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ID PMID Title PublicationDate abstract
10817552 A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombi 2000 May OBJECTIVE: To evaluate radiographic progression and the relationship of radiologic scores obtained by the Genant and Larsen methods in a clinical trial of recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS: Patients with rheumatoid arthritis (RA) were randomized into 4 groups: placebo (n = 121) or IL-1Ra at a daily dosage of 30 mg (n = 119), 75 mg (n = 116), or 150 mg (n = 116). Hand radiographs obtained at baseline, 24 weeks, and 48 weeks were scored using both methods. RESULTS: At 24 weeks, by the Genant method, there was significant reduction in the score for progression of joint space narrowing (JSN) and the total score (a combination of erosion and JSN) in all treatment groups. Least-squares mean changes in the Genant erosion score from baseline to 24 weeks were significantly reduced after treatment with IL-1Ra at 30 mg/day and for all IL-1Ra treatment groups combined. The changes corresponded to a reduction of 38% in erosion, 58% in JSN, and 47% in total score. Patients treated with IL-1Ra at 75 mg/day had a significant reduction in the Larsen erosive joint count (LEJC), and all IL-1RA-treated groups combined showed a 45% reduction. Correlations (r) between the Genant total and Larsen scores were 0.84 at baseline, 0.83 at week 24, and 0.83 at week 48 (P < 0.0001); correlations between the Genant erosion score and the LEJC were 0.83 (P < 0.0001) at all visits; correlations between the Genant total and the Larsen scores were 0.32 and 0.49 (P < 0.0001) for progression from baseline to week 24 and from baseline to week 48, respectively; correlations between the Genant erosion score and the LEJC were 0.36 and 0.41 (P < 0.0001) for progression to weeks 24 and 48, respectively. CONCLUSION: IL-1Ra reduced radiologic progression of RA. Scores by the 2 methods correlated strongly for each individual time point, but much less strongly for assessments of disease progression.
11249494 Tumour necrosis factor-alpha blockade: a new era for effective management of rheumatoid ar 2000 Jul Tumour necrosis factor (TNF)-alpha inhibitors have emerged as a new treatment option for rheumatoid arthritis (RA). The scientific rationale for targeting TNF-alpha in RA derives from extensive work in the laboratory, showing the importance of this pro-inflammatory cytokine as a mediator of joint inflammation. Proof of principle has now been firmly established in clinical trials where TNF-alpha inhibitors have been shown to decrease the signs and symptoms of joint inflammation and slow radiological progression of joint damage. Presently, the two TNF-alpha inhibitors available for use in RA are etanercept and infliximab. Etanercept is a soluble TNF receptor: Fc fusion protein that competes with the endogenous TNF receptors for TNF-alpha binding. Infliximab is a chimeric anti-TNF-alpha monoclonal antibody, which also binds with high affinity to soluble TNF-alpha. Etanercept and infliximab will be rapidly incorporated into current treatment paradigms, which call for early and intensive treatment of RA using disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, sulfasalazine and hydroxychloroquine. A major drawback to the widespread use of these biologics is their high costs. Some patients with limited financial means may be denied access to these effective anti-inflammatory agents. Moreover, long-term experience with TNF-alpha inhibitor therapy has been limited and concerns linger about the possibility that etanercept and infliximab may cause unforeseen side effects or increase the risk for opportunistic infection. Despite these caveats, TNF-alpha inhibitors represent a major advance for the treatment of RA and will likely spawn new indications for anti-TNF-alpha therapy and the development of novel therapeutic compounds with similar biological activity.
10833963 [Felty's syndrome]. 2000 Mar 30 BACKGROUND: Felty's syndrome is a complication of rheumatoid arthritis whereby patients develop neutropenia of varying severity and splenomegaly. The major sources of morbidity and mortality are recurrent local and systemic infections, although some patients remain asymptomatic. MATERIAL AND METHODS: In this paper two patients with Felty's syndrome are presented. RESULTS: One patient had recurrent infections. Clinical manifestations, laboratory features and different modalities of treatment are reviewed. INTERPRETATION: Splenectomy has long been standard therapy, but disease modifying antirheumatic drugs (such as gold salts and methotrexate) and colony stimulating factors should also be considered in Felty's neutropenia complicated with infections.
