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Objectives: Rheumatoid arthritis (RA) related interstitial lung disease (ILD) impacts on the treatment strategy and its prognosis in patients with RA. However, the relationship between RA disease activity and the severity of comorbid ILD has not been fully investigated. This study aimed to investigate the impact of RA disease activity on the severity of comorbid ILD in detail based on currently established visual scoring method along with physiological severity., Methods: Consecutive patients with RA visiting to our Rheumatology Centre between December 2020 and December 2023 were analysed. The radiological severity of ILD was evaluated by averaging the extent of the combined lesion of ground glass opacity, reticulation and honeycombing in 5% increments in six representative high-resolution computed tomography slices ranging from 0% (no involvement) to 100% (all lung fields affected) according to Goh and Walsh's method. Associations between the radiological and physiological severity of ILD and patients' features were investigated using linear regression analysis., Results: Among 124 patients (32 men, 92 women), the median age was 70 years, and the median disease duration was 2.92 years. Radiological severity of ILD was 0% (without ILD) in 107 (86.2%), ILD with extent < 10% in nine (7.2%), ILD with extent ≥10% and < 20% in three (2.4%), ILD with extent ≥20% in five (4.0%). Both disease activity score (DAS)28-erythrocyte sedimentation rate (ESR) (standardized coefficient = 0.199, P = 0.03) and rheumatoid factor titre (standardized coefficient = 0.247, P = 0.01) were significantly associated with the radiological quantitative severity of ILD in multivariate analysis adjusted for age, sex, disease duration, smoking status and anti-citrullinated peptide antibody titre. DAS28-ESR was significantly associated with forced vital capacity% predicted (standardized coefficient = -0.230, P = 0.047)., Conclusions: Disease activity of RA was significantly associated with the severity of RA-ILD both radiologically and physiologically., (© 2024. The Author(s).)

Objective: To investigate earlier prediction of future articular destruction in patients with early rheumatoid arthritis (RA)., Methods: We randomly allocated patients with RA with disease duration < 2 years to different nonbiologic disease modifying antirheumatic drug (DMARD) therapies in a double-blind trial. Progression of articular destruction over the 96-week treatment period was assessed using the modified Sharp method., Results: Progression of articular destruction correlated more strongly with the American College of Rheumatology (ACR) core set measures after 12 weeks of treatment than with pretreatment values. Multiple regression analysis of data after 12 weeks yielded a correlation coefficient of 0.711. The sensitivity and specificity to predict articular destruction over the 75th percentile of the cohort were 78.6% and 84.6%, respectively. Patients who showed articular destruction over the 75th percentile of the cohort had low response to treatment at 12 weeks, and continued to have high clinical disease activity thereafter. Contrasting data were found in patients with slow progression of articular destruction., Conclusion: In patients with early RA, ACR core set measures after 12 weeks of nonbiologic DMARD treatment may predict articular destruction 2 years later. Low response to treatment at 12 weeks and continuing high disease activity thereafter were found in patients with rapid radiological progression. These data can be used to determine the appropriateness of treatment at 12 weeks and aid the decision to introduce biologic DMARD.

Objective: A placebo controlled, double-blind trial (DBT) was conducted for Japanese patients with active rheumatoid arthritis (RA) despite treatment with low dose methotrexate (MTX) to evaluate the efficacy and safety of infliximab. Extended treatment with infliximab was conducted in an open-label trial (OLT)., Methods: In the DBT, 147 patients were randomly assigned and treated with a placebo or 3 mg/kg or 10 mg/kg infliximab at Weeks 0, 2 and 6, combined with MTX. In the OLT, 129 patients from the DBT received 3 mg/kg infliximab every 8 weeks., Results: The mean dose of MTX was 7.2 +/- 2.0 mg/week. Significantly more patients receiving 3 mg/kg (61.2%) and 10 mg/kg (52.9%)infliximab achieved a 20% improvement according to the American College of Rheumatology (ACR) criteria at Week 14, compared to placebo (23.4%) (p < 0.001). There was no significant difference in incidence of adverse events among the treatment groups. In patients receiving infliximab in the DBT, 11.6% of patients with serum infliximab just before the OLT developed antibodies to infliximab (ATI) in the OLT, whereas 62.2% of patients without serum infliximab did. In patients receiving placebo in the DBT, 43.9% developed ATI., Conclusion: The efficacy and safety of infliximab combined with low dose MTX were similar to those of the ATTRACT study. The data from the DBT and OLT also supported the importance of an induction treatment of infliximab, followed by a maintenance treatment without a long interval, giving stable serum concentrations in order to prevent formation of ATI.

