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PMID	Title	PublicationDate	abstract
7945474	The efficacy and toxicity of combination therapy in rheumatoid arthritis. A meta-analysis.	1994 Oct	OBJECTIVE: To evaluate the efficacy and toxicity of combination therapy, compared with single second-line drug therapy, in rheumatoid arthritis. METHODS: This study was a meta-analysis of published trials that evaluated combinations of full-dose second-line drugs and compared them with single second-line drugs at full dose. Using a random effects model, we summarized the difference between improvement with combination therapy and improvement with single-drug therapy. RESULTS: Five trials that met inclusion criteria, which contained 749 entering patients and 516 completing patients, were identified. The mean +/- SEM difference in improvement in tender joint count between combination and single-drug therapy at end of trial (24-52 weeks) was 2.4 +/- 0.7 joints (out of 60) (P < 0.001). At end of trial the difference between therapies in swollen joint counts was 1.0 +/- 1.2 joints (P = 0.42). The difference in grip strength improvement was 3.7 +/- 4.3 mm Hg (P = 0.40), and for erythrocyte sedimentation rate it was 3.4 +/- 3.1 mm/hour (P = 0.27). In general, the differences in efficacy between combination and single-drug therapy were clinically marginal. Nine percent more combination therapy-treated patients experienced side effect-related discontinuation of therapy than patients receiving single-drug therapy (P = 0.008). CONCLUSION: Combination therapy, as it has been used in recent clinical trials, does not offer a substantial improvement in efficacy, but does have higher toxicity than single drug therapy. These combination therapy regimens are not recommended for widespread use. Other more aggressive regimens with additional drugs or higher drug doses than have been studied might be more efficacious, but with an even higher rate of toxicity.
7921749	Changes in central opioid receptor binding in relation to inflammation and pain in patient	1994 Oct	A group of four patients with RA were examined to test the hypothesis that there is a change in the endogenous opioid system in the brain during inflammatory pain. Regional cerebral opioid receptor binding was quantified using the opioid receptor antagonist [11C] diprenorphine and positron emission tomography (PET). In the four patients studied in and out of pain, significant increases in [11C]diprenorphine binding were seen in association with a reduction in pain. Increases were seen in most of the areas of the brain that were sampled apart from the occipital cortex. Significant region-specific increases over and above the more generalized changes were also seen in the frontal, cingulate and temporal cortices in addition to the straight gyrus. These findings are consistent with the hypothesis that there are substantial increases in occupancy by endogenous opioid peptides during inflammatory pain.
8448641	Cyclosporin A nephropathy in patients with rheumatoid arthritis.	1993 Mar	Patients with RA are at risk of cyclosporin A (CyA) toxicity as they have an increased incidence of underlying renal pathology and because of the probable co-administration of NSAIDs. CyA dose, blood levels, and changes in serum creatinine are linked to the severity of renal biopsy changes in patients with RA and other autoimmune disorders, but only limited data regarding the safety of long-term CyA therapy have been reported. Low-dose CyA (preferably without NSAID co-administration) should be reserved for those patients with a poor prognosis who can be carefully monitored using a combination of renal function studies, CyA blood levels and renal biopsy assessment. Consideration should be given to the development of a management strategy that includes renal biopsy at defined intervals in order to detect the onset of progressive renal damage, and which could potentially allow eligible patients to benefit from long-term CyA therapy.
8311085	Renal biopsy specimens from patients with rheumatoid arthritis and apparently normal renal	1994 Feb	Renal biopsies were performed in 14 patients with severe rheumatoid arthritis who had no evidence of compromised renal function after completion of treatment with low-dose cyclosporine (< or = 5 mg/kg/d). Mean serum creatinine at the time of biopsy was 0.84 mg/dL (range, 0.59 to 1.23 mg/dL). In the 13 patients who had received 6 months of cyclosporine therapy, mild glomerular expansion was noted in two biopsy specimens, obsolescent glomeruli (range, 5% to 20%) in five, and glomerular amyloid deposits in one. Five biopsy specimens had mild and three had mild to moderate interstitial fibrosis. Moderate interstitial fibrosis with a striped pattern was attributed to cyclosporine in the 14th patient. The results of a second biopsy performed in one patient after a further 18 months of therapy were unchanged. Although the renal biopsy changes were minimal in 13 patients and pathologic features characteristic of cyclosporine nephropathy were absent from all but one biopsy, a greater frequency of adverse effects due to cyclosporine could not be excluded. In the absence of clinical data, long-term cyclosporine therapy must be administered with caution to patients with rheumatoid arthritis, who commonly have underlying renal damage, and the value of renal biopsies in predicting and preventing end-stage renal failure remains to be determined.