9158580 Oral staphylococcus in older subjects with rheumatoid arthritis. 1997 May OBJECTIVE: To determine if Staphylococcus aureus and Staphylococcus epidermidis, etiologic bacterial agents to late prosthetic joint infections (LPJI), are more prevalent in the oral flora of older individuals with rheumatoid arthritis (RA) than in an age and gender-matched nonarthritic control population (NA). DESIGN: Cultures were obtained from the nares, oropharynx, saliva, tongue, and gingival crevice, and the results were compared between older patients with RA and controls. SETTING: University of Michigan Medical Center, Ann Arbor, VA Medical Center, and University of Michigan School of Dentistry. PARTICIPANTS: A total of 111 community-dwelling subjects with a diagnosis of RA and 83 gender-matched control subjects. MEASUREMENTS: Colistin nalidixic acid agar plates with 5% sheep's blood were inoculated and incubated. Isolates were speciated using the API Staph Trac micro method and catalase and coagulase tests. MAIN RESULTS: Individuals with RA had a higher prevalence of S. aureus isolated from the oral cavity. However, only the oropharynx and tongue revealed higher rates; all other sites were insignificant. The presence of oral S. aureus was associated with xerostomia. Staphylococcus epidermidis was not detected from any of the oral sites sampled. Sixty-two percent (10/16) of the S. aureus isolates from the RA subjects were resistant to penicillin and ampicillin, whereas none were resistant to a cephalosporin. CONCLUSIONS: These findings suggest that rheumatoid arthritis may be a risk factor for LPJI in older prosthetic joint patients undergoing invasive dental procedure in the posterior oral cavity. This increased risk is caused, in part, by a higher prevalence of S. aureus in the posterior oral cavity. The prevalence and the antibiotic resistance of S. aureus must be considered when determining the need for chemoprophylaxis.
11155307 Functional outcome comparison of semiconstrained and unconstrained total elbow arthroplast 2000 Nov Twenty-six patients, each of whom had undergone either a semiconstrained (linked) or an unconstrained (unlinked) total elbow arthroplasty, were examined specifically to evaluate the restoration of function with respect to activities of daily living. The functional outcomes of these 2 groups were then compared to identify any significant differences. All of the unlinked/unconstrained prostheses were Ewald total elbow arthroplasties; the linked/semiconstrained prostheses, all of which were performed by a single surgeon, were Mayo-Coonrad prostheses. Follow-up radiographs, taken to rule out loosening or failure of the prosthesis as a cause for functional deficits, were available for review for 25 elbows. There were 14 elbows in 13 patients who had semiconstrained prostheses and 12 elbows in 10 patients who had unconstrained total prostheses. Average age at the time of elbow replacement surgery was 62.8 years (range, 47-75 years) for the semiconstrained group and 63.1 years (range, 54-74 years) for the unconstrained group. The semiconstrained group consisted of 8 female and 6 male elbows; the unconstrained group consisted of 10 female and 2 male elbows. Follow-up averaged 35.5 months (range, 24-73 months) in the semiconstrained group and 73 months (range, 27-110 months) in the unconstrained group. Twenty-two operations were performed for rheumatoid arthritis, 3 for posttraumatic humeral nonunion, and 1 for posttraumatic degenerative arthritis. Two elbows required revision, one (in the semiconstrained group) for aseptic loosening and the other (in the unconstrained group) for metal synovitis and pain from a chronically dislocated prosthesis; both of these elbows were considered failures and excluded from the functional comparison. No significant differences in functional performance were found, and no elbows demonstrated progressive radiolucencies suggestive of loosening. With the exception of 1 patient (in addition to the patients who had revisions) with a dislocated unconstrained prosthesis, all patients were satisfied with the procedure. It appears that when it is properly performed, total elbow arthroplasty with either type of prosthesis yields satisfactory functional results.
