Identification of the gene loci that predispose to rheumatoid arthritis

We have searched the human genome for genes that predispose to rheumatoid arthritis (RA) using fluorescence-based microsatellite marker analysis and affected sib-pair linkage study. A panel of 41 Japanese families, each with at least two affected siblings, was typed for genome-wide 358 polymorphic microsatellite marker loci. Markers were amplified by the PCR using fluorescence-tagged primers and sized based on the difference of CA repeats on DNA. Linkage analysis was made using maximum lod score (MLS). The MLS for D1S214 and D8S556 was 3.27 and 3.33, while the MLS for the HLA-DRB1 region was <3.0. According to detailed analysis by single-point analysis using MAPMAKER/SIBS, the MLS for D1S253 and D1S214 was 3.77 and 3.58. The MLS by multipoint analysis was 6.13 for D1S253. The MLS for D8S556 by single-point analysis was 4.20. The MLS for DXS1232 was 2.35 by single-point analysis, whereas the MLS for the region 2 cM right to DXS1232 and the region between DXS1227 and DXS1200 was 3.03 and 2.93 by multi-point analysis. Three principal chromosome regions of linkage, D1S253/214, D8S556 and DXS1232, have been identified which we call RA1, RA2 and RA3 for RA disease loci.     

Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group

BACKGROUND: Phase II trials of leflunomide, an inhibitor of de-novo pyrimidine synthesis, have shown efficacy in rheumatoid arthritis. This double-blind randomised trial compared leflunomide with placebo and sulphasalazine in active rheumatoid arthritis. METHODS: 358 patients were randomly assigned leflunomide (100 mg daily on days 1-3, then 20 mg daily), placebo, or sulphasalazine (0.5 g daily, titrated progressively to 2.0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigator's and patient's overall assessments. Analyses were by intention to treat. FINDINGS: The mean changes in the leflunomide, placebo, and sulphasalazine groups were -9.7, -4.3, and -8.1 for tender joint count; -7.2, -3.4, and -6.2 for swollen joint count; -1.1, -0.3, and -1.0 for physician's overall assessment; and -1.1, -0.4, and -1.1 for patient's overall assessment. Leflunomide and sulphasalazine were significantly superior to placebo (p=0.0001 for joint counts; p<0.001 for assessments). Radiographic disease progression was significantly slower with leflunomide and sulphasalazine than with placebo (p<0.01). Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%). Transiently abnormal liver function was seen in three leflunomide-group patients and five sulphasalazine-group patients. There were two cases of reversible agranulocytosis in the sulphasalazine group. INTERPRETATION: Leflunomide was more effective than placebo in treatment of rheumatoid arthritis and showed similar efficacy to sulphasalazine. Leflunomide was well tolerated. This drug may be a useful option as a disease-modifying antirheumatic drug.     

A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis

1. A comparison of the effects of dietary and genetically-induced hypercholesterolaemia on the vasodilator and antiaggregatory capacity of the endothelium was made in rabbit isolated subclavian artery rings. 2. Dietary-induced hypercholesterolaemia in NZW rabbits decreased the maximum relaxation to carbachol (0.01-10 microM) and calcimycin (0.01-0.1 microM) in vessel rings precontracted with 5-hydroxytryptamine (5-HT), 0.1 microM), when compared to responses observed in rings obtained from control normocholesterolaemic NZW rabbits. The relaxant responses to SIN-1 (3-(4-morpholinyl)-sydnonimine hydrochloride) were attenuated but were not significantly different from controls. In Froxfield genetically hypercholesterolaemic (FHH) rabbits, the maximum relaxations to carbachol, calcimycin and SIN-1 were all reduced significantly. 3. Neither genetic nor dietary-induced hypercholesterolaemia modified the contractile responses of vessel rings to either KCl (10-100 mM) or 5-HT (0.01-10 microM). 4. Endothelium-dependent inhibition of collagen-induced platelet aggregation in whole blood was demonstrated by stimulation of a vessel ring, incorporated into the blood sample, with carbachol (10 microM, final blood concentration). This effect was inhibited by NG-nitro-L-arginine (L-NOARG, 100 microM). SIN-1 (10 microM, final blood concentration) also decreased whole blood platelet aggregation, but only in the presence of an unstimulated vessel ring, and this was unaffected by L-NOARG. Superoxide dismutase (150 u ml-1) did not influence the inhibition of aggregation by either a carbachol-stimulated vessel ring or by SIN-1. 5. Carbachol-stimulated artery rings from FHH rabbits inhibited platelet aggregation to a similar extent to that seen with rings from control normocholesterolaemic rabbits. Rings from hypercholesterolaemic NZW rabbits, however, did not significantly inhibit platelet aggregation when stimulated with carbachol. SIN-1 inhibited platelet aggregation in the presence of rings from either group of hypercholesterolaemic rabbits. 6. Hypercholesterolaemia induced by dietary modification induces changes in endothelial function which are characteristically different from those seen in genetically hypercholesterolaemic rabbits. It appears that dietary-induced hypercholesterolaemia primarily decreases NO release from the endothelium, while in genetically-induced hypercholesterolaemic vessel rings NO is released but there is a decreased responsiveness of the vascular smooth muscle cells to NO. This may reflect differences in the age and severity of the atherosclerotic lesions in the two groups of rabbits.     