7858103	Exacerbation of collagen-induced arthritis in rats by rat cytomegalovirus is antigen-speci	1994	Collagen-Induced Arthritis (CIA) is an experimentally induced and genetically controlled animal model of chronic joint inflammation. In rats, there are informative strain differences in susceptibility to CIA. DA rats (RT1avl) develop severe CIA after immunization with bovine (BII), chick (CII), or homologous rat (RII) type II collagens. In contrast, the MHC-congenic DA. 1N(BN) and WF.1N(BN) rats (RT1n) are relatively resistant to CIA and develop moderate CIA in response to immunization with CII but not BII or RII. We previously found that simultaneous infection with rat cytomegalovirus (RCMV) greatly exacerbates the severity of arthritis that develops in BII-immunized DA rats. To examine the mechanism of RCMV amplification of CIA, the effect of simultaneous infection with RCMV on arthritis and autoimmunity to type II collagen was determined in WF.1N and DA.1N rats after immunization with BII, CII and RII. RCMV increased the incidence of CIA and the level of autoimmunity to type II collagen (skin-testing and IgG antibody titer) selectively in DA.1N and WF.1N rats immunized with CII, but not in littermates immunized with BII, although the transient reversal of CD4+/CD8+ mononuclear cell ratios in peripheral blood that is associated with RCMV infection occurred equally in both BII- and CII- immunized DA.1N rats. Likewise, RCMV infection moderately increased the levels of anti-RII autoimmunity and arthritis in DA rats sub-optimally immunized with RII but had no consistent effect on either anti-RII immunity or arthritis in RII-immunized DA.1N and WF.1n rats. The data show that RCMV augments arthritis only in rats that are genetically susceptible to CIA and that are appropriately immunized with a species of type II collagen that is arthritogenic for the MHC-haplotype being tested. Two possible mechanisms are suggested by these data: RCMV-associated increases in anti-RII autoimmunity in rats with CIA may result from amino acid sequence homologies between RCMV and type II collagen; alternatively, virus-induced pro-inflammatory cytokines may activate RII-reactive lymphocytes thereby potentiating autoimmunity and arthritis.
7788148	Human leucocyte antigen phenotypes and gold-induced remissions in patients with rheumatoid	1995 Apr	To assess possible associations between human leucocyte antigens (HLA) and the achievement of remission during gold treatment, HLA typing was performed in 67 rheumatoid arthritis (RA) patients with a gold-induced remission and in 25 control RA patients who discontinued gold therapy because of lack of efficacy. Both groups of RA patients showed a significantly higher frequency of DR4 antigen and lower frequency of DR6 than a control population. There were no significant differences in HLA antigens between remission-responders and non-responders. It is concluded that HLA typing is not helpful in predicting the therapeutic response to parenteral gold therapy.
1403714	Peptide stability in drug development: a comparison of peptide reactivity in different bio	1992 Aug	Degradation kinetics for several peptides that bind to the major histocompatibility complex on antigen-presenting cells were determined in both human serum (HS; 25%) and synovial fluid (SF; 25%) from patients with rheumatoid arthritis to test whether therapeutic intervention of rheumatoid arthritis by direct intrasynovial injection is feasible (at least in terms of peptide stability). Controls consisted of enzymatically immature 10% fetal calf serum and peptidase-rich 5% liver homogenate (all diluted with RPMI-1040 tissue culture medium). Peptide half-lives ranged from approximately 4 to greater than 10,000 min, with most peptides showing half-lives of approximately 10-100 min. These studies show that, even though the populations of inflammatory and other cell types in SF and HS are different (and may, therefore, generate different peptidase profiles), the observed peptide stabilities in SF and HS are similar. This finding indicates that the effect of SF on peptide stability is similar to that of HS.