We discribe a rare case of rheumatoid arthritis (RA) complicated with bronchiolitis obliterans that was successfully treated with minocycline. Sixty four-year old woman with a four-years history of RA was admitted to the hospital because of dyspnea on exertion and polyarthritis. Pulmonary function test revealed marked decrease in V25 (0.10 l/s: 6.9%) and MMFR (12.6%). High resolution CT of the lung showed scattered centri-lobular micronodules in both lung fields, mucoid impaction, and hyperinflation. These findings indicated the presence of bronchiolitis obliterans. After 3 months of the treatment with minocycline, the patient showed a significant improvement of both arthritis and pulmonary function. Chest CT findings also improved after 1 year. The present case suggests that minocycline is effective for the treatment of bronchiolitis obliterans seen in patients with RA.

Objective: Osteoclasts may be involved in the process of rheumatoid bone destruction. To test this hypothesis, we developed an in vitro model of bone destruction by osteoclast-like cells derived from cultured rheumatoid synovial tissue without using any inducers., Methods: Synovial tissues were obtained from rheumatoid arthritis and osteoarthritis patients and tissue pieces of about 2 mm(3) that contained synovial lining were cultured. Multinucleated cells derived from cultured synovial tissues were studied cytochemically and morphologically for osteoclast-specific markers., Results: Fibroblast-like and macrophage-like cells from the tissue pieces proliferated in the coexistence of lymphocytes. After 14 days of culture, multinucleated cells with tartrate-resistant acid phosphatase activity appeared. These cells expressed vacuolar H(+)-ATPase, the vitronectin receptor and cathepsin K. Although binding of (125)I-labelled salmon calcitonin was very low, the cells contained ringed structures of F-actin and showed strong bone-resorbing activity on ivory slices. Proliferation of macrophage-like cells and formation of multinucleated cells continued during 6 months of culture in the presence of fibroblast-like cells. The bone-resorbing activity of multinucleated cells derived from rheumatoid synovial tissue was much higher than that of cells from osteoarthritis synovial tissue, and was related to the disease activity of rheumatoid arthritis., Conclusion: Our culture system reproduced in vitro the process of bone destruction by rheumatoid synovium, including the proliferation and fusion of precursor cells, polarization, activation and bone tissue resorption. This system may provide a tool for understanding the mechanisms of bone destruction in rheumatoid arthritis and for the development of new therapies to prevent bone destruction.

Sixty-six rheumatoid arthritis (RA) patients were analyzed retrospectively to assess the incidence and risk factors for elevation of serum hepatic aminotransferases during methotrexate (MTX) therapy. The effect of folate supplementation on serum ALT and RA activity was evaluated prospectively in 14 patients who showed a sustained high serum level of ALT. The frequency of elevation of serum AST or ALT was 4-5 times greater than in patients taking other DMARDs. Multivariate linear regression analysis demonstrated that elevation of ALT was independently associated with sex (female), obesity, baseline ALT, MTX dose, and gastrointestinal side effects. Folate supplementation caused ALT levels to decrease in all patients within 3 months. Eleven patients showed no change of RA activity, but 3 patients dropped out of the study because of the exacerbation of RA. These results suggest that careful monitoring of serum hepatic aminotransferases is necessary in patients with predisposing factors, especially those receiving more than 0.15 mg/kg of MTX weekly. Folate supplementation can reverse the sustained elevation of ALT, but might cause exacerbation of RA in some patients.

