Search

Objective: Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study., Methods: A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies., Results: Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048)., Conclusion: We provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).

Introduction: A candidate gene approach, in a large case-control association study in the Dutch population, has shown that a 480 kb block on chromosome 4q27 encompassing KIAA1109/Tenr/IL2/IL21 genes is associated with rheumatoid arthritis. Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure. Therefore, our aim was to test this association in populations of European origin by using a family-based approach., Methods: A total of 1,302 West European white individuals from 434 trio families were genotyped for the rs4505848, rs11732095, rs6822844, rs4492018 and rs1398553 polymorphisms using the TaqMan Allelic discrimination assay (Applied Biosystems). The genetic association analyses for each SNP and haplotype were performed using the Transmission Disequilibrium Test and the genotype relative risk., Results: We observed evidence for association of the heterozygous rs4505848-AG genotype with rheumatoid arthritis (P = 0.04); however, no significance was found after Bonferroni correction. In concordance with previous findings in the Dutch population, we observed a trend of undertransmission for the rs6822844-T allele and rs6822844-GT genotype to rheumatoid arthritis patients. We further investigated the five SNP haplotypes of the KIAA1109/Tenr/IL2/IL21 gene region. We observed, as described in the Dutch population, a nonsignificant undertransmission of the AATGG haplotype to rheumatoid arthritis patients., Conclusions: Using a family-based study, we have provided a trend for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in populations of European descent. Nevertheless, we failed to replicate a significant association of this region in our rheumatoid arthritis family sample. Further investigation of this region, including detection and testing of all variants, is required to confirm rheumatoid arthritis association.

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of approximately 5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 "trio" families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a "linkage-proven" autoimmunity gene. PTPN22 accounting for approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.

The integrin alpha(v)beta3, whose alpha(v) subunit is encoded by the ITGAV gene, plays a key role in angiogenesis. Hyperangiogenesis is involved in rheumatoid arthritis (RA) and the ITGAV gene is located in 2q31, one of the suggested RA susceptibility loci. Our aim was to test the ITGAV gene for association and linkage to RA in a family-based study from the European Caucasian population. Two single nucleotide polymorphisms were genotyped by PCR-restriction fragment length polymorphism in 100 French Caucasian RA trio families (one RA patient and both parents), 100 other French families and 265 European families available for replication. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies (affected family-based controls), the transmission disequilibrium test, and the genotype relative risk.We observed a significant RA association for the C allele of rs3738919 in the first sample (affected family-based controls, RA index cases 66.5% versus controls 56.7%; P = 0.04). The second sample showed the same trend, and the third sample again showed a significant RA association. When all sets were combined, the association was confirmed (affected family-based controls, RA index cases 64.6% versus controls 58.1%; P = 0.005). The rs3738919-C allele was also linked to RA (transmission disequilibrium test, 56.5% versus 50% of transmission; P = 0.009) and the C-allele-containing genotype was more frequent in RA index cases than in controls (RA index cases 372 versus controls 339; P = 0.002, odds ratio = 1.94, 95% confidence interval = 1.3-2.9). The rs3738919-C allele of the ITGAV gene is associated with RA in the European Caucasian population, suggesting ITGAV as a new minor RA susceptibility gene.

Some controversial issues in the current literature in relation to osteoporosis and rheumatoid arthritis are updated and discussed. Because most studies agree that osteoporosis in postmenopausal women and in men with RA is more evident at the hip and radius than at the spine, and that the most important determinants of bone loss are disability, local disease activity, and cumulative corticosteroid dose, osteoporosis is not a common systemic extra-articular manifestation of RA. In early arthritis, periarticular osteoporosis does indeed reflect disease activity because it is closely related to the acute phase reactants, but once periarticular osteoporosis is established it is no longer a marker of disease severity. The threshold dose for corticosteroid-induced osteoporotic fractures is the cumulative rather than the actual dose. Statements based on quantitative tomography concerning the acute effects (and their reversal) of corticosteroids on bone have to be interpreted with care because of important body composition changes, in particular in bone marrow fat, during corticosteroid treatment. At present there is no evidence that anti-resorbing drugs can change the progress of RA erosions, probably because erosions are the result of non-osteoclast mediated mechanisms. Stress fractures in RA are underdiagnosed and are often confused with synovitis, and therefore it is likely that they are more frequent than commonly thought, especially in the lower limbs. Methotrexate osteopathy is known in oncological practice. Whether low dose methotrexate is toxic for bone is not clear, but a number of clinical observations suggest that the occurrence of spontaneous fractures and lower extremity pain is more frequent in methotrexate treated patients than expected. Prospective studies are necessary to confirm these impressions.