7780041	Synovial fluid from rheumatoid arthritis patients contains sufficient levels of IL-1 beta	1995 Feb	The presence of positive acute phase proteins within the circulation of rheumatoid arthritis patients suggests that elevated cytokine production associated with this chronic inflammatory disorder initiates the hepatic acute phase response. Cytokines produced at inflammatory lesions are believed to travel via the circulation to the liver where they induce acute phase protein production by hepatocytes. To test whether serum from rheumatoid arthritis patients contained sufficient levels of cytokines to promote an acute phase response in vitro, a bioassay was developed that employed the human hepatoma cell line Hep3B. These cells produced the acute phase protein serum amyloid A (SAA) in response to a combination of recombinant IL-1 beta and IL-6 or to monocyte conditioned medium. Serum (or plasma) from normal individuals or from rheumatoid arthritis patients did not induce SAA production by Hep3B cells. Moreover, these serum samples did not prevent SAA production induced by monocyte conditioned medium, indicating that they did not contain inhibitors of cytokine activity. Despite the inactivity of serum samples, synovial fluid samples obtained from rheumatoid arthritis patients were active in the hepatocyte bioassay and promoted SAA synthesis. One synovial fluid sample was analysed in detail to identify cytokines responsible for the SAA-inducing activity. Neutralizing antisera against IL-6 and IL-1 beta blocked this activity by > 90% whereas anti-IL1 alpha and anti-TNF-alpha sera were without effect. Absolute cytokine levels within the synovial fluid sample were determined by ELISA; IL-6, IL-beta and TNF-alpha, but not IL-1 alpha, were confirmed to be present. Moreover, the synovial fluid sample contained a large amount of the IL-1 receptor antagonist. These data indicate, therefore, that synovial fluid recovered from an inflamed joint contains all the necessary cytokines in balance with inhibitors to promote SAA production by Hep3B cells. The steady state levels of these factors within the plasma compartment, however, were insufficient to induce the acute phase response by cultured Hep3B cells, suggesting that this system does not mimic the relationship between the circulation and the liver that likely exists in rheumatoid arthritis patients.
8039045	Small cell carcinoma of the lung in a patient with rheumatoid arthritis: a case report.	1994 May	We describe an occurrence of small cell carcinoma of the lung in a 37-year-old woman with rheumatoid arthritis who did not receive any kind of cytotoxic agents for the rheumatic condition. There seemed to have no predisposing factor for the development of malignancy. The diagnosis of small cell carcinoma was based on repeated hemoptysis and cytologic finding of a rapidly growing mass over the forehead. The patient responded dramatically to chemotherapy with rapid resolution of forehead mass, relief of arthritis in the hands, and decrease of serum rheumatoid factor from 4800U/ml to 1200U/ml. This appeared to be the first report of small cell carcinoma of the lung developing in a patient with rheumatoid arthritis.
7997605	[Evaluation of rheumatoid arthritis of the knee with Doppler color].	1994 Oct	Color-Doppler US was used to study the vascularization of the synovial membrane and of the periarticular tissues of the knee in 14 normal subjects and 15 patients with active rheumatoid arthritis. The normal subjects exhibited few spot signals within the connectival spaces surrounding the knee and adjacent to the femoral condyles and to the tibial plates. The signals were mostly arterial and impedance was high because of the absence of inversion of diastole. A hypervascular pattern was detected in 13/15 patients with rheumatoid arthritis as a result of hyperemia associated with inflammation and synovial neoangiogenesis. In these patients, the signals came mostly from the synovial pannus and the soft tissues surrounding the joint. Spectral analysis detected both venous and arterial waveforms with lower resistance than normal (resistive index ranging 0.65 to 0.76). After local treatment, both venous and low-impedance arterial signals were no longer detectable in 4/9 patients with clinical remission. In conclusion, color-Doppler US can support gray-scale US in the assessment of joint inflammation in rheumatoid arthritis patients. Vascular findings seem to correlate well with local symptoms. Color-Doppler US could make a useful tool for monitoring the clinical activity of the disease in selected joints.