Objective: Rheumatoid factors (RFs) in sera from rheumatoid arthritis (RA) patients bind better to agalactosyl IgG [gal(-) IgG] than to native IgG. Recently, a novel lectin-enzyme immunoassay (LEIA) which can detect all isotypes of the immunoglobulins was developed in Japan. Since RFs are also detectable in Sjögren's syndrome (SS), we determined anti-gal(-) IgG antibodies and RF isotypes in sera from primary or secondary SS and RA patients to elucidate the clinical significance of these antibody profiles., Methods: A series of 128 patients with primary SS (35 pts.), RA (57 pts.), or secondary SS [n = 36 pts., the SS being associated with RA (RA-SS) in 12 pts., systemic lupus erythematosus (SLE-SS) in 17 pts., and mixed connective tissue disease (MCTD-SS) in 7 pts.] and 38 healthy females were examined. Anti-gal(-) IgG antibodies were measured with a LEIA kit (ED055) using human gal(-) IgG as antigen. IgG-, IgA- and IgM-RF were determined with an enzyme-linked immunosorbent assay kit using human IgG-Fc as antigen. RFs were also examined by a conventional assay (laser nephelometry; LN-RF)., Results: Serum anti-gal(-) IgG antibody titers were higher in RA than in primary SS, SLE-SS or MCTD-SS, but the incidence of the antibodies did not differ between RA and primary SS. In both RA and primary SS, the antibodies were positive in half of the LN-RF-negative patients, and were also detected in almost all of those patients who had at least one of the RF isotypes. LN-RF, IgG-RF, IgA-RF and IgM-RF were present more frequently and their titers were higher in RA than in primary SS, but IgA-RF levels were similar in both groups. In RA-SS, all of the antibody titers were notably higher than in RA or primary SS. In RA and primary SS, IgA-RF and IgM-RF were common RF isotypes, and anti-gal(-) IgG antibody levels correlated well with LN-RF, IgA-RF and IgM-RF levels. These antibody profiles did not relate to any of the clinical parameters in RA, but all the antibody titers correlated with anti-SS-A/Ro antibody levels in primary SS., Conclusions: The anti-gal(-) IgG antibodies are not specific for RA; they are also frequent in SS. Our LEIA for antibodies is a very sensitive method to detect all RF isotypes in both RA and SS. Most of the antibody profiles are common to both diseases, although antibody titers are higher in RA, especially in RA-SS.

Objective: Plasmin and matrix metalloproteinase-3 (MMP-3) have been linked to articular destruction in rheumatoid arthritis (RA). We compared circulating levels of plasmin-mediated fibrin degradation product (FDP D-dimer) and MMP-3 with traditional parameters of disease activity in RA to determine their clinical utility., Materials and Methods: Serum levels of MMP-3 and D-dimer were determined by enzyme-linked immunoassays in 60 patients with RA. Twenty healthy females and 21 patients with systemic lupus erythematosus (SLE) served as controls., Results: MMP-3 (436.8 +/- 474.2 ng/ml) and D-dimer levels (351.2 +/- 296.3 ng/ml) were markedly elevated in the sera from RA patients as compared with healthy controls (43.9 +/- 15.2 ng/ml and 63.0 +/- 64.1 ng/ml, p < 0.0001, respectively). Both levels strongly correlated with each other (r = 0.627, p < 0.0001) and were closely associated with various clinical parameters for the disease activity of RA, including the erythrocyte sedimentation rate (ESR) and the Lansbury's activity index (p < 0.0001). MMP-3 levels were more highly correlated with articular parameters such as the swollen and painful joint counts (r = 0.454, p = 0.0002), whereas D-dimer levels correlated well with C-reactive protein (CRP) levels (r = 0.581, p < 0.0001). In SLE patients, MMP-3 (239.1 +/- 199.6 ng/ml, p < 0.0001) and D-dimer levels (86.9 +/- 85.2 ng/ml, p = 0.0278) were also higher than in healthy controls. Both levels correlated with each other (r = 0.612, p = 0.0025), and were associated with ESR and CRP levels, as was observed in RA patients, but not with most of the other clinical indicators for SLE., Conclusions: Serum levels of MMP-3 and D-dimer are clinically useful indicators for disease activity in RA. Our results further support the hypothesis that MMP-3 and plasmin may interact in the inflammatory synovial tissues, and thus augment the articular destruction seen in RA. In SLE patients, however, MMP-3 producing cells could be different from in RA patients, and further studies will be required to clarify the pathogenetic mechanism underlying the raised serum levels of MMP-3 and/or D-dimer.