Thirty-four total knee arthroplasties were performed for severe rheumatoid arthritis in 25 patients younger than 45 years. All patients were available for follow-up evaluation at an average of 7.2 years. According to the Knee Society scoring system, the knee score improved from an average of 21 points preoperatively to 85 points at follow-up (p < 0.001). The average functional score improved from 23 points to 87 points (p < 0.001). Average range of motion improved from 71 degrees to 93 degrees (p < 0.001). Nonprogressive radiolucencies less than 1-mm thick were observed in 6 knees. One knee was revised for severe polyethylene wear; another case was revised for chronic patellar dislocation. Actuarial survivorship analysis estimates a 97% survivorship after 5 years and 90% after after 10 years. In young rheumatoid patients, total knee arthroplasty can therefore be considered as a reliable procedure, with satisfactory results during at least the first 5 to 10 postoperative years.

The objectives were to assess bone mineral density (BMD) at different body sites in rheumatoid arthritis (RA) patients related to disease severity parameters, disease duration and corticosteroid intake, and to look for body composition measurements as lean body mass (LBM) and per cent fat as possible prognostic factors in RA. Body composition values were measured cross-sectionally in 89 RA patients and compared with 157 controls. Patients were divided into males and postmenopausal females, ever steroid treated and never steroid treated. BMD values of all body sites were significantly lower compared to normals in all subgroups, except for the lumbar spine (L2 L4) in all postmenopausal women and males never treated with steroids. There was also no clear BMD decrease in the arms of male RA patients. LBM was significantly lower in all body parts compared to controls, whereas the fat distribution ratio (FDR) showed a clear shift to abdominal in all patients. These are parameters of chronic illness and a predictor of cardiovascular disease, respectively. BMD data confirm our previous data in different patient groups (low at appendicular sites, normal lumbar BMD), but no clear influence of disease severity and steroid intake could be found. Body composition data, as LBM and FDR, are also altered in RA patients: decreased LMB and more central FDR. Their usefulness as prognostic markers in early RA patients needs to be clarified prospectively in these patient groups.

Objective: To examine the reactivity pattern and T cell receptor (TCR) characteristics of mycobacterial heat-shock protein 65 (hsp65)-reactive T cells generated from paired synovial fluid (SF) and peripheral blood (PB) samples obtained from rheumatoid arthritis (RA) patients and from healthy subjects., Methods: The reactivity pattern of hsp65-reactive T cell clones generated under limiting-dilution conditions was analyzed in 3H-thymidine incorporation assays. The TCR variable regions of these hsp65-reactive T cells were characterized by polymerase chain reaction with TCR AV- and BV-specific primers and by DNA sequence analysis of the third complementarity-determining region (CDR3)., Results: The hsp65-reactive T cells derived both from RA patients and controls preferentially recognized the 1-170 and 303-540 regions of hsp65 and did not cross-react with human hsp60. The hsp65-reactive T cell clones derived from RA patients displayed a restricted TCR AV and BV gene usage, which can be attributed to the limited clonal origin(s) of the independent T cell clones, as evidenced by CDR3 sequence analysis. These clonally expanded T cells were found in both PB and SF and in different inflamed joints of RA patients., Conclusion: Our study suggests that there is in vivo clonal activation and expansion of mycobacterial hsp65-reactive T cells in patients with RA.

Objective: To report the findings of a 10-year followup of patients enrolled in a randomized trial of total lymphoid irradiation (TLI) versus chemotherapy for rheumatoid arthritis (RA)., Methods: A retrospective analysis of the charts of 19 patients who had been included in a randomized trial comparing TLI and chemotherapy for the treatment of RA., Results: Ten years after the start of the trial, a higher number of TLI-treated patients had died (7 of 10), compared with patients who had received chemotherapy (2 of 9). In addition, 3 of the TLI-treated patients developed B cell-related malignancies, whereas no such malignancies developed in the control group., Conclusion: TLI was associated with a less-favorable long-term outcome than chemotherapy. These data stress the importance of careful long-term followup in experimental trials of immunosuppressive agents.

