells.
11357896 The effects of intravenous doxycycline therapy for rheumatoid arthritis: a randomized, dou 2001 May OBJECTIVE: To determine the feasibility, safety, and potential clinical efficacy of intravenous (IV) doxycycline therapy for rheumatoid arthritis (RA), as well as its possible effects on serum and urinary markers of collagen breakdown. METHODS: The exploratory trial was designed as a 16-week, single-center, randomized, double-blind, placebo-controlled trial. Eligible subjects with active seropositive or erosive RA were randomly allocated into 3 treatment groups: doxycycline 200 mg IV, azithromycin 250 mg orally, or placebo. The blinded IV study drug was administered once daily for the first 3 weeks by home self-infusion and then weekly for the next 8 weeks, concurrent with the blinded oral study drug at the prescribed doses. The primary end points were the change between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline. RESULTS: The trial was stopped prematurely after enrollment of 31 patients. Three subjects were withdrawn because of worsening arthritis, and 1 patient was withdrawn when newly diagnosed with breast cancer. Infusion-related events occurred in 13 (42%) of 31 patients, but none were serious. There were 4 serious adverse events unrelated to the study drug, including a new diagnosis of breast cancer in 3 cases and hospitalization for abdominal pain in 1 case. No significant differences were observed across treatment groups in any of the 3 primary clinical end points. CONCLUSION: Although IV doxycycline therapy was generally well-tolerated by patients in this trial, it did not show any evidence of reducing disease activity or collagen crosslink production.
10953409 [Secondary hemophagocytic syndrome in a systemic disease]. 2000 Jun 21 20 year old man 2 years treated for the seropositive rheumatoid arthritis was admitted for fever accompanied with jaundice, anemia and leukopenia. The underlying disease has been compensated already for long period of time, before his admission only Prednisone (in the dose of 5 mg daily) and Methotrexate (15 mg once a week) was given. His physical examination of admission was without any significant abnormalities, out of the routine laboratory examination the value of leukocytes count was 2.1 x 10(9)/L, erythrocytes 3.7 x 10(12)/L, hemoglobin 95 g/l, hematocrit 0.29, platelets 156 x 10(9)/L. Since admission to hospital the hepatic enzymes ALT, AST, GMT, ALP were about ten times elevated comparing to normal values, the coagulation examination has shown the decrease of Quick test to 55%. With respect to the permanent leukopenia the bone marrow aspiration was taken with the finding of the increase number the RES elements (18.4%) with the signs of hemophagocytosis. The phagocytic reticulum absorbs blood elements erythrocytes, normoblasts, granulocytes, platelets. According to the literature experience we started the combination of the immunosuppressive treatment consisting of corticosteroids and Cyclosporine. Already the day following the application of the high dose of corticosteroids the fever subsided, icterus went away gradually with the normalization of the liver tests. After 20 days of hospitalisation the patient was discharged in good shape. Now, after 4 months the is stabilized on the follow-up treatment of Prednisone a Cyclosporine.
9231504 [Treatment with low dose methotrexate in rheumatoid arthritis: risk factors for severe com 1997 Mar Treatment with low dose methotrexate in rheumatoid arthritis is associated with serious side effects in about 5 per cent of cases (respiratory, haematological or infectious). The goal of a null risk seems unrealistic because of the idiosyncrasy of some of the risks and our poor understanding of others (enzymatic polymorphisms might be operational, and infectious agents could act as co-factors). However, risk can be greatly reduced by a careful selection of patients. Some contraindications are strict: poor compliance and the possibility of mistake in the timing of the administration; pregnancy or desire for pregnancy; treatment with trimetoprim; haemodialysis; renal insufficiency (clearance < or = 50 ml/min) (and therefore old age), alcoholism. Others remain relative although well established; hypoalbuminaemia, diabetes mellitus, obesity, past infection with hepatitis virus. Others are dubious: starvation, macrocytosis, surgical stress, NSAIDs. An extensive large study of side effects is warranted.
