Search

Background: The study was undertaken to assess the efficacy of methotrexate (MTX) monotherapy on the radiographic progression of individual rheumatoid arthritis (RA) patients, each of whom had received MTX monotherapy for 3 years with an option to change to biological disease-modifying anti-rheumatic drugs (bDMARDs). We also looked for predictors of radiographic non-progression in these patients., Methods: Rheumatoid patients (n = 161) were prospectively followed for 3 years while receiving low-dose MTX monotherapy unless disease was otherwise active and/or adverse events appeared. Their disease activity and radiographic progression were evaluated with reference to disease activity score 28 (DAS28), modified health assessment of questionnaire (mHAQ) and other indices. The change in van der Heijde-modified total Sharp score per year (∆TSS) was assessed using probability plots, in which the patients were classified into the subgroups showing structural remission (REM; ∆TSS ≤0.5), radiographic progression (∆TSS >3) or rapid radiographic progression (RRP; ∆TSS >5)., Results: MTX monotherapy, continued until disease became active and/or adverse event appeared, was associated with a significant improvement (p <0.0001) in the DAS28-ESR (3) scores, % DAS28 remission, and mHAQ scores each year, from baseline to 3 years. The mHAQ remission rate (∆mHAQ <0.5) and Boolean remission were also improved from 16 to 60 % and 0.8 to 24.0 %, respectively. We found that the ratio of patients classified as REM increased yearly from 62/161 (38.5 %) to 69/137 (50.4 %), while those classified as ∆TSS >3 decreased from 55/161 (34.2 %) to 28/137 (20.4 %) and those in RRP decreased from 35/161 (21.7 %) to 15/137 (10.9 %). Receiver operating characteristic (ROC) curve analyses showed that serum matrix metalloproteinase-3 (MMP-3) <103.7 ng/ml at outset predicts a patient subgroup that exhibits no radiographic progression., Conclusions: Half of rheumatoid patients treated with MTX monotherapy for 3 years exhibited structural remission, and this outcome can be predicted at the outset by lower serum MMP-3.

Rheumatoid arthritis (RA) frequently affects finger joints, and persistent synovitis is believed to cause not only bone destruction but also various deformities of the fingers in the long run. Synovectomy of the finger joints is carried out when chronic swelling of the synovium does not respond to any conservative treatment with medication and rehabilitation. In the present study the short-term results of finger joint synovectomy in RA were reviewed in 49 finger joints. The subjects were evaluated at two time points, with average follow-up periods of 14 and 62 months, and the results were compared between the two follow-up time points. In regard to results, pain relief, swelling abatement, and only a little loss of motion were observed in most fingers. Moreover, only a few patients demonstrated progression of bone destruction, suggesting that synovectomy has a retarding effect and tends to be effective especially in the early stages of the disease. In conclusion, we recommend synovectomy for finger joints in RA patients before bone changes occur, and when chronic synovitis of the finger joints does not respond to any other conservative treatment.

Long-term results of open synovectomy of the elbow with rheumatoid arthritis (RA) were reviewed in 15 elbows. The subjects were evaluated at two time points with average follow-up periods of 4 and 8.7 years, and the results were compared between the two follow-ups. The Mayo Clinic performance score showed significant improvement in pain, motion, and daily function from the intermediate to the long-term follow-up. Overall results were satisfactory with little time-dependent deterioration in radiological grading, confirming the long-term effectiveness of this procedure.

A single giant geode at the olecranon in a patient with rheumatoid arthritis (RA) is relatively rare, and may cause diagnostic difficulties or cause a spontaneous pathological fracture owing to weakness of the cortical bone associated with osteoporosis. We report two cases of patients presenting with single giant geodes at the olecranon. In one case we performed an open reduction and internal fixation with bone grafting for a pathological fracture due to the geode. In the other case we performed curettage of the geode with bone grafting to prevent a pathological fracture, and a synovectomy of the elbow. We suggest that the presence of a giant geode at the olecranon may necessitate surgical intervention to prevent the occurrence of a spontaneous pathological fracture.