Objective: To answer and comment on a number of controversial issues in relation to osteoporosis and rheumatoid arthritis (RA), including: Is osteoporosis an extra-articular manifestation of rheumatoid arthritis? Does periarticular osteoporosis reflect disease activity in early arthritis? Is there a threshold for corticosteroid-induced osteoporosis? Can anti-resorbing drugs prevent rheumatoid arthritis progression? Are stress fractures rare in rheumatoid arthritis Is methotrexate toxic for bone?, Methods: Confrontation of current literature and our own experience in order to formulate a general opinion., Results and Conclusions: Because most studies agree that osteoporosis in postmenopausal women and in men with RA is more evident at the hip and radius than at the spine, and that the most important determinants of bone loss are disability, local disease activity and cumulative corticosteroid dose, osteoporosis is not a common systemic extra-articular manifestation of RA. In early arthritis, periarticular osteoporosis does indeed reflect disease activity because it is closely related to the acute phase reactants, but once periarticular osteoporosis is established it is no longer a marker of disease activity. The threshold does for corticosteroid-induced osteoporotic fractures is the cumulative rather than the actual dose. Statements based on quantitative computed tomography concerning the acute effects (and their reversal) of corticosteroids on bone have to be interpreted with care because of important body composition changes, in particular in bone marrow fat, during corticosteroid treatment. At present there is no evidence that anti-resorbing drugs can change the progress of RA erosions, probably because erosions are the result of non-osteoclast mediated mechanisms. Stress fractures in RA are underdiagnosed and are often confused with synovitis, and therefore it is likely that they are more frequent than commonly thought, in particular at the lower limbs. Methotrexate osteopathy is known in oncological practice. Whether low dose methotrexate is toxic for bone is not clear, but a number of clinical observations suggest that the occurrence of spontaneous fractures and lower extremity pain is more frequent in methotrexate treated patients than expected. Prospective studies are necessary to confirm these impressions.

Objective: To study the long-term effects of supplementation with omega-3 fatty acids (omega 3) in patients with active rheumatoid arthritis., Methods: Ninety patients were enrolled in a 12-month, double-blind, randomized study comparing daily supplementations with either 2.6 gm of omega 3, or 1.3 gm of omega 3 + 3 gm of olive oil, or 6 gm of olive oil., Results: Significant improvement in the patient's global evaluation and in the physician's assessment of pain was observed only in those taking 2.6 gm/day of omega 3. The proportions of patients who improved and of those who were able to reduce their concomitant antirheumatic medications were significantly greater with 2.6 gm/day of omega 3., Conclusion: Daily supplementation with 2.6 gm of omega 3 results in significant clinical benefit and may reduce the need for concomitant antirheumatic medication.

Twenty patients with classical or definite rheumatoid arthritis received one intra-articular injection of 40, 80, 120, 160 or 200 mg rimexolone (Org 6216) into one knee joint. Rimexolone was well tolerated and the incidence of side-effects was low. A beneficial effect was sustained over the study period of 94 days and a long-lasting effect was observed in 84% of the patients after one year and in 79% after 2 years. Safety parameters remained unaffected. Individual changes in adrenal response to ACTH and morning cortisol levels did not correlate with the dose or with serum levels of rimexolone. Rimexolone showed linear kinetics. The mean residence time in the intra-articular depot was 44 days (SD +/- 53) with a median of 26 days. Ninety percent was absorbed after 4 months. Outside the intra-articular depot the mean residence time was less than 0.1 days.

Sequential lung function tests were performed on 28 rheumatoid arthritis (RA) patients who were treated with D-penicillamine (total of 101 treatment years) and on 42 control RA patients who were not treated or who were treated with NSAIDs, chloroquine, gold salts, corticosteroids, salazopyrine or methotrexate. A decline in lung function parameters was found in both groups, although it was only significant for the carbon monoxide diffusing capacity corrected for lung volume (DLCO/VL). This decrease in DLCO/VL was less pronounced in the D-penicillamine group (mean -6.9%) than in the control group (mean -11.3%). This difference could not be attributed to smoking, which was more frequent in the control group. When reviewing only the patients with an initial DLCO/VL < 80% of the predicted value and having, with some exceptions, chest X-ray abnormalities, we even observed an amelioration in the mean DLCO/VL in the D-penicillamine group, in contrast with a deterioration in the control group (+5.1% versus -5.6%).

Hand deformities resembling those of rheumatoid arthritis have been depicted in a painting by an anonymous artist of the Flemish-Dutch School, mid-15th to early 16th century. The painting is presently in the Escorial Museum near Madrid, Spain. This observation, like other earlier observations of rheumatoid deformities in paintings of the Middle Ages, suggests that rheumatoid arthritis is not a modern disease; it had, indeed, appeared several centuries before Landré-Beauvais' description in 1800.