Relationship between apneic episodes and destruction of temporomandibular joints in patients with rheumatoid arthritis

There have been only a few investigational reports of sleep apnea syndrome (SAS) in patients with rheumatoid arthritis (RA), although it may not be a rare condition and may be life-threatening occasionally. The factor precipitating SAS in such patients is thought to be destruction of the temporomandibular joints (TMJs) from RA processes. To assess the relationship of the degree of destruction of the TMJs to the frequency of apnea, we examined them in 10 RA patients who complained of snoring. Those patients were classified as classical RA according to the criteria of American Rheumatism Association. They consisted of 3 males and 7 females with a mean age of 57.8 + 11.0 years and a mean disease duration of 15.9 +/- 9.4 years. In order to numerically evaluate the degree of destruction of the mandibular rami, we quoted a method from the literature (Redlund-Johnell I, Scand J Rheumatol 16:355, 1987) and measured the vertical distance (= ramal height) from the mandibular angle to the palato-occipital line on the lateral view film of the cervical spine in each patient. The mean values of ramal height (RH) of the normal material (we studied in Japanese) are 46.0 mm in males and 38.3 mm in females. There were 8 cases of SAS out of the 10 RA patients studied. Their mean total apneic episode (TAE) was 289.9 mm with a range of 0-611. The mean ratio (%) of RH to mean value of the normal material (%RH) was 68.8 +/- 22.2% for all. There was a significant statistic correlation between TAE and %RH (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pneumonitis

OBJECTIVE: To determine the clinical features of methotrexate (MTX) pneumonitis in patients treated for rheumatoid arthritis (RA). METHODS: The medical records of 284 patients with RA who had been treated with oral MTX (mean followup 33.2 mo) were reviewed retrospectively. RESULTS: MTX induced interstitial pneumonitis developed in 6 patients (2.1%). The affected patients were significantly older than those without MTX pneumonitis (67.3 +/- 9.8 vs 52.4 +/- 12.6 yrs, respectively; p < 0.005). The cumulative MTX dose ranged from 65 to 580 mg at the time pneumonitis developed. Five of the patients (83%) had preexisting interstitial abnormalities, while only 29 of the 278 patients without MTX pneumonitis (10%) had such abnormalities (p < 0.001). The frequency of adverse effects due to previous treatment with disease modifying antirheumatic drugs (DMARD) was 66.7% in MTX pneumonitis patients and 14.3% in the other 278 patients (p < 0.01). CONCLUSION: Advanced age, preexisting interstitial abnormalities, and previous adverse reactions to DMARD may be associated with MTX pneumonitis. Patients with these characteristics require careful monitoring during MTX therapy.     

Clinical and radiographic evaluation of juvenile rheumatoid arthritis: report of a case

Rheumatoid arthritis (RA) is an inflammatory disease of the synovium which may lead to proliferative and degenerative changes in the body's joints, including the temporomandibular joint (TM Joint). Although the exact etiology of rheumatoid arthritis remains unknown, it is suspected that the disease is often initiated by an infectious organism, or by genetic and/or environmental factors. Juvenile rheumatoid arthritis (JRA) is a chronic disease of childhood with a spectrum of joint involvement and associated systemic and other organ involvement. Five percent of all rheumatoid arthritis patients are children. In the United States, approximately 150,000 children are affected by JRA. With upper limb involvement, routine oral hygiene procedures become difficult. Dental evaluations/screenings may not be included in the initial team assessment of these patients until the TM Joint is affected; however, prior to this time, the patient may have had years of poor oral hygiene which could contribute to severe decay and early tooth loss. This case report describes the oral health status of a child with polyarticular juvenile rheumatoid arthritis and the specific recommendations for dental management.     