11808980 Nitric oxide in rheumatology. 2001 Dec Nitric oxide (NO) is attracting considerable interest because it mediates many functions. This gas is ubiquitously produced in the body by three enzymes, called NO synthases. Two NO synthases are constitutively expressed, one in the nervous system and the other in the blood vessels, where it regulates tissue perfusion. The third NO synthase can be induced by several stimuli (bacterial endotoxins, cytokines), most notably in inflammatory cells and chondrocytes. The effects of NO produced by the inducible NO synthase range from T-cell response modulation to formation of free radicals responsible fortissue damage and cartilage matrix degradation. Administration of NO synthase inhibitors in animal models of arthritis yields ambiguous effects, often with prevention of arthritis, but sometimes with worsening of established arthritis. The data available to date do not support the use of such inhibitors in the treatment of human arthritis.
9821615 Free tendon interposition grafting for the repair of ruptured extensor tendons in the rheu 1998 Oct Sixteen ruptured extensor tendons were repaired in seven rheumatoid hands using autogenous palmaris longus tendon as a free interposition graft. The patients were reviewed at an average of 17 months (range, 5-45) after repair. Subjectively all patients were satisfied with the clinical results, and achieved a return to their level of ability before tendon rupture. A biomechanical model suggests that tendon repair using an interposition graft, rather than a traditional end-to-side tendon transfer retains the anatomical axis of tendon function, and achieves greater forces during active finger extension.
10408141 Tumor necrosis factor inhibitors for rheumatoid arthritis. 1999 Tumor necrosis factor antagonists such as infliximab and etanercept represent a new and powerful approach to managing RA. In studies published to date, TNF antagonists appear to be safe and effective agents for short-term therapeutic use in RA. Defining when in the course of RA to use TNF antagonists and determining the effectiveness of combinations of these biologic agents with DMARDs or other cytokine antagonists are areas of current and future studies. Other cytokine antagonists that may be promising subjects for further study are IL-1 antagonists. Like TNF, IL-1 is a member of the inflammatory cascade, but may play a different role in the development of inflammatory arthritis. In animal models, inhibition of TNF suppressed the inflammatory response while IL-1 antagonism prevented joint destruction (2). These results imply that combination therapy providing inhibition of both IL-1 and TNF might be an effective treatment in humans with RA, but clinical trials in humans have not yet been performed. Studies are underway in people with early RA to determine if the new TNF inhibitors are more effective or safer than currently available therapies, such as methotrexate. Other agents that inhibit TNF activity are also being tested at this time in people with RA.
9533047 Kinematic posterior cruciate ligament-retaining total knee replacements. A 10-year survivo 1998 Winter Survival was tested in 445 primary Kinematic knee replacements performed between January 1981 and December 1990. Three criteria were applied to indicate failure: 1) revision or recommended revision, 2) presence of moderate to severe pain or revision, and 3) lost to follow-up or revision. Using these three criteria, the survival rate at 10 years was 96%, 78%, and 69%, respectively. At last follow-up examination, 84% of knees had good or excellent Bristol knee scores with mean range of motion 100 degrees. Overall, 11 knees (2.5%) have been revised and 27 cases (6%) were graded as failures due to presence of moderate to severe pain at the time of the last evaluation. These results indicate that the posterior cruciate ligament-retaining Kinematic prosthesis provides satisfactory function and survival up to 10 years.