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.

The reports on the patients with rheumatoid arthritis (RA) complicated with the myeloperoxidase specific-antineutrophil cytoplasmic antibody (MPO-ANCA) associated glomerulonephritis, whose clinical feature is rapidly progressive glomerulonephritis (RPGN), have been rare. We here report three cases of RPGN with MPO-ANCA in RA patients. Case 1. A 44-year-old woman with RA for 25 years was admitted because of RPGN. The level of MPO-ANCA was markedly high (293 EU) and the histological examination of the kidney showed diffuse crescentic glomerulonephritis. In spite of the intensive immunosuppressive therapy, her renal function did not recover and she underwent hemodialysis (HD). Case 2. A 58-year-old man with RA for 5 years was admitted due to RPGN (MPO-ANCA ; 147 EU, Ccr ; 16 ml/min) with the nephrotic syndrome and fever. The treatment with the immunosuppressive agents and the plasma exchange was partially effective to stop the rapid progression of the disease, but a few months later, his renal function worsened (Ccr 7 ml/min). A recent histological examination of the kidney failed to establish the CrGN because of endstage kidney. Case 3. A 56-year-old woman with RA for the past 10 years was admitted because of RPGN (MPO-ANCA ; 652EU). Intensive therapy could not be performed because of an active duodenal ulcer and markedly impaired renal function (Ccr ; 6 ml/min), and soon she underwent HD. Renal biopsy was not done. These three cases suggest that RPGN can occur in part of RA patients with MPO-ANCA.

Thirty-four patients with osteoarthritis (OA) and 32 patients with rheumatoid arthritis (RA) were studied to determine the effects of OA and RA on the laxity of the knee joints. Laxity was measured with the Genucom Knee Analysis System. The antero-posterior laxity of the OA and RA knees was greater than the control, normal knees in the early stage, and decreased with the severity of disease in OA, but not in RA. Severe OA and RA were associated with a restricted internal-external rotation at the knee joint compared with the control. Internal-external rotation decreased with worsening of both diseases. Varus-valgus laxity tended to increase slightly with the severity of disease. While the morphological changes of the cruciate ligaments in advanced OA and RA were not statistically different, the laxity of OA-afflicted knees was affected slightly by the severity of the damage to the cruciate ligaments.

To elucidate the mechanism of cell binding to cartilage, using an immunoperoxidase technique with monoclonal antibodies against adhesion molecules, the pattern of distribution of these molecules at the rheumatoid pannus-cartilage junction has been investigated. Treatment with purified anti-human-monoclonal antibody CD54 anti-(ICAM-1) resulted in membrane staining of most of the large cells infiltrating the synovial tissue and bordering the pannus cartilage junction. When the specimen was treated with purified anti-human-monoclonal antibody CDw49d anti-(VLA-4), purified anti-human-monoclonal antibody CDw49e anti-(VLA-5), most of the cells in the cartilage pannus junction stained, but there were few staining cells against purified anti-human-monoclonal antibody CD11a anti-(LFA-1). There were some anti-ICAM-1 and anti-VLA-5 staining of the chondrocytes at or close to the junction. Human umbilical vein ECBBA1 (ELAM-1) staining was only observed on the endothelial cells of postcapillary venules in the synovial tissue. These results show that the specific adhesion molecules tested may play a role in rheumatoid pannus formation and that the increased expression of VLA-4, VLA-5, and ICAM-1 at the cartilage pannus junction may represent interaction with matrix protein. The VLA interaction appear to be involved in pannus attachment, whereas LFA-1 and ICAM-1 are involved in cell-cell interaction and may upregulate molecules such as VLA that are involved in attachment.