9228127 Reference curves of radiographic damage in patients with rheumatoid arthritis: application 1997 Jul OBJECTIVE: To (1) introduce the methodology of quantile regression and fractional polynomials; (2) test the application of this methodology to develop, conditional on disease duration, preliminary reference curves of radiographic damage in patients with rheumatoid arthritis (RA); and (3) prove the importance of the definition and selection of the reference group when developing reference curves. METHODS: The study design was cross sectional. The main study factors were disease duration and radiographic damage using the Larsen score. The 2 study samples were 98 patients from a multicenter trial of cyclosporine and 203 patients with RA from a teaching hospital clinic. RESULTS: Using disease duration as the time dependent covariate we constructed quantile regression reference curves of radiographic damage. The reference curves for the 2 samples differed in shape, location, and slope. CONCLUSION: Quantile regression and fractional polynomials simplify the construction of reference curves when data cannot be easily modified to meet assumptions of normality, linearity, and constant variance. Quantile reference curves provide clinicians with a useful clinical tool to measure outcome at arbitrary timepoints, to interpret change, and to set treatment objectives. However, the definition and selection of the reference used to construct the reference curves is of critical importance.
11354579 Efficacy theory and its utility in arthritis rehabilitation: review and recommendations. 2001 May 10 PURPOSE: Self-efficacy, a cognitive construct implicating one's self-perception about one's performance ability, has been found to be a significant predictor of psychological well-being, adherence to prescribed treatments, and pain coping mechanisms of persons with arthritis. Heightened self-efficacy may also ameliorate arthritis-related symptoms of fatigue and depression, and preserve function and prolong physical well-being. METHODS: To elaborate upon the utility of self-efficacy enhancing strategies as this pertains to ameliorating arthritis-related disability, this paper examined the related literature on this topic and detailed the outcomes and nature of those self-efficacy enhancing strategies that have been incorporated into arthritis treatment regimens. RESULTS: Despite limitations in the prevailing database, results indicated: (1) self-efficacy is potentially a potent predictor of the overall health status of the person with arthritis; and (2) carefully designed self-efficacy enhancing strategies are likely to impact favourably upon the magnitude of the disability experienced by individuals with arthritis. CONCLUSIONS: In relation to maximizing the therapeutic outcomes for disabling arthritis, the concept of self-efficacy is very worthy of the clinical practitioners and the clinical researchers attention.
9492563 [A clinical study of arthroscopic cystectomy on popliteal cysts associated with rheumatoid 1997 Dec PURPOSE: We performed a prospective study of arthroscopic cystectomy on popliteal cysts associated with rheumatoid arthritis. MATERIALS: We performed arthroscopic cystectomy on three patients, four knees, and an open excision of a cyst on one patient, one knee, who had pain and swelling in the popliteal region. Of these five rheumatoid knees, three were grade I on the Larsen radiographic scale, one was II, and one was III. OPERATIVE METHOD: First, we performed synovectomy on the posterior compartment using a multi-portal approach. Second, we confirmed a small communication hole between the posterior compartment and the Popliteal cyst after the synovectomy with an angled arthroscope through the anterior compartment. Third, we enlarged the communication hole and performed a cystectomy (the excision of the membranous septum and the contents of the cyst) from the inside by using a motorized shaver. Finally, we performed a synovectomy on the anterior compartment. The follow-up period ranged from 1 year 6 months to 3 years, 4 months (the mean was 2 years, 4 months). EVALUATION: We assessed the results using objective oriteria based on the evaluation of swelling, pain and subjective criteria based on the evaluation of the range of motion of the knee and confirmation of the disappearance of the cyst using MRI. RESULT: We had good results in this study. All the four knees on which the arthroscopic cystectomy was performed had a reduction of pain and swelling right after the operation. The absence of the cyst was verified using MRI. We had no patient whose ROM was aggravated. However, synovitis and popliteal cysts reoccurred in one knee after the open excision (this case had the vasculitis, larsen grade III radiographically, and severe rheumatism). DISCUSSION: The recurrence rate of the popliteal cyst was very high (over 50%) when a cyst was performed open exision using a posterior approach. Open synovectomy of an anterior compartment needed the manipulation in several cases because of limited knee movement. We had a reduction in pain and a disappearance of the cyst right after operation. Further more, there was no restriction in ROM resulting from this operative method. CONCLUSION: Arthroscopic cystectomy is a superior procedure for treating the popliteal cysts associated with rheumatoid arthritis.