10873967 Neutrophil function in pregnancy and rheumatoid arthritis. 2000 Jul BACKGROUND: Pregnancy exerts suppressive effects on rheumatoid arthritis (RA). An attenuation in neutrophil function in late pregnancy which may explain this amelioration has previously been reported. OBJECTIVE: A longitudinal investigation of neutrophil activity in healthy pregnant women (n=9) and pregnant patients with RA (n=9), compared with age matched non-pregnant patients with RA (n=12) and healthy controls (n=22). METHODS: Neutrophil activation was measured in response to the physiological receptor agonists, n-formyl-methionyl-leucyl-phenylalanine (fMLP) and zymosan activated serum (ZAS). Superoxide anion production (respiratory burst) was determined by lucigenin enhanced chemiluminescence (LUCL); secondary granule lactoferrin release by enzyme linked immunosorbent assay (ELISA); and CD11b, CD18, and CD62L expression by flow cytometric analysis. RESULTS: Stimulated neutrophil LUCL was significantly reduced in both pregnant women with RA and healthy pregnant women in the second (fMLP 43% and 69%, ZAS 43% and 59%, respectively) and third trimesters (fMLP 24% and 44%, ZAS 32% and 38%, respectively). Responses returned to normal within eight weeks of delivery and unstimulated levels remained unchanged throughout pregnancy. Basal and stimulated CD11b, CD18, and CD62L expression showed no variations throughout gestation for both pregnancy groups. Likewise, stimulated lactoferrin release and plasma lactoferrin remained unchanged. Certain morphological differences in RA neutrophils were highlighted by the flow cytometric analysis. Moreover, resting neutrophils and stimulated cells from patients with RA, including pregnant subjects, showed a marked increase in LUCL, but a reduction in CD11b, CD18, and CD62L. Low dose prednisolone and methylprednisolone had no effect on neutrophil parameters over the period of treatment with non-steroidal anti-inflammatory drugs. CONCLUSION: The attenuation to neutrophil respiratory burst in both healthy and RA pregnancies may offer an explanation for the pregnancy induced remission of this inflammatory disorder.
9085257 Normal human epidermal keratinocytes express in vitro specific molecular forms of (pro)fil 1997 Feb BACKGROUND: The so-called antikeratin antibodies and the antiperinuclear factor are the most specific serological markers of rheumatoid arthritis (RA). They were recently shown to be largely the same autoantibodies and to recognize human epidermal filaggrins and profilaggrin-related proteins of buccal epithelial cells (collectively referred to as (pro)filaggrin). MATERIALS AND METHODS: To further characterize the target antigens, we investigated their expression by normal human epidermal keratinocytes cultured in differentiating conditions, using immunofluorescence and immunoblotting with RA sera and three different monoclonal antibodies to (pro)filaggrin. RESULTS: On the cornified, stratified epithelial sheets obtained in vitro, RA sera with anti(pro)filaggrin autoantibodies (AFA) produced granular staining of the stratum granulosum and diffuse staining of the stratum corneum. The antigens recognized by RA sera strictly colocalized with (pro)filaggrin in keratohyalin granules. Following sequential extraction of the proteins from the epithelial sheets, the RA sera and the three monoclonal antibodies to (pro)filaggrin, recognized a series of low-salt-soluble molecules, including a neutral/acidic isoform of filaggrin and several proteins with sizes and pI intermediates between this isoform and profilaggrin. They also recognized urea-soluble high-molecular-weight profilaggrin-related molecules. CONCLUSIONS: These results show that in vitro epidermal keratinocytes express various molecular forms of (pro) filaggrin that bear epitopes targeted by AFA of RA sera, and that some of these are absent from epidermis. Moreover, these epitopes, which are present on the keratohyalin granules of buccal epithelial cells but not on those of epidermal cells, are present on the granules of the cultured keratinocytes. This work completes the molecular characterization of the proteins targeted by AFA.