Self assessment health status questionnaires are increasingly used to measure health status or the effect of treatment in patients with rheumatoid arthritis (RA). Most of these questionnaires measure functional (physical) disabilities. The question arises, however, as to how well self assessment questionnaires reflect the true functional status of patients or whether they only reflect their imaginary functional capacities. How valid is the opinion of patients with RA about their own functional capacity? To answer this question an investigation was performed in 80 patients with RA. Forty Dutch and 40 Belgian patients with RA completed the functional items of the DUTCH-AIMS, the Dutch version of the Arthritis Impact Measurement Scales (AIMS), a self assessment questionnaire specific to arthritis. Their scores on the functional scales were compared with the scores on the same scales completed by two experienced physiotherapists after evaluation of the functional ability of these patients. This was achieved by observing the patients perform the tasks given in the questionnaire. Correlation coefficients between the scores of the patients and the physiotherapists were highly significant for all the scales. No significant differences were found between the patients' and physiotherapists' mean scale scores except for the mobility scale in the Dutch patients. The strength of agreement (Cohen's kappa) of most scale scores of the patients and physiotherapists was substantial. The estimates of the overall functional capacity (the mean of the five scale scores) of the Belgian and Dutch patients show high correlations between the patients and the physiotherapists. It is concluded that patients' opinion about their functional ability is valid in that it is in agreement with their real functional abilities. This study provides further evidence for the validity of the DUTCH-AIMS as a measure of functional disability and health status in Dutch and Belgian patients with RA.

The effect of intranasal salmon calcitonin on pain, erosion progression, and bone loss in 40 women with rheumatoid arthritis was investigated. The study design was double blind, placebo controlled for the first four months and open for the next 36 months, allowing for cross over to active drug treatment or to the control group. Morning stiffness was reduced in the group treated with salmon calcitonin after two and four months. After an average follow up of 28 months no significant effect on erosion progression was observed using the Larsen score. The mean (SD) monthly progressions in the Larsen score in the calcitonin and control groups were 0.21 (0.22) and 0.23 (0.28) respectively. The bone mineral density was evaluated in the forearm and spine. During the 12 months of follow up the control group lost bone at a rate of 2%/year at the spine and 4.8%/year at the radius distal third. In contrast, the group receiving nasal calcitonin gained 1% in bone mineral density at the lumbar spine and no loss at the radius distal third. The increase in bone density at the spine in the calcitonin group was not sustained and a loss of 1.8%/year was observed in the second year. The difference with the placebo group remained significant.

Rheumatoid arthritis of the robust reaction type has been diagnosed in a seventeenth century Dutch priest, Siebrandus Sixtius, based on pictorial evidence of typical hand deformities and historical evidence affirming that he had chronic nodular rheumatism for many years. This case report, in conjunction with other pictorial depictions of probable rheumatoid arthritis, questions the view that rheumatoid arthritis is a modern disease which prevailed in the New World and was found in the Old World only after the discovery of America.

A 14-year-old boy with a two year history of seronegative rheumatoid arthritis developed left leg lymphedema and subsequently a severe episode of lymphangitis. The diagnosis of "rheumatoid lymphedema" was confirmed by lymphscintigraphy and conventional lymphography. Treatment consisted of bedrest and antibiotic drugs. When the signs of inflammation had subsided, therapy with corticosteroids was started with improvement of both joint pain and leg swelling. Whereas lymphedema associated with rheumatoid arthritis has been described in the upper limb of adults, to our knowledge this is the first report of the coexistent condition in the lower leg of a child.

The pharmacokinetics of rimexolone were investigated after intra-articular injection into the knee joints of patients with rheumatoid arthritis. After a single dose of 40 mg rimexolone the drug could be detected in plasma over 3 months. The suspension dissolves in the synovia very slowly and provides a sustained release of the steroid in the joint. Pharmacokinetic analysis was performed on the assumption that the disposition of rimexolone after intra-articular administration is absorption limited ("flip-flop-case"). Dose linearity was studied in a range from 40 to 200 mg. Total body clearance averaged 106 L/h and was independent of dose. The mean residence time of rimexolone in the knee joint is very long and averaged 25 days. It could be shown that the mean residence time of different glucocorticoids correlates well with the duration of their clinical effectiveness.