9437147	Lycra working splint for the rheumatoid arthritic hand with MCP ulnar deviation.	1996 Nov	Rheumatoid arthritis is described by Swanson (1995) as 'the greatest crippler from the standpoint of severity and prolonged disability' (p. 1307). One key factor in keeping persons with rheumatoid arthritis independent in their activities of daily living is maintaining functional use of their hands. In rural areas, where a move to assisted accommodation may require a person to leave the locality, this splint may help older citizens to remain functional and at home. The deformity and instability caused in rheumatoid arthritic hands by radial deviation of the wrist and subsequent ulnar deviation of the metacarpophalangeal (MCP) joints can greatly affect functional use of the hands. In this article, design and fabrication instructions for a lycra working splint which is suitable for the rheumatoid arthritic hand with MCP ulnar deviation are presented. Health professionals working in rural areas will find this splint inexpensive and easy to design, either alone or, ideally, with the assistance of regional occupational therapists.
1568518	Multiple intra-articular treatment of rheumatoid arthritis: a randomized prospective study	1992 Feb	In a randomized, prospective study the efficacy and tolerability of extensive multiple intra-articular administrations of two antibiotics, rifamycin SV and pefloxacin, were evaluated in 40 patients with classical or definite rheumatoid arthritis. Total weekly doses of 525 mg rifamycin or 560 mg pefloxacin were given for 10 weeks, and 12 months after treatment all clinical indices, erythrocyte sedimentation rate and C-reactive protein improved significantly in the rifamycin group. Some of the treatment indices (morning stiffness, severity of pain by visual analogue scale, grip strength and Ritchie's index) were already improved when the treatment ended, whereas others (erythrocyte sedimentation rate, C-reactive protein, number of painful and swollen joints) improved progressively during the follow-up. In the pefloxacin treatment group all indices except C-reactive protein and severity of pain determined using a visual analogue scale were significantly improved 12 months after treatment. Comparison of the two treatments showed a significant difference in erythrocyte sedimentation rate (P less than 0.047), Ritchie's index (P less than 0.036) and C-reactive protein (P less than 0.028) in favour of rifamycin.
8311536	Adjuvant oestrogen therapy does not improve disease activity in postmenopausal patients wi	1993 Dec	OBJECTIVE: To investigate whether oestrogens can be used as treatment to diminish disease activity in women with rheumatoid arthritis. METHODS: Forty postmenopausal female patients with active rheumatoid arthritis participated in a placebo-controlled, double-blind study on the possible beneficial effect of adjuvant treatment of oestradiol on disease activity. RESULTS: Thirty three patients completed 52 weeks of treatment with 2 mg oestradiol-valerate or placebo. No statistically significant difference was found in and between both treatment groups with regard to articular indices, pain score by visual analogue scale, erythrocyte sedimentation rate and health questionnaire on daily activities before, during and at the end of the study. CONCLUSION: This first randomised prospective placebo-controlled study shows no beneficial effect of oestrogens on disease activity in postmenopausal female patients with rheumatoid arthritis.