Patients with rheumatoid arthritis (RA) develop both periarticular and generalized osteoporosis. Periarticular osteopenia in appendicular bones occurs early in the course of RA and is one of the earliest radiological signs of RA. An uncoupled state in bone resorption-formation linkage, contributes to the development of periarticular osteopenia and it might be mediated through an increased productions of cytokines and prostaglandins by synovium and bone marrow. Accordingly, early suppression of rheumatoid synovitis is necessary for the prevention of periarticular osteopenia. Generalized osteoporosis is also common in RA and leads to increased risk of fractures. Generalized osteoporosis considered to be multifactorial and factors contributing to lumbar osteoporosis might be different from those to loss of appendicular bones, such as femur and radius. Corticosteroids and menopausal state are important risk factors for lumbar osteoporosis. Rheumatoid activity and reduced physical activity are also important determinants. According to the previous studies, however, the influence of functional impairment is more prominent in the femoral BMD compared to spinal BMD. In addition to control of RA and maintenance of physical activity, hormone replacement therapy (HRT) and bisphosphonate are possible agents for the treatment of osteoporosis in RA patients, especially postmenopausal women.

A case-controlled study was performed, based on early active RA patients treated with MTX; Prednisolone (PSL) was also given in sixteen patients (PSL + MTX group) and each of them was matched for age and sex with a control who have never received PSL (MTX group). No significant differences in radiographic progression were found between the 2 groups. Analysis of radiographic parameters showed that CRP, erythrocyte sedimentation rate, and titers of serum rheumatoid factors after 6 months treatment and their integral amounts during cource were significantly high in the patients with marked radiographic progression. There was no relationship between radiographic progression and treatment with PSL. These results suggested that the indication of PSL therapy for RA is limited for patients with the poor decrease in the level of CRP, erythrocyte sedimentation rate, and rheumatoid factor by MTX treatment.

Objective: To clarify the incidence and background of clinical relapse (escape phenomenon) during low-dose methotrexate therapy for rheumatoid arthritis., Methods: Seventy one patients with rheumatoid arthritis (RA) were analyzed. They were started on therapy with methotrexate (MTX) between April 1, 1991 and May 30, 1995. Among them, 60 patients showed clinical improvement within 6 months after the start of the therapy and were subjected to the analysis for clinical relapse (escape phenomenon)., Results: Twelve patients showed an initial improvement followed by a relapse with increased serum CRP and number of painful joints despite the MTX therapy was continued. Two types of the relapses were seen; (1) early, escape (relapse after an initial brief improvement) in 7 patients, and (2) late escape (relapse after a long-term improvement with MTX therapy) in 5 patients. The early escape was seen at 9.0 +/- 0.7 months after the start of therapy while the late escape was seen at 23.3 +/- 4.8 months. Patients with both types of escape phenomenon had the longer duration of the disease and more advanced stage. There was no relationship between clinical relapse and age, baseline RA activity, MTX dose, or concurrent use of corticosteroids and other disease modifying anti-rheumatic drugs. The efficacy of MTX for RA was restored by increasing dose of MTX in 11 patients., Conclusion: These results suggest that clinical relapse is not rare in RA patients during low-dose methotrexate therapy, but could be improved by increasing dose.

Pentoxifylline (POF) has been shown to have anti-inflammatory and immunomodulatory effects. including suppression of TNF-alpha production by activated macrophages, Th-1 response of T cells, and fibroblasts' proliferation and metalloproteinase production. Pentoxifylline was also reported to possess therapeutic properties in 50% of severe refractory RA in an open study. We experienced a 64 year-old man with seronegative RA, stage 2, class 3. He showed 23 swollen joints, 32 painful joints, ADL score 37/40, and ESR 135 mm/h. All these parameters were dramatically improved 3 weeks after administration of POF 300 mg/d and prednisolone 5 mg/d. Discontinuation of POF resulted in rapid exacerbation of RA. POF was restarted and the patient showed complete recovery from arthritis with normalization of ESR within 3 months and was maintained a complete remission for another 1 year. This case further supports a potential antirheumatic effect of POF on some patients with RA.