11414692 alpha(2)-Macroglobulin from rheumatoid arthritis synovial fluid: functional analysis defin 2001 Jul 1 A hallmark of inflammation is the release of oxidants, proteinases, and cytokines, all important mediators of the inflammatory cascade. alpha(2)-Macroglobulin (alpha(2)M) is a high-affinity, broad-specificity proteinase inhibitor that also binds and regulates the biological activities of a number of cytokines. We demonstrated recently that hypochlorite-oxidized alpha(2)M has decreased ability to inhibit proteinases and regulate cytokines in vitro. The role of oxidation in regulating alpha(2)M functions in vivo is largely unknown. To determine the extent and biological consequence of in vivo alpha(2)M oxidation, we measured the degree of oxidative alpha(2)M modification from rheumatoid arthritis (RA) synovial fluid and compared this with osteoarthritis (OA) as noninflammatory controls. We found that RA synovial fluid alpha(2)M is significantly more oxidized than that from OA. RA synovial fluid also contains a twofold higher median alpha(2)M level than OA, while having only half the alpha(2)M-proteinase inhibitory activity. Detailed biochemical analysis demonstrates proteolytically degraded alpha(2)M in RA greater than in OA synovial fluid. Additionally, the hypochlorite-mediated oxidation product, chlorotyrosine, is present in RA more than in OA or plasma alpha(2)M samples. Taken together, these findings confirm a role for oxidative regulation of inflammation by altering the functions of extracellular mediators such as alpha(2)M.
9462166 Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheuma 1997 Nov OBJECTIVE: Vitamin E, the most potent naturally occurring lipid soluble antioxidant has been suggested to possess both anti-inflammatory and analgesic activity in humans. This double blind and randomised study used a broad spectrum of clinical and laboratory parameters to investigate whether there was any additional anti-inflammatory or analgesic effects, or both, of orally administered alpha-tocopherol in rheumatoid arthritis patients who were already receiving anti-rheumatic drugs. METHODS: Forty two patients were enrolled and treated with alpha-tocopherol (n = 20) at a dose of 600 mg twice a day (2 x 2 capsules) or with placebo (n = 22) for 12 weeks. The following parameters were measured: (1) Three clinical indices of inflammation--the Ritchie articular index, the duration of morning stiffness, and the number of swollen joints; (2) three measures of pain--pain in the morning, pain in the evening, and pain after chosen activity; (3) haematological and biochemical measures of inflammatory activity; (4) assays for the oxidative modification of proteins and lipids. RESULTS: All laboratory measures of inflammatory activity and oxidative modification were unchanged. Furthermore, the clinical indices of inflammation were not influenced by the treatment. However, the pain parameters were significantly decreased after vitamin E treatment when compared with placebo. CONCLUSION: The results provide preliminary evidence that vitamin E may exert a small but significant analgesic activity independent of a peripheral anti-inflammatory effect, but which complements standard anti-inflammatory treatment.
10025101 [Quality management in the interdisciplinary specialty hospital]. 1998 Dec The aim of quality management in rheumatology is to improve care and outcome in patients with rheumatic diseases. This can be achieved by means of prospective long-term observation of the patient with regular documentation of clinical, radiological, biochemical and functional data using certain validated scoring methods (DAS, radiological score, ADL score Hanover or Health assessment questionnaire, SF36, etc.). Long-term observation and documentation including radiographs have been performed in the rheumatology hospital in Ratingen for 20 years without even knowing the term quality management. Quality management in a hospital for rheumatic diseases begins with certain structural prerequisites: possibility of direct admission of a patient to the hospital by the family physician, outpatient clinic to investigate and to follow patients over a long period of time, multidisciplinary team with specialists in rheumatology, orthopedic surgery, physiotherapy, ergotherapy, special care, psychological, and social services, close cooperation with specialists in neurology, dermatology, ophthalmology, etc., department of radiology, special laboratory, facilities for internal diagnostic and treatment. The hospital needs a training program for the qualification of rheumatologists and orthopaedic surgeons. The hospital staff should closely cooperate with the doctors in private practice who admit patients and should continuously support patient organizations. The quality of outcome is influenced by the process quality which depends on the following factors: selection, training and motivation of the hospital staff; supervision of clinical assessment and documentation by senior physicians, daily x-ray demonstrations and case reports, interdisciplinary case demonstrations at least every week in addition to daily consultation, team reports, regular education including review of actual literature for physicians, education programs exchanging knowledge with physiotherapists and nurses, and regular education programs for patients. Process quality can only be achieved by an interdisciplinary approach and regular communication between all participants including the patient, whose opinion must be noted and regarded. As far as possible, the same doctor who treats the patient in the hospital should follow her/him in the outpatient clinic. The quality of outcome can be improved by regular reinvestigation of the patient with control of medication, side effects, efficacy, documentation of clinical, biochemical, radiological, and functional data. Decisions for further treatment have to be based on these follow-up data. A standardized follow up and documentation system for all rheumatology units with prompt feedback could definitely improve the quality of rheumatologic care in Germany.