8587069	Use of second line drugs for the treatment of rheumatoid arthritis in Edmonton, Alberta. P	1995 May	OBJECTIVE: Our purpose was to compare the patterns of prescription of 2nd line drugs for the treatment of rheumatoid arthritis (RA) among rheumatologists in Edmonton, Alberta, and to examine the longterm effectiveness of these drugs. METHODS: A 1985 inception cohort of 128 patients with RA was assessed between 1991 and 1992, using measures of disease activity, radiological scores and physical functional status. Use of different therapies was retrieved from the medical charts. RESULTS: All patients had seen a rheumatologist at any time between January, 1985 and December, 1991, 88% within the first 3 years of disease. Most (85%) had received at least one 2nd line drug, the majority within the first 2 years. Overall, gold salts were the most frequently prescribed drugs. Patterns of prescription varied among different rheumatologists; some drugs were never prescribed by some and very often by others (e.g., auranofin). Terminations because of toxicity and lack of efficacy were high. Methotrexate (MTX) had the lowest termination rate and sulfasalazine the highest, mostly due to lack of efficacy. CONCLUSION: In this cohort, patients were treated early in the course of RA. Patterns of prescription of 2nd line drugs varied among rheumatologists. Termination rates were highest for sulfasalazine and lowest for MTX.
8712877	Diagnostic and prognostic characteristics of the enzyme linked immunosorbent rheumatoid fa	1996 Mar	OBJECTIVE: To determine the diagnostic and prognostic test qualities of the enzyme linked immunosorbent assays (ELISA) for rheumatoid factor isotypes in rheumatoid arthritis (RA), and to compare them with the latex fixation test. METHODS: Rheumatoid factor tests were performed in 1988 consecutive new rheumatology outpatients within two months after their first visit to the outpatient clinic of the Department of Rheumatology of Leiden University hospital. The sensitivity, specificity, accuracy, and predictive values of the tests in discriminating RA from non-rheumatoid arthritis and erosive from non-erosive disease after two years of follow up were determined and presented as receiver operating characteristic curves and post-test probability curves. RESULTS: The sensitivity of the ELISA for IgG, IgA, and IgM rheumatoid factor for RA versus all controls at optimal cut off titres was 72%, 44%, and 69%, respectively; the specificity was 52%, 84%, and 86%. For the latex fixation test the sensitivity was 66% and the specificity 91%. The post-test probability of RA, at a clinical prevalence rate of 12%, given a positive test result in the ELISAs for IgG, IgA, and IgM rheumatoid factor and the latex fixation test, was 17%, 27%, 40%, and 49%, respectively; with negative test results the probability was 7%, 8%, 5%, and 5%, respectively. The specificity of all tests in discriminating erosive from non-erosive RA at two years was low: 41%, 44%, 47%, and 58% for the ELISAs for IgG, IgA, and IgM rheumatoid factor and the latex fixation test, respectively. CONCLUSION: The ELISAs for IgG and IgA rheumatoid factor are of no significance in diagnosing RA and in the prediction of erosive disease. The ELISA for IgM rheumatoid factor is a reasonable alternative for the latex fixation test when age and gender are taken in to consideration. The specificity of all rheumatoid factor tests in discriminating erosive from non-erosive RA is low.
8804360	Increased circulating serum amyloid A protein derivatives in rheumatoid arthritis patients	1996 Sep	Secondary amyloidosis, a serious complication of chronic inflammatory diseases, is caused by the deposition of amyloid fibrils in various organs. The major component of amyloid fibrils is derived from serum amyloid A protein (SAA) by proteolysis. To explore the mechanisms of amyloidogenesis, we measured SAA concentrations in the sera of 38 patients with rheumatoid arthritis (RA) without secondary amyloidosis and in the sera of 18 RA patients with secondary amyloidosis, using the latex agglutination immunoassay. We also determined whether SAA was present as a full-length protein in the sera of RA patients by immunoblotting. Although SAA concentrations were elevated in the sera, there were no significant differences in these concentrations between RA patients without amyloidosis (128.2 +/- 145.4 micrograms/ml) and RA patients with amyloidosis (165.0 +/- 162.9 micrograms/ml). To test for qualitative abnormalities of SAA, the isolated SAA proteins from individual RA patients were analyzed by anti-SAA immunoblot. In addition to full-length SAA protein, 6-kd and 4.5-kd SAA-derived fragments were detected in the sera of RA patients, and the ratio of these fragments to total SAA proteins was significantly higher in RA patients with amyloidosis (37.0% +/- 0.7%) compared with that of RA patients without amyloidosis (15.0% +/- 5.5%). Although a high serum level of SAA is a predisposing condition for amyloid formation in RA patients, our data suggest that the increased circulating proteolytic cleavage of SAA may potentially contribute to the development of AA-amyloid deposition.