In a study to evaluate the usefulness of DMARDs combination therapy for RA, AF and MTX were concurrently given to RA patients who had responded poorly to over three months of monotherapy of either AF or MTX. The study was composed of two stages. In the first stage, patients were concurrently given AF and MTX for six months in order to evaluate the efficacy of combination therapy. In the second stage, patients who had responded to the earlier combination therapy were again put on monotherapy of the additive DMARD. Safety evaluation was conducted with 126 patients, and both efficacy and utility were evaluated in 100 patients. Lansbury index for RA significantly improved in both groups of patients starting with the AF and followed by the MTX combination (Group I) and those who started with MTX alone followed by the AF combination (Group II). The ratio of patients who achieved slight improvement or better in the overall improvement rating was significantly higher in Group I at 74.6%, vs. 51.1% in Group II patients. Ten patients (16.9%) and 2 patients (4.9%) were switched to their additive DMARD monotherapy of MTX and AF respectively, having responded to the combination therapy in stage I with slight improvement or a better rating. Adverse events were observed in 44 patients (34.9%), but the combination therapy neither increased the incidence of adverse events nor caused new adverse events. Combination therapy of AF and MTX appeared to be useful both in terms of efficacy and safety for patients who have experienced the dwindling effect of monotherapy.

To elucidate the clinical characteristics and pathogenesis of scleroderma-rheumatoid arthritis (SSc-RA) overlap syndrome, we analyzed the clinical features of 5 patients with SSc-RA overlap. Their HLA phenotypes and genotypes were also determined. Generalized skin sclerosis, severe seropositive polyarthritis, pulmonary fibrosis, anti-topoisomerase I antibodies, and HLA-DR4,53;DQA1*0301;DBQ1*04 haplotype were observed in all of the patients. Similar clinical features were recognized in most of the 10 cases reported previously. Our case studies indicate that SSc-RA overlap may be a distinct entity.

Long term treatment of 190 cases of rheumatoid arthritis with either methotrexate or salazosulfapyridine was analyzed for their efficacy and adverse effects. Both treatment groups showed improvement of clinical symptoms, erythrocyte sedimentation rate, and CRP after 1 month of treatment, while RAHA titers decreased significantly after several months. Erythrocyte sedimentation rate and CRP of salazo-sulfapyridine group, once improved, deteriorated again after 12 months of treatment, while methotrexate group showed sustained improvement for 48 months. Radiologic progression estimated according to JF Fries was significantly less in MTX group than in SASP group. Life table analysis showed that the overall probability of continuing methotrexate or salazosulfapyridine at 4 years was 63% and 55%, respectively. The main reason of treatment termination in methotrexate group was adverse effects, while that in salazo-sulfapyridine group was inefficacy.

The hemostatic mechanism is thought to contribute to the inflammatory process of rheumatoid arthritis (RA). Thrombomodulin (TM), an inhibitor of blood coagulation, is synthesized by various cells which are recognized in the inflammatory lesions of RA. To elucidate a possible relation of TM with the process of RA, therefore, we measured soluble forms of TM in the plasma and joint fluid (JF) from RA patients by a recently developed sandwich enzyme immunoassay using monoclonal antibodies. TM levels in the plasma and JF were not significantly elevated in RA patients, although TM levels in plasma were positively correlated with those in JF. The plasma TM levels were related to renal functions (serum creatinine levels), but the levels showed no connection with systemic inflammatory indices of RA such as erythrocyte sedimentation rates, serum C-reactive protein levels and Lansbury's activity index. In the JF, TM levels were not correlated with the numbers of neutrophils or monocytes/macrophages associated with articular inflammations. Our results indicate that TM levels in the plasma and JF do not reflect systemic and articular inflammations of RA, and suggest that TM molecules in JF are mainly recruited from circulating TM.