Reactivity toward soluble recall antigens (Candida albicans, cytomegalovirus, herpes simplex, streptokinase-streptodornase, and influenza) was determined in cultures of peripheral blood mononuclear cells from 41 rheumatoid arthritis patients (with clinically active as well as inactive disease) and from 28 controls. In the group with clinically active rheumatoid arthritis we found an increased incidence of "anergy," defined as nonreactivity to three or more antigens. In an attempt to explain this decreased antigen reactivity, the latter was correlated with peripheral blood lymphocyte subsets, as defined by two-color immunofluorescence with a panel of eight monoclonal antibodies. We found a significantly lower number of memory T4 cells (CD4+CD45RA-) and a significantly higher number of the CD3-CD57+ (nonspecific suppressor) cells and of CD3-CD56+/CD16+ (natural killer) cells in anergic RA patients. In the total group of rheumatoid arthritis patients, the antigen reactivity correlated positively with the percentage of memory T4 cells. Antigen reactivity was negatively correlated with the percentage of CD3-CD57+ cells and of the CD3- natural killer cells in peripheral blood. Our data suggest that a decrease in memory T4 cells and an increase in nonspecific suppressor cells may contribute to the impaired cellular immune function in peripheral blood of rheumatoid arthritis patients.

Forty patients with active rheumatoid arthritis were included in this monocentre double-blind study comparing the therapeutic efficacy and safety of the immunomodulator OM-8980 with that of D-penicillamine. After 12 months of treatment, the parameters of Ritchie index, duration of morning stiffness, pain assessed by a visual analogue scale and categories, number of swollen joints, grip strength and erythrocyte sedimentation rate (ESR) were all significantly improved with OM-8980, as was the case for the Ritchie index, number of swollen joints and ESR with D-penicillamine. Significant intergroup differences were recorded for pain categories in favour of OM-8980 and for the Ritchie index and number of swollen joints in favour of D-penicillamine. The need for concomitant anti-inflammatory therapies and the assessment of efficacy by physicians and patients did not differ significantly between the two groups. OM-8980 was significantly better tolerated than D-penicillamine (5 patients with 5 side effects as compared with 12 patients with 16 side effects). OM-8980 can thus be regarded as an efficient and well-tolerated slow-acting drug for the treatment of rheumatoid arthritis.

The effects of lymphoplasmapheresis on immunologic indices, including T cell subsets, and on clinical parameters of rheumatoid arthritis were evaluated in a controlled double-blind trial. Twenty patients were randomized to receive either 6 lymphoplasmapheresis sessions or a seemingly identical control procedure over a 3-week period. Lymphoplasmapheresis produced significant reduction in serum levels of total lymphocytes, erythrocyte sedimentation rate, C-reactive protein, and IgG. These serologic measures returned to baseline 5 weeks after lymphoplasmapheresis. No change in the imbalance of T cell subsets (increased helper/suppressor ratio) was observed. No changes in the serologic measures, except IgA, were observed in the control group. An improvement in some of the clinical parameters was observed in both the lymphoplasmapheresis and control groups. A rebound above baseline values for several parameters was observed in both the lymphoplasmapheresis and the sham apheresis groups.

Alpha 2-HS glycoprotein is one of the plasma proteins found in high concentrations in bone tissue. In order to study the relationship between this glycoprotein plasma concentration and bone damage in rheumatoid arthritis, plasma concentrations of this substance were measured in the serums of 32 patients with rheumatoid arthritis before and after treatment. Our results demonstrated that the concentration of alpha 2-HS glycoprotein, although slightly higher than normal values, did not vary in rheumatoid arthritis. Treatment of the disease did not seem to modify alpha 2-HS glycoprotein plasma levels, whereas other biological and clinical parameters of inflammation improved. The probable biological role of alpha 2-HS glycoprotein in rheumatoid arthritis is debated.

Plasmapheresis has been performed in eleven cases with connective tissue diseases, three with systemic lupus erythematosus, three with mixed connective tissue disease and five with rheumatoid arthritis. Plasmapheresis was in all cases instituted as an additional therapy during disease activity which was not under control with conventional modes of therapy. The best results were obtained in systemic lupus erythematosus and rheumatoid arthritis complicated with vasculitis. In mixed connective tissue disease with severe Raynaud's phenomenon, no striking and lasting results were obtained. Plasmapheresis seems to be a valuable adjunct in the management of acute exacerbation of connective tissue disease, especially when it is associated with drugs which can block antibody rebound.