Clinical and radiographic outcomes of rheumatoid arthritis patients not treated with disease-modifying drugs

OBJECTIVE: To compare the radiographic and clinical features of rheumatoid arthritis (RA) patients who were not given disease-modifying antirheumatic drugs (DMARDs) with those of RA patients who were followed up and treated with DMARDs at a rheumatology clinic. METHODS: The population of this case-control study includes a series of RA patients who immigrated to Israel from the previous Union of Soviet Socialist Republics and who were treated only with nonsteroidal antiinflammatory drugs. Control patients who were followed up and treated with DMARDs at our rheumatology clinic were matched by sex, disease duration, number of actively inflamed joints, and the presence of serum rheumatoid factor. The outcome measures were the number of deformed and radiographically damaged joints. Radiographic damage was evaluated by the methods of Steinbrocker and Sharp. RESULTS: The study population consisted of 22 RA patients (15 women, 7 men) who were not treated with DMARDs and 22 patients (15 women, 7 men) who were treated with DMARDs. The mean disease duration was 16.2 years for the study patients and 14.3 years for the controls. Compared with the matched controls, RA patients who were not treated with DMARDs were found to have a significantly higher mean number of deformed joints (13.8 versus 7.2), a higher mean number of damaged joints (24.4 versus 15.5), and a higher overall damage score by the Sharp criteria (146.1 versus 65.7). CONCLUSION: RA patients who were not given DMARDs had a 1.57-fold increased number of radiographically damaged joints and a 2.22-fold increased overall Sharp damage score compared with patients who were treated with second-line agents.     

Viscosupplementation with hylan G-F 20: a 26-week controlled trial of efficacy and safety in the osteoarthritic knee

Cortical color blindness, or cerebral achromatopsia, has been likened by some authors to "blindsight" for color or an instance of "covert" processing of color. Recently, it has been shown that, although such patients are unable to identify or discriminate hue differences, they nevertheless show a striking ability to process wavelength differences, which can result in preserved sensitivity to chromatic contrast and motion in equiluminant displays. Moreover, visually evoked cortical potentials can still be elicited in response to chromatic stimuli. We suggest that these demonstrations reveal intact residual processes rather than the operation of covert processes, where proficient performance is accompanied by a denial of phenomenal awareness. We sought evidence for such covert processes by conducting appropriate tests on achromatopsic subject M.S. An "indirect" test entailing measurement of reaction times for letter identification failed to reveal covert color processes. In contrast, in a forced choice oddity task for color, M.S. was unable to verbally indicate the position of the different color, but was surprisingly adept at making an appropriate eye movement to its location. This "direct" test thus revealed the possible covert use of chromatic differences.     

A long-term five-year randomized controlled trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis

OBJECTIVE: To compare the efficacy of hydroxychloroquine, penicillamine, sodium aurothiomalate and auranofin in the treatment of active rheumatoid arthritis over a period of 5 yr. METHOD: Five hundred and forty-one patients with definite or classical rheumatoid arthritis were entered into an open randomized controlled trial with a flexible dose regimen designed to reflect clinical practice. Decisions to stop treatment with any one of the disease-modifying anti-rheumatic drugs (DMARDs) were based on an agreed trial protocol which defined criteria for adverse reactions and therapeutic failure. The managing physicians' decisions were confirmed in a separate monitor clinic. RESULTS: The proportion of patients who remained on their first DMARD or who were in remission at 5 yr was 53% for penicillamine, 34% for sodium aurothiomalate, 31%, for auranofin and 30% for hydroxychloroquine (P < 0.001). In patients who stayed on their first DMARD, all groups showed a 30-50% improvement in C-reactive protein, erythrocyte sedimentation rate, Ritchie Index and joint stiffness, and a deterioration in their Larsen score. There was no evidence of physician bias to explain the larger proportion of patients remaining on penicillamine for 5 yr. CONCLUSION: Despite the increased popularity of sulphasalazine and inmmunosuppressives, the drugs in this study continue to be used worldwide. The natural history of rheumatoid arthritis requires long-term follow up to establish drug efficacy. Evidence is needed as to whether the newer regimens will prove to be more effective and safer in the longer term than the commonly prescribed DMARDs. The data from this trial will provide a reference for comparison with future studies.     

Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis

To investigate the pathophysiologic effects of chronically elevated intra-articular levels of IL-1 beta, we used an ex vivo gene transfer method to deliver and express human IL-1 beta (hIL-1 beta) in the knee joints of rabbits. Expression of hIL-1 beta resulted in a severe, highly aggressive form of arthritis analogous to chronic rheumatoid arthritis in humans. Intra-articular manifestations included intense inflammation, leukocytosis, synovial hypertrophy and hyperplasia, and highly aggressive pannus formation with erosion of the articular cartilage and periarticular bone. Systemic effects were also observed, including diarrhea, fever, weight loss, and an increased erythrocyte sedimentation rate. In addition, the hIL-1 beta was found to induce elevated levels of both rabbit IL-1 beta and TNF-alpha in synovial fluid. Following the loss of hIL-1 beta transgene expression between 14 and 28 days post-transplantation, many of these changes began to normalize. These results suggest that chronically elevated intra-articular levels of IL-1 beta alone are sufficient to produce virtually all the pathologies found in rheumatoid arthritis, and furthermore, demonstrate that gene transfer can be used to investigate the roles of specific gene products in the pathogenesis of arthritis.     

A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema

BACKGROUND: No effective treatment exists in the United States for acute attacks of hereditary angioedema (HAE). STUDY DESIGN AND METHODS: To evaluate the efficacy and safety of C1 inhibitor concentrate in treating HAE, a large primary care and referral center hospital conducted a randomized, placebo-controlled, double-blind trial with intent-to-treat analysis. Of the 36 patients enrolled in the study, 23 received treatment, and 22 completed the trial. C1 inhibitor concentrate or albumin (placebo) infusions were administered in a blind fashion to HAE patients who came to the hospital for treatment no later than 5 hours after an attack began. RESULTS: Relief was almost twice as fast in persons receiving C1 inhibitor concentrate than in the controls: 7.62 hours (mean; SD 7.08) versus 15.35 hours (mean; SD 8.31), respectively. The difference for time-to-relief was highly significant (p = 0.007, Mann-Whitney U test). The median time-to-relief was 6.17 hours (interquartile range 0.33-15.35) in the treatment group and 15.35 hours (interquartile range 14.00-22.83) in the control group. Resolution of symptoms was one-third faster in the C1 inhibitor concentrate group than in the placebo group: 23.98 hours (mean; SD 14.81) and 34.58 hours (mean; SD 13.56), respectively (p = 0.09, Mann-Whitney U test). Recovery of functional C1 inhibitor was 119.65 percent (mean; SD 50.80), and half-life was 37.87 hours (mean; SD 19.75). Recovery of antigenic C1 inhibitor was 147.75 percent (mean; SD 97.68), and half-life was 24.01 hours (mean; SD 9.70). There were no viral infections or serious adverse effects from the drug after 70 attacks in the treatment group and 96 attacks in the control group. CONCLUSIONS: C1 inhibitor concentrate is a safe, effective treatment for acute attacks of HAE.     

Immunoblotting detection of autoantibodies to human epidermis filaggrin: a new diagnostic test for rheumatoid arthritis

OBJECTIVE: We previously reported that so-called antikeratin antibodies (AKA) and antiperinuclear factor (APF) recognize epitope(s) present on human epidermal filaggrin. In the present study, we developed a new diagnostic test for rheumatoid arthritis (RA) based on detection of antifilaggrin autoantibodies (AFA) by immunoblotting. METHODS: We tested 670 serum samples, including 190 RA. AFA titers were estimated by immunoblotting on filaggrin enriched human epidermis extracts, and AKA titers by indirect immunofluorescence (IIF) on rat esophagus epithelium. Diagnostic values of the tests were compared. RESULTS: Each test resulted in diagnosis of more than 40% of RA samples, with a specificity of 0.99. Although the tests were strongly correlated, their association allowed the diagnosis of more than 60% of RA samples, with the same specificity. CONCLUSION: Immunoblot detection of AFA, a simple and standardizable test, may be an alternative or complement to conventional IIF detection of AKA.     

Effects of cytogenin, a novel anti-arthritic agent, on type II collagen-induced arthritis in DBA/1J mice and adjuvant arthritis in Lewis rats

The anti-arthritic effects of cytogenin (8-hydroxy-3-hydroxymethyl-6- methoxyisocoumarin) on type II collagen-induced arthritis in DBA/1J mice and adjuvant arthritis in Lewis rats were examined. Prophylactic treatment with cytogenin (30, 100 mg/kg) had a potent inhibitory effect on type II collagen-induced arthritis. Prophylactic or therapeutic treatment with cytogenin (10, 30 and 100 mg/kg) also had a potent inhibitory effect on adjuvant arthritis. In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), cytogenin (10, 30 and 100 mg/kg) had neither an anti-inflammatory effect on carrageenan-induced paw oedema in rats nor an analgesic effect on acetic acid-induced writhing in mice. These results suggest that the mode of the anti-arthritic action of cytogenin is different from that of NSAIDs and that cytogenin may become a useful drug for the treatment of rheumatoid arthritis.