7578851	T-cell receptor polymorphisms in Tlingit Indians with rheumatoid arthritis.	1994	Rheumatoid arthritis (RA) develops as a result of the interaction of both genetic and environmental factors. Among the genes in humans that have been suggested as candidate susceptibility genes in RA are those encoding the T cell receptor for antigen (TCR). A high prevalence and early age of onset of RA has previously been reported in Alaskan Tlingit Indians. In this study, the frequency of seven different restriction fragment length polymorphisms (RFLPs) in the TCR alpha and beta gene complexes were measured in a population of Alaskan Tlingit Indians. No statistically significant differences were noted when the frequencies of these RFLPs were compared between Tlingits with RA and healthy controls (p > 0.05). These results do not support the hypothesis of an RA-susceptibility allele in the vicinity of these TCR alpha or beta genes. Since TCR RFLPs have not been extensively studied in native American populations, TCR polymorphism frequencies in the Tlingits were also compared to the frequencies observed in a second control group of healthy Caucasians. Statistically significant differences were observed in these comparisons implying a different distribution of individuals in these populations with different TCR repertoires.
8382250	Long-term follow-up of Swanson's silastic arthroplasty of the metacarpophalangeal joints i	1993 Feb	77 patients with rheumatoid arthritis, 62 female and 15 male, underwent metacarpophalangeal joint arthroplasty on 375 joints using the Swanson design silicone rubber spacer between 1976 and 1985. Retrospectively, 48 of these patients were evaluated by postal questionnaire and 35 of them also underwent objective assessment at intervals ranging from five to 14 years post-operatively. Objective variables recorded included range of active motion, recurrence of ulnar drift and radiographic appearances. Both in the early and late stages, the vast majority of patients were satisfied with the outcome, with abolition of pain, correction of deformity and improved range of motion. There was some loss of mobility with time. However, functional improvement was maintained in the majority. Complication rates compare favourably with other reported series and no case of silicone synovitis was diagnosed. We agree with previous studies that the procedure is useful for lasting relief of pain and enhancement of a patient's sense of well-being and is associated with few complications.
8448643	Malignancies in rheumatoid arthritis patients treated with cyclosporin A.	1993 Mar	More than a thousand RA patients have been treated with cyclosporin A (CyA) in clinical trials. In seventeen of them, tumours developed after treatment with the drug. An indirect approach used to calculate the relative risk associated with the use of CyA in clinical trials suggested that: (i) RA itself increases the risk of cancer development; (ii) the use of CyA further increases the risk by approximately the same degree as DMARDs; and (iii) neither the pattern of malignancies nor the risk associated with CyA seems to be different from that observed with conventional DMARDs. Nevertheless, patients treated with CyA should be carefully monitored while more experience is gathered.
7801058	Quantitative assessment of joint pain following treatment of rheumatoid arthritis with ibu	1994	The antiinflammatory effect of percutaneous application of NSAID (DOLGIT cream) was evaluated quantitatively on 11 patients with symmetric rheumatoid arthritis of the metacarpophalangeal and/or proximal interphalangeal joints. The pressure pain detection threshold (PDT) and pressure pain tolerance threshold (PTT) on the test joints were measured before and on days 3 and 7 after double-blind placebo controlled application of NSAID cream. The clinical pain was assessed by a visual analog scale (VAS) following controlled finger movements. The relative median PDT differences between NSAID and placebo treatment median were 10 kPa (N.S.) on day 3 and 17 kPa (N.S.) on day 7. The corresponding median differences in PTT were -5 kPa (N.S.) and 23 kPa (P < 0.05), respectively. The corresponding median decreases in VAS score were 4.2 mm (N.S.) and 15.5 mm (N.S.), respectively. The experimental joint pressure techniques can assess selectively pain from small joints and is a new useful tool to evaluate antinociceptive and/or antiinflammatory effects.