Forty patients with definite or classical rheumatoid arthritis were entered for 3 months in a double-blind trial, 20 patients each on 200 mg flurbiprofen or 4.0 g enteric-coated aspirin daily. Statistically significant improvements (Page Test, p less than 0.05) on flurbiprofen were reported during the course of the study for 7 out of 20 parameters: degree of pain, duration of morning stiffness, grip strength, torquometer, Ritchie articular index, number of swollen joints and patient's overall assessment, while for aspirin a significant improvement was reported for 5 parameters: degree of pain, PIP joint size, Ritchie articular index and physician's overall assessment. The amount of improvement between flurbiprofen and enteric-coated aspirin differed significantly (Kruskal-Wallis H Test) only for 2 parameters: Ritchie articular index and number of swollen joints. In both cases the degree of improvement was greater on flurbiprofen than an aspirin. Side-effects were reported for 7 patients receiving aspirin (2 of which were severe enough that treatment had to be stopped) and for 3 patients receiving flurbiprofen. Except for 2 cases of tinnitus on aspirin, the side-effects were mostly gastro-intestinal in nature. A significant decrease was found for patients receiving aspirin. A significant increase in blood urea occurred on flurbiprofen. Most values, however, remained within normal limits. The results suggests that flurbiprofen is better tolerated and at least as effective as enteric-coated aspirin in the treatment of patients with rheumatoid arthritis.

Forty-four patients with definite or classical rheumatoid arthritis were entered in a 48-week open study, comparing the long-term effects of Timegadine and D-penicillamine. Twenty-three and 21 patients were respectively allocated to the Timegadine and D-penicillamine groups. Two patients of the former group were lost for follow-up, soon after the first baseline. Thus data were available only for 42 patients, 21 in each group of whom eleven completed the 48-week period in each group. Seven patients in the Timegadine group stopped because of ineffectiveness, 2 because of skin eruption and 1 because of acute interstitial pneumonitis. In the D-penicillamine group, 9 patients dropped out: 3 because of proteinuria, 2 because of stomatitis, 1 because of dizziness and 1 because of headache. Pain (visual analogue scale), number of swollen and painful joints improved significantly in both groups (p less than 0.05). The acute phase reactants alpha1-acid-glycoprotein and ESR and the thrombocyte count significantly decreased in the penicillamine group (p less than 0.05). The other clinical, hematological and immunological tests did not change; neither did the liver and kidney function tests. The clinical results suggest that Timegadine is as effective as D-penicillamine in the treatment of rheumatoid arthritis. D-penicillamine takes advantage over Timegadine by decreasing significantly the acute phase reactants. However, Timegadine has a low profile of side-effects.

Oral gold (auranofin) has been used in 31 patients, 20 with active rheumatoid arthritis and 11 with active psoriatic arthritis. In rheumatoid arthritis the oral gold treatment was compared to parenteral gold treatment in a patient blind trial for two years. The psoriatic arthritis cases were incorporated in an open trial. Auranofin 6 mg once daily reduced significantly the activity in rheumatoid arthritis and in psoriatic arthritis. The beneficial effect obtained with auranofin at a dose of 6 mg/day during the first year of treatment could not be maintained by 3 mg/day in the second year. Auranofin compared to parenteral gold had a distinct advantage of better systemic tolerability, although parenteral gold was found to be more potent. There was no greater risk for toxic skin reaction to oral gold in psoriatic arthritis than in rheumatoid arthritis. The overall conclusion of this longterm study is that oral gold (auranofin) 6 mg once daily, although slightly less effective than parenteral gold, can be considered to be the first choice of gold treatment for rheumatoid arthritis and psoriatic arthritis, because the compliance, which is a reflection of a combination of tolerance and efficacy, for oral gold therapy was, in our hands, undoubtedly superior to parenteral gold.

A case is reported of a 72 year old man suffering from classical seropositive RA for 10 years. Two months before admission he experienced general illness, fever and itching. Lymph nodes enlargement and hepatosplenomegaly were found. Histologic features of lymph node biopsy were compatible with angioimmunoblastic lymphadenopathy and Lennert lymphoma. Rapidly progressive pulmonary deterioration followed with hilar invasion and honeycombing. Sternal punction, bone biopsy, bronchus biopsy and blind lung biopsy however, did not reveal lymphomatous invasion. On the contrary, lung biopsy, showed bronchiolitis obliterans, an often fatal, small airway disease whose connection with RA is discussed. Plasmapheresis induced a correction of leucopenia and thrombocytopenia. A fatal evolution evolved within six months. Autopsy revealed diffuse invasion by immunoblastic sarcoma. The clinicopathological entities angioimmunoblastic lymphadenopathy and Lennert lymphoma are referred to. The relationship with autoimmune disorders is stressed.