The staining pattern of a group of adhesion molecules on the immunoreactive cells in the lining layer of lymphocytic infiltrates of the rheumatoid synovial membrane was studied, using monoclonal antibodies by immunoperoxidase staining method against LFA-1, VLA-4, VLA-5, ELAM-1, and ICAM-1. The cells of the lining layer were strongly ICAM-1+ and VLA-5+, suggesting (1) that ICAM-1 may function to facilitate the adhesion of ICAM-1 bearing type A cells to type B cells, and (2) that the lining cells may utilize VLA-5 for anchorage to fibronectin at the surface of the synovial membrane. In the lymphocyte-rich and transitional area, the endothelial cells of the postcapillary venules were both ELAM-1+ and ICAM-1+. ICAM-1 staining of mononuclear cells was weak in lymphoid aggregates, but strong in the transitional area, indicating a paucity of ICAM-1 bearing cells in the lymphocyte-rich areas. On the other hand, LFA-1 staining was very strong in the lymphoid aggregates and only moderate in transitional areas. This suggests that the large numbers of T4 cells in the lymphocyte rich areas are sufficiently activated to express substantial levels of LFA-1, and also that the LFA-1 molecule is an important receptor for emigration from postcapillary venules. In germinal center-like areas in lymphoid aggregates, most of the cells stained strongly for ICAM-1 and VLA-4, suggesting that the proliferation of B lymphocytes may be facilitated by LFA-1 and VLA-4 dependent T and B cell interaction. The VLA molecules stained in the transitional areas may provide appropriate adhesion and anchorage for the achievement of the variety of immune reactions which occur in these areas.

To identify the local factors in cartilage that are responsible for the induction of pannus invasion, a 14 day organ culture study in which rheumatoid synovium was grown in contact with cartilage pieces was carried out. Rheumatoid synovium preferentially extended over hyaluronidase treated cartilage pieces, but detached from untreated pieces. Rheumatoid synovium extended over hyaluronidase treated cartilage surfaces containing fibronectin more extensively than over surfaces treated with hyaluronidase only. Extension over hyaluronidase treated cartilage surfaces containing immune complexes was small. The adherence of synovial cells to hyaluronidase treated cartilage slices in vitro was specifically inhibited by the synthetic peptide, Gly-Arg-Gly-Asp-Ser-Pro, which is the adhesive portion of the fibronectin molecule. Furthermore, synovial fibroblast-like cellular extension, morphologically similar to rheumatoid pannus, was observed in the organ culture experiments in which rheumatoid synovium grew over hyaluronidase treated cartilage surfaces containing fibronectin. Synovial tissue extension over fibronectin coated surfaces was inhibited when hyaluronic acid and chondroitin-4-sulphate, major components of cartilage proteoglycans, were present on the cartilage surface. These findings suggest that fibronectin present in the superficial region of cartilage potentiates rheumatoid synovial extension and proteoglycans and immune complexes inhibit rheumatoid synovial extension. It is likely that fibronectin deposited on the eroded surface of articular cartilage induces pannus formation in rheumatoid arthritis.

A 12-week, double-blind controlled study comparing low dose alpha-interferon (5 x 10(5) iu, twice a week) and placebo was carried out to determine whether this drug has an immunomodulatory effect in rheumatoid arthritis. There were statistically significant improvements in the patients' joint score, C-reactive protein value and platelet count, without any side effects. Interferon-alpha caused an increase of serum calcium and a decrease of alkaline phosphatase. Thus, alpha-interferon requires further investigation as a possible additional useful treatment for rheumatoid arthritis.