9378726 Midkine, a retinoic acid-inducible heparin-binding cytokine in inflammatory responses: che 1997 Aug Midkine (MK) is a retinoic acid-inducible heparin-binding cytokine. In the inflammatory synovitis of rheumatoid arthritis and osteoarthritis, MK was detected in synovial fluid, synoviocytes, and endothelial cells of new blood vessels. Normal synovial fluid and noninflammatory synovial tissue did not contain detectable MK. Therefore, MK showed inflammation-associated expression in these cases. Furthermore, MK was found to promote chemotaxis of neutrophils in the range of 10 ng/ml. The mode of action of MK was found to be haptotactic; the substrate-bound form of MK was the active one. MK is also known to promote fibrinolysis. These activities of MK are in agreement with the modes of MK expression in various pathological statuses, and thus MK is proposed to be an important molecule regulating inflammatory responses.
10912841 Detailed analyses of periarticular osteoporosis in rheumatoid arthritis. 2000 Periarticular osteopenia is the earliest radiographic sign of rheumatoid arthritis (RA). Recent studies using dual-energy X-ray absorptiometry (DXA) have indicated that the loss of periarticular BMD can be quantified by whole-hand bone mineral density (BMD) measurements. The aim of this study was to analyze periarticular BMD in more detail by DXA and quantitative ultrasound (QUS). In a cross-sectional study 23 women aged 30-76 years with early RA, mean disease duration 26 +/- 19 months, and 18 men aged 42-69 years, mean disease duration 24 +/- 25 months, were examined. All patients received antirheumatic therapy. The reference population consisted of 103 age-matched controls (68 females, 35 males) and young healthy controls. BMD measurements were performed using a DXA Expert XL densitometer (Lunar). BMD of the whole-hand and two subregions was determined: two subchondral regions of interest (S.CH.) were set within the trabecular bone, distal to the proximal interphalangeal joints of digits II and III excluding the dense subchondral bone of the metacarpophalangeal (MCP) joint and two metacarpal regions of interest (MCP) were set including the entire MCP joint of these fingers. QUS measurements at the proximal phalanges of digits II-V were performed using a DBM Sonic (Igea); amplitude-dependent speed of sound (Ad-SoS) was determined. In comparison with whole-hand BMD measurements, bone loss was pronounced in patients with a disease duration of 18-72 months at the subchondral regions of interest in both genders compared with age-matched controls (women: mean BMD loss S.CH. -23%, p<0.001, whole-hand -16%, p<0.001; men: mean BMD loss S.CH. -19%, p < 0.05, whole-hand -12%, p<0.05). The bone changes were also shown by QUS (women: Ad-SOS values of 1950 +/- 90 m/s in RA vs 2137 +/- 35 m/s in young healthy controls (p <0.005); men AD-SOS 1956 +/- 87 m/s in RA vs 2146 +/- 41 m/s in young healthy controls (p <0.05)). These results show that BMD and Ad-SOS values are significantly lowered in patients with early RA and indicate that periarticular osteoporosis in early RA might possibly be better detected using detailed hand scan analyses.