Eight patients with a severe exacerbation of rheumatoid arthritis were treated by twice weekly plasma-exchange for 3 weeks in order to evaluate the effect of plasma-exchange on synovitis. During the plasma-exchange period, patients remained on the drug regimen they were on at admission to the hospital. Plasma was replaced isovolemically with human, purified plasma protein fraction. Improvement in clinical parameters of synovitis and serological parameters of inflammation occurred in almost all patients. After 6 months the clinical remissions were sustained. Three patients experienced a rebound synovitis and one patient a rebound vasculitis at the end of or just after the plasma-exchange period. The rebound phenomena were moderate and of short duration. Plasma-exchange may exert its beneficial effects by depleting important mediators of injury such a complement fibrinogen and circulating immune complexes, by improving reticuloendothelial function, and by increasing the drug response of the inflammatory target tissue. The role of depletion of circulating immune complexes was not so clear in this study. It is concluded that limited plasma-exchange is an effective means to induce a symptomatic improvement in an acute exacerbation of polyarthritis, without changing the basic therapy and thus avoiding corticosteroid dependency.

HLA B27 has been tested systematically in 246 patients attending a rheumatology clinic for chronic inflammatory arthritis or spondylitis. Patients were allocated to nine groups: typical ankylosing spondylitis, ankylosing spondylitis with moderate involvement without peripheral arthritis, ankylosing spondylitis with moderate involvement and with peripheral arthritis, juvenile chronic arthritis, Reiter's syndrome, Yersinia arthritis, arthropathies of inflammatory bowel disease, psoriatic arthritis, seronegative and seropositive rheumatoid arthritis. Except for seropositive rheumatoid arthritis, a significant association with HLA B27 antigen was found in all groups. In the seronegative rheumatoid arthritis group HLA B27 was present in 40% of the cases in contrast to 5.6% of the seropositive rheumatoid arthritis cases. These data confirm that a wide range of the so called "seronegative arthropathies" are associated with HLA B27 and suggest that sex and HLA B27 antigen are important factors in the manifestation of rheumatic disease. Women had less severe spondylitic changes but more peripheral arthritis of the small joints. Ankylosing spondylitis in its various forms had a comparable sex distribution despite relatively mild disease in females. The mean age of onset in the HLA B27 associated diseases was found to be significantly lower than in the seropositive rheumatoid arthritis group.

Forty-five patients with definite or classical rheumatoid arthritis were randomly allocated into two groups and treated with piroxicam 20 mg once daily or naproxen 250 mg twice daily in a 3-month, double-blind study. The results were available in 38 patients (21 in the piroxicam group and 17 in the naproxen group). Both drugs showed significant effects on the majority of clinical parameters compared to baseline. However, piroxicam was significantly superior to naproxen in reducing the grade of swollen joints. Moreover, piroxicam had better efficacy as shown by the number of patients who preferred it to previous therapy; 13 (62% of the patients entered) compared to 8 patients (47%) who preferred naproxen. Tolerance of the two drugs was similar. Two patients in each group dropped out due to side-effects.

A parallel double-blind trial was carried out over a 3-month period in 40 patients suffering from active rheumatoid arthritis to compare the anti-inflammatory effectiveness and side-effects of treatment with oxaprozin and aspirin. The results showed that 1200 mg oxaprozin daily had similar anti-inflammatory properties to those of 3.9 g aspirin daily in rheumatoid arthritis. Better results were produced with 1200 mg oxaproxin daily than with a 600 mg dosage level, suggesting that there is a close dose-response relationship. The incidence of side-effects was similar with both drugs. Gastrointestinal intolerance was more frequent and severe in the aspirin group, whereas rash and headache were noted more often in patients receiving oxaprozin.

A 54-year-old male with a 10-year history of seropositive rheumatoid arthritis subsequently developed generalized osteoporosis, multiple cervical spine subluxation, vertebral collapses, and massive osteolysis of the humeral and femoral heads and carpal bones. These lesions were accompanied by neurologic manifestations in both the upper and lower extremities. Bone matrix collagen and noncollagenous proteins in this rare syndrome were analyzed. The pathogenesis of this rare phenomenon is discussed.