The ability of enzyme-dissociated synovial adherent cells (SAC) obtained from patients with active rheumatoid arthritis to restore the proliferation and differention of peripheral blood mononuclear non-adherent cells (NAC) into immunoglobulin-secreting cells (ISC) was investigated. Autologous combinations of cells were used in this study to eliminate allogeneic reactions. Peripheral blood NAC, prepared by glass adherence and leucine methylester treatment to remove monocytes, almost completely lost their capacity to proliferate and differentiate into ISC in response to pokeweed mitogen. The response of NAC was restored by adding 12.5% of 'fresh SAC', which was obtained by glass-adherence after an overnight culture of non-rosette forming, enzyme-dissociated rheumatoid synovial cells. Although the response was also restorable by adding more than 25% fresh SAC, this was less satisfactory than adding 12.5% SAC. 'Old SAC', obtained by glass-adherence after 7 days culture of enzyme-dissociated synovial cells, did not restore the response of NAC. Immunohistochemical studies showed that 55% of fresh SAC and 3% of old SAC expressed HLA-DR antigens. When 100 units/ml of interferon gamma was present, 25% of old SAC remained HLA-DR-positive and some of these cells retained a dendritic morphology after 7 days culture. The results indicate that rheumatoid synovia contain macrophage-like cells that can effectively support the ultimate differentiation of lymphocytes to ISC.

The pathogenesis of periarticular osteopenia in rheumatoid arthritis (RA) was investigated by histomorphometry on juxtaarticular bone removed during joint surgery. Twenty areas from 12 RA patients were compared with 14 areas from 6 osteoarthritis (OA) patients. There was no difference between the 2 groups in the percent of total bone volume. However, increased bone formation was suggested by an increase in the percent of active osteoid surface in RA compared with that in OA. Bone resorption was also increased in RA, as evidenced by increases versus OA in percent total resorptive surface, percent active resorptive surface, and number of osteoclasts. These results demonstrate increased turnover of bone in RA, especially in the resorptive phase of the periarticular trabecular bone. It is proposed that soluble factor(s) synthesized in the contiguous rheumatoid synovium may be transferred to the periarticular bone space, stimulating osteoclasts to resorb bone.

In order to detect the interstitial pulmonary disease of rheumatoid arthritis (RA), we studied 91 patients with RA and compared the appearances of high resolution CT with those of plain chest X-ray film. We found 43 cases of interstitial pneumonitis on CT. We classified the CT and X-ray appearances as 4 groups (0-3) based on the degrees of pulmonary lesions. The both classifications accorded only in 46 cases (51%). In 46 cases who were not detected any changes by plain X-ray film, 17 were detected interstitial changes by CT. As to the early interstitial changes, the detectability of CT was superior to that of plain X-ray film.

Immunohistochemical study showed selective localisation of human epidermal growth factor (hEGF) to the synovial lining layer. Although the synovial lining layer of the rheumatoid, osteoarthritic, and traumatic joints was hEGF positive, hEGF staining was especially dense at the rheumatoid synovial lining layer; the staining increasing linearly according to the degree of stratification of the lining layer (r = 1). Human epidermal growth factor was ultrastructurally localised to cytoplasm, especially to rough endoplasmic reticulum, of the synovial lining fibroblast-like (type B) cell. Only the cell surface of macrophage-like (type A) cells was hEGF positive. When different histological variables were compared with each other a positive correlation was found between hEGF staining of the synovial lining layer and the degree of neovascularisation of rheumatoid synovium (r = 0.72). Although some lymphocytes were weakly hEGF positive, neovascularisation did not correlate with the extent of lymphocyte infiltration or of hEGF staining of lymphocytes. Lymphocyte infiltration or hEGF staining of lymphocytes did not correlate with hEGF staining of the synovial lining layer, whereas the lymphocyte infiltration correlated positively with the extent of perivascular accumulation of lymphocytes (r = 0.89). These findings suggest that (a) hEGF is synthesised by and secreted through endoplasmic reticulum and Golgi apparatus from the synovial lining type B cell; (b) hEGF is at least partially responsible for the pathogenesis of stratification of the rheumatoid synovial lining layer, and perhaps of neovascularisation of the rheumatoid synovium, whereas it is not responsible for lymphocyte accumulation to the rheumatoid synovium.