10025931 Dose-loading with hydroxychloroquine improves the rate of response in early, active rheuma 1999 Feb OBJECTIVE: To investigate the usefulness of hydroxychloroquine (HCQ) dose-loading to increase the percentage of responders or rate of response in treating rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with early RA (mean duration 1.5 years) were enrolled in a 24-week trial. Patients were stabilized with 1,000 mg naproxen/day and then began a 6-week, double-blind trial comparing treatment with HCQ at 400 mg/day (n = 71), 800 mg/day (n = 71), and 1,200 mg/day (n = 66), followed by 18 weeks of open-label HCQ treatment at 400 mg/day. RESULTS: All patients had mild, active disease at the time of initiation of HCQ treatment (31-43% rheumatoid factor positive; no previous disease-modifying antirheumatic drugs; mean swollen joint count 8.6-10.4). Based on the Paulus criteria, response during the 6-week double-blind portion of the study was 47.97%, 57.7%, and 63.6% in the 400 mg/day, 800 mg/day, and 1,200 mg/day groups, respectively (P = 0.052). Discontinuations for adverse events were dose related (3 in the 400 mg/day group, 5 in the 800 mg/day group, 6 in the 1,200 mg/day group). Most involved the gastrointestinal (GI) system, with the background naproxen treatment possibly contributing. Ocular abnormalities occurred in 17 of 212 patients (8%) but were not dose related. CONCLUSION: Dose-loading with HCQ increased the degree of response at 6 weeks in this group of patients with early, predominantly seronegative RA. Adverse GI events were dose related, while adverse ocular events were not.
11297029 The health-related quality of life of patients with epilepsy compared with angina pectoris 2000 The objective of this study was to compare the health-related quality of life (HRQL) of patients with epilepsy with populations suffering from different chronic diseases, using the short form 36 (SF-36) health profile measure. The populations to be compared were adult patients drawn from hospital based registers, with confirmed epilepsy (n = 397), angina pectoris (n = 785), rheumatoid arthritis (n = 1,030), asthma (n = 117) and chronic obstructive pulmonary disease (COPD) (n = 221). Health-related quality of life scores were compared using analysis of covariance (ANCOVA) for predicting mean scores adjusted for age, gender, education and comorbidity. Patients with epilepsy on average scored highest on all scales, reflecting that in our sample the majority had well-controlled epilepsy. Our results indicate that the HRQL of a representative sample of patients with epilepsy is good, when compared with other chronic disorders, although reduced in several dimensions compared with a general reference population. Patients with rheumatoid arthritis (RA) and COPD scored lowest on the physical function scales, while rheumatoid arthritis patients reported most pain.
11503785 Nabumetone: new preparation. Just another NSAID. 2000 Apr (1) Nabumetone is a nonsteroidal antiinflammatory drug recently marketed in France. It has been available in other countries for about 15 years. Its licensed indications cover chronic inflammatory rheumatism and osteoarthritis. (2) The clinical file is bulky, but available trials in chronic inflammatory rheumatism involve only rheumatoid arthritis. (3) In rheumatoid arthritis (4 trials) and osteoarthritis (11 trials), nabumetone was no more effective than other nonsteroidal antiinflammatory drugs with which it was compared. (4) Clinical trial data, pharmacovigilance surveys and epidemiological studies suggest that nabumetone is among the antiinflammatory drugs with the least gastrointestinal adverse effects, but it has not yet been shown that they are less frequent than those of diclofenac, etodolac, ibuprofen or sulindac.
9808404 The homozygote of HLA-DRB1*0901, not its heterozygote, is associated with rheumatoid arthr 1998 To assess the association between HLA-DRB1*0901 and Japanese rheumatoid arthritis (RA) patients, we analyzed the frequency of HLA-DRB1*0901 in 852 Japanese RA patients. We found that the homozygote of DRB1*0901 was associated with Japanese RA patients, while the heterozygote of DRB1*0901 was not. These findings suggest that DRB1*0901 is a weakly susceptible allele of RA, which in our investigation was not associated with RA by a single allele, but can be by a homozygote. DRB1*0901 does not have the shared epitope, and it is suggested that there may be some mechanism ofthe association between HLA-DRB1 and RA other than the shared epitope, which was not strong.
10939757 Pauci-immune necrotizing glomerulonephritis complicating rheumatoid arthritis. 2000 Jul Necrotizing glomerulonephritis associated with rheumatoid arthritis typically occurs in the setting of frankly apparent systemic vasculitic signs and symptoms. We report two recent cases that differed from this paradigm. Both patients had rheumatoid arthritis and deteriorating renal function due to P-ANCA positive pauci-immune necrotizing crescentic glomerulonephritis, but minimal systemic symptoms. Delay in diagnosis and institution of appropriate therapy may have contributed to the dialysis dependence of one of these patients. We suggest that heightened suspicion of an aggressive necrotizing glomerulonephritis should be maintained in all patients with rheumatoid arthritis who present with acute renal insufficiency even in the absence of frank vasculitis.