Serum and urinary variables of bone mineral metabolism were studied in 49 postmenopausal women with rheumatoid arthritis (RA). Results were compared to those in a sex, age and menopausal age matched control group. No patient took corticosteroids, or had any disease other than RA which might affect bone. Total serum calcium was low in patients with RA compared to controls (9.0 +/- 0.5 mg% vs 9.3 +/- 0.3 mg%, p less than 0.005), but was normal when corrected for albumin (9.5 +/- 0.6 mg% vs 9.3 +/- 0.4 mg%, NS). Serum phosphorus was significantly higher in patients with RA than in controls (3.6 +/- 0.3 mg% vs 3.3 +/- 0.4 mg%, p less than 0.001) as well as serum alkaline phosphatase activity (107.6 +/- 27.2 IU/l vs. 9.6 +/- 28.91 IU/l). Serum creatinine, vitamin D and parathyroid hormone levels were comparable in both groups. Urinary hydroxyproline and mucopolysaccharide excretions were higher in patients with RA than controls, both for fasting (respectively 0.089 +/- 0.028 vs 0.039 +/- 0.023, p less than 0.001 and 0.072 +/- 0.027 vs 0.047 +/- 0.019, p less than 0.001) and for 24 h values (50.3 +/- 17.9 mg vs 36.2 +/- 15.4 mg, p less than 0.001 and 54.6 +/- 26.0 mg vs 41.7 +/- 16.5 mg, p less than 0.05). Urinary calcium excretion was comparable in the 2 groups. Our findings of raised serum phosphorus and alkaline phosphatase activity, raised urinary hydroxyproline and mucopolysaccharides excretion suggest that in patients with RA there is a higher metabolic activity of bone. In none of the patients could any indication of osteomalacia or of parathyroid overactivity be found.

A case is reported of a hyperviscosity-like syndrome in a 53-year-old male suffering from rheumatoid arthritis. The clinical presentation was an acute abdomen, peripheral neuritis, otovestibular areflexy, and central retinal vein thrombosis (papilloedema and retinopathy with venous engorgement, haemorrhages and exudates). Plasma viscosity was normal and whole blood viscosity, measured with an Oswald viscometer, was slightly elevated. The patient had markedly elevated rheumatoid factor tire and fibrinogen level. Histologically, there were no signs of arteritis in the mesentery. Intermittent plasma-exchange resulted in general improvement and no new vascular accidents after 2.5 years.

The anti-inflammamtory effectiveness and side-effects of magnesium dithiosalicylate were compared to aspirin in a 3-month, parallel, double-blind trial in 40 patients suffering from active rheumatoid arthritis. The results showed that 3 g magnesium dithiosalicylate daily had anti-inflammatory properties similar to those of 3 g aspirin daily in rheumatoid arthritis. A statistically significant change in morning stiffness, number of tender joints, pain score and erythrocyte sedimentation rate was observed in the magnesium dithiosalicylate group. In the magnesium dithiosalicylate group, 8 patients had to be withdrawn from the trial because of serious side-effects compared to 5 in the aspirin group. Gastro-intestinal intolerance occurred as frequently in both treatment groups. Hypersensitivity to magnesium dithiosalicylate was a serious problem and the reason for withdrawal in 4 cases. The high frequency of side-effects to magnesium dithiosalicylate makes this drug unacceptable for treatment of rheumatoid arthritis at the present time. Further pharmacological studies might reveal new derivatives which are as effective but with less side-effects. The anti-inflammatory activity of magnesium dithiosalicylate resembled that observed with gold and penicillamine. The fact that all these drugs have a sulphhydril group in common is stressed.

The effect of three different therapeutic regimens on bone mineral content at the radius and lumbar spine was studied in a group of 60 postmenopausal rheumatoid arthritis patients. Results were compared to those in a group of controls matched for sex, age, disease duration and menopausal state. Serum and urinary parameters of calcium metabolism were also evaluated in the three treatment groups. The three treatment regimens were: 1 alpha hydroxyvitamin D + calcium + placebo; 1 alpha hydroxyvitamin D + calcium + lynestrenol; and 1 alpha hydroxyvitamin D + calcium + sodium fluoride. In all treatment groups there was a positive effect of therapy compared to controls, though this was only significant in the 1 alpha hydroxyvitamin D + calcium + lynestrenol group at the axial skeleton after 1 and 2 years of treatment. Serum calcium rose significantly in the 1 alpha hydroxyvitamin D + calcium + placebo group and serum creatinin was raised in all the treatment groups during therapy. In the 1 alpha hydroxyvitamin D + calcium + lynestrenol group, serum alkaline phosphatase activity and urinary hydroxyproline excretion decreased significantly.