9182922 Human cartilage glycoprotein-39 as a candidate autoantigen in rheumatoid arthritis. 1997 Jun OBJECTIVE: To identify a cartilage-derived autoantigen that is relevant to the rheumatoid arthritis (RA) disease process. METHODS: A DR4 (DRB1*0401) peptide binding motif was used for the selection of potential self reactive peptides within human cartilage glycoprotein-39 (HC gp-39), a protein that is differentially expressed at the site of chronic inflammation. Synthetic peptides accommodating the motif were tested for binding the RA-associated DR4 (DRB1*0401) molecules. High-affinity binders were then tested for their capacity to stimulate peripheral blood mononuclear cell responses in RA patients or healthy donors. To assess the arthritogenic nature of native HC gp-39, the protein was injected into BALB/c mice. RESULTS: HC gp-39-derived motif-based peptides were selectively recognized by peripheral blood T cells from RA patients. Injection of the intact protein into BALB/c mice resulted in immunity to HC gp-39, which was found to be associated with the development of a chronic, relapsing arthritis. Moreover, inhalation of the protein led to tolerization of antigen-specific T cells and to suppression of HC gp-39-induced arthritis. CONCLUSION: These data indicate that HC gp-39 is a target of the immune response in RA. Consequently, HC gp-39 is a candidate for antigen-specific immunotherapy.
9259416 Allelic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles amo 1997 Aug OBJECTIVE: To investigate linkage disequilibrium between HLA-DRB1 disease susceptibility alleles and microsatellite markers close to the prolactin gene, among women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and normal controls. METHODS: DNA from 89 women with RA, 76 women with SLE, and 94 controls was typed for HLA-DRB1 status and D6S422 and D6S285, 2 highly polymorphic microsatellite markers close to the prolactin gene. RA patients were stratified by DRB1*0401 status, and SLE patients were stratified by *0301 status. RESULTS: There was an excess frequency of D6S422*1 among SLE patients with DRB1*0301 (odds ratio [OR] 3.1). The frequency of this allele was also slightly in excess among RA patients with DRB1*0401 (OR 1.9). D6S285*5 was also in excess among female RA patients with DRB1*0401 (OR 3.5), and was slightly increased among female SLE patients with DRB1*0301. None of these alleles were found to be increased among *0401-positive or *0301-positive controls. CONCLUSION: These data indicate that there may be linkage disequilibrium between HLA-DRB1 alleles and microsatellite marker alleles close to the prolactin gene among women with RA and SLE. This suggests the possibility of extended haplotypes encoding for HLA-DRB1 susceptibility and high prolactin production, which contribute to susceptibility to both RA and SLE.
10334255 Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: 1999 May 8 BACKGROUND: The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis. METHODS: 199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat. FINDINGS: 87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events were similar in both treatment groups. INTERPRETATION: Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.
9502430 Structural motifs in rheumatoid T-cell receptors. 1998 Feb The linkage of rheumatoid arthritis (RA) to HLA-DR haplotypes, high levels of HLA-DR expression, and T-cell infiltration in the joints, indicate a central role for the interaction of T-cell receptors (TCR) with antigen (Ag) + major histocompatibility complex (MHC) complexes in pathogenesis. Receptor analysis in RA has uncovered a restricted heterogeneity of TCR transcripts, suggesting an antigen-driven response. We analyzed the sequence and structural features of RA-associated TCRs in light of the recently published TCR crystal structures. The surface-exposed residues of the third complementarity-determining region (CDR3s) showed preferential use of certain amino acid residues when sequences derived from synovial fluid or tissue were compared with those derived from peripheral blood, particularly for alpha chains. Sequence alignment of oligoclonal synovial TCR CDR3s revealed groupings with similar CDR3 lengths and amino acid compositions, which suggests shared antigen recognition. Given the limitations of analyzing TCR sequences without knowing their structures, we developed several in vivo-activated synovial-tissue Vbeta17 + RA T-cell clones. Two Vbeta17/V alpha7 clones with different CDR3 sequences were analyzed by molecular modeling. Although distinct topologic features were seen, a central patch of residues with similar chemical and geometric characteristics was present in both. Electrostatic maps revealed similar binding surfaces of both alpha domains and central patches, with differences in the beta domains. This suggests that an alpha-domain-focused binding trajectory would allow shared antigen recognition by these TCRs. These studies support recognition of a limited diversity of Ag + MHC complexes by synovial RA TCRs.