9718501 Establishing the level of digitization for wrist and hand radiographs for the third Nation 1998 Aug In the third National Health and Nutrition Examination Survey (NHANES III) conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention, radiographs of the hands and knees were taken of participants 60 years and older as part of the study of arthritis and musculoskeletal conditions. The purpose of the study was to decide the digitizing resolution to be used for these radiographs. A set of wrist and hand radiographs (N = 49) was graded by two radiologists for degree of bone erosions and served as a "gold standard." The radiographs were then digitized at three resolution levels; low-resolution 150 microns (2001 x 1634 x 12 bit matrix); intermediate-resolution 100 microns (3000 x 2400 x 12 bit matrix); and high-resolution 50 microns (4900 x 3000 x 12 bit matrix). A comparison of the digital images versus the gold standard reading was made at the three resolutions by two radiologists. Kappa statistics suggested fair (K > .4) to excellent (K > .75) agreement between the gold standard and the images at all levels. Intraclass correlation coefficient suggested high agreement between readers (ICC > .5), with minimal individual reader effect. Variance component estimates showed that the major contribution (78-83%) to scoring came from variability in the images themselves, not from the readers. The 100 microns resolution was selected over the 150 and 50 microns on the basis of practical considerations such as storage requirements, display time, and easier manipulation of the digital images by the readers.
9195508 Direct and indirect medical costs incurred by Canadian patients with rheumatoid arthritis: 1997 Jun OBJECTIVE: To perform the first prospective longitudinal study of direct (health services utilized) and indirect costs (diminished productivity represented by income loss) incurred by patients with rheumatoid arthritis (RA) in Saskatoon and Montreal, followed for up to 12 and 4 years, respectively. METHODS: 1063 patients reported on health status, health services utilization, and diminished productivity every 6 months. RESULTS: Annual direct costs were $3788 (1994 Canadian dollars) in the late 1980s and $4656 in the early 1990s. Given that the average age exceeded 60 years, few participated in labor force activities or considered themselves disabled from the labor force and their indirect costs were substantially less, $2165 in the late 1980s and $1597 in the early 1990s. Institutional stays and medications made up at least 80% of total direct costs. Lengths of stay in acute care facilities remained constant, but the rate of hospitalization increased in the early 1990s, increasing average hospital costs per patient from $1563 in the late 1980s to $2023 in the early 1990s. For nonacute care facilities, rate of admission as well as length of stay increased over time, increasing costs per patient in Saskatoon 5-fold, from $291 to $1605. Those with greater functional disability incurred substantially higher direct and those under 65 years incurred higher indirect costs. CONCLUSION: Direct costs are higher than indirect costs. The major component is due to institutional stays that, in contrast to other direct cost components, is increased in the older and more disabled. Measures to reduce longterm disability by earlier, more aggressive intervention have the potential to produce considerable cost savings. However, it is unknown which strategies will have the greatest effect on outcome and accordingly, how resources can be optimally allocated.
11816835 Leflunomide Aventis Pharma. 2001 Feb Hoechst Marion Roussel (HMR; now Aventis Pharma) launched leflunomide (HWA-486), an immunomodulator and a disease-modifying antirheumatic drug (DMARD), for the treatment of rheumatoid arthritis (RA) in the US in late 1998 [310118]. By August 2000, the compound had been launched extensively across all of Latin America and in all major European countries [380046]. The compound is also under preclinical investigationfor the prevention of transplant rejection [279727], [304402]. In 1998, HMR filed for approvalfor RA in Europe [279727]. In September 1998, the FDA approved leflunomide for the treatment of active RA in adults and it was launched shortly thereafter [298204], [299258], [310118]. In September 1999, the EU Commission accepted the view of the Committee for Proprietary Medicinal Products, published in May 1999 [326040], [337534], and gave approval for the use of leflunomide in RA in adults [339128]. Lehman Brothers has reported that EU launch was delayed by rare side effects including pancytopenia [354434]. In August 1998, the Arthritis Advisory Committee unanimously recommended that leflunomide be contraindicatedfor pregnancy, and that a pregnancy registry should be established to monitor possible teratogenic effects of the drug [296187]. Kyorin had a licence to develop leflunomide in Japan. Product approval was scheduled for 1998 [159079], but no development has been reported since 1994. Preclinical studies in an animal model of experimental allergic encephalomyelitis (EAE) have shown leflunomide to be a powerful immunosuppressant which may have potential in diseases such as multiple sclerosis [187881]. Leflunomide is rapidly processed in vivo to its active metabolite, A-771726 (RS-61980) [202941], [253615]. In 1996, leflunomide was designated as one of HMR's nine top-priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].