Sjögren's syndrome (SS) is currently classified into two groups (primary and secondary), because of differences in the disease in the two groups. We determined antinuclear antibody and other immunohematological parameters by using newer, more sensitive serologic methods on patients with primary SS, or secondary SS associated with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), and patients with just the systemic disease free of SS. This study defined both distinctive and common features between primary SS and each systemic disease: High titers of fluorescent antinuclear antibodies (FANAs), anti-SS-A/SS-B antibodies, and rheumatoid factors (RFs), as well as leukocytopenia were considered the main features of primary SS. Elevated levels of RFs and C-reactive protein were prominent in RA patients. In contrast, high titers of FANAs and anti-single stranded or anti-double stranded DNA antibodies, positive anti-ribonucleoprotein or Sm antibodies, leukocytopenia, and hypocomplementemia were characteristic for SLE. Furthermore, patients with secondary SS plus RA or SLE were found to have mixed features of SS and the associated systemic disease. The results strongly suggest that patients with secondary SS have two separate diseases, SS and the associated systemic disease.

We previously demonstrated that the cells expressed by activation antigens were increased in several T cell subsets from the peripheral blood (PB) and joint fluid (JF) of patients with Sjögren's syndrome (SS) or rheumatoid arthritis (RA). In the present report, we further determined by three-color flow cytometry the homing receptors (Leu8) for peripheral lymph nodes expressed on naive (CD45RA+) or memory (CD45RA-) CD4+ cells and on the two subsets of CD8+ cells (CD11b+ and CD11b-) in the PB and JF from SS and RA patients. In addition, the activation antigens (HLA-DR) and two adhesion molecules, including the alpha-chain of the leukocyte function associated antigen-1 (LFA 1 alpha: CD11a) and its ligand (intercellular adhesion molecule-1: ICAM-1: CD54) expressed on T cells, were compared. We found that CD45RA-CD4+ cells were markedly increased in JF, while CD45RA+CD4+ cells were almost absent. Leu8+ cells were decreased in both CD45RA-CD4+ and CD8+CD11b-cells (cytotoxic T cells) in the JF, and were also decreased in the CD8+CD11b-subset in the patients' PB. Furthermore, activated (DR+) T cells were markedly increased in JF, and the cells expressed more adhesion molecules in both the PB and JF from patients, compared with the DR-T cells. The DR+ T cells therefore are considered to be memory T cells, which are more efficient for cell-to-cell interactions. These observations also suggest that the Leu8- and DR+ T cells with increased adhesion molecules might preferentially migrate into inflammatory tissues, and that naive T cells are being further converted to to memory T cells by in vivo stimulation within the tissues.

Cell surface antigens, such as CR3, Fc gamma RIII, cALLa and Leu 8 antigen, expressed on polymorphonuclear cells (PMN) in the peripheral blood (PB) are associated with certain functions of PMN. Functional alterations of PMN have been reported in some rheumatic diseases. In this study, therefore, the cell surface antigens were examined by 2-color flow-cytometry using monoclonal antibodies to clarify whether expressions of the antigens on PMN are abnormal in patients with rheumatic diseases including Behçet's disease (BD), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). We found that expressions of CR3 and cALLa were increased on PB-PMN from patients with BD or RA, but not from those with SS. In BD, we further determined the phagocytic activity of PMN by a flow-cytometric method using fluorescent particles. The phagocytic activity was significantly higher in BD patients than in healthy controls, and correlated slightly with the expression of CR3 on PMN in the patients. In addition, prednisolone or colchicine seemed to decrease the expression of CR3 and/or cALLa in patients. The above results indicated that PB-PMN in BD and RA, but not SS, are phenotypically activated in vivo, and the activation probably reflects several cytokines and/or other stimuli to PMN produced in the inflammatory process.

Follicular bronchiolitis is a rare disorder, though it has been recognized as a pulmonary involvement of rheumatoid arthritis in recent years. A 57-year-old woman with rheumatoid arthritis was admitted to the hospital with persistent productive cough and breathlessness on exertion. An open lung biopsy was performed to establish a definite pathologic diagnosis of her disease, and she was diagnosed as having follicular bronchiolitis on the basis of the histopathological findings. It is essential to differentiate this disease from other bronchiolar or lymphoproliferative disorders of the lung.

To study the role of the superoxide radical (O2-) in the pathogenesis of rheumatoid arthritis (RA), both the O2- generation of peripheral blood (PB) polymorphonuclear cells (PMN) and the superoxide scavenging activity (SSA) of PB-PMN, plasma, joint fluid (JF) and PB- or JF-mononuclear cells (MNC) were measured in forty-five patients with RA using the highly sensitive and specific 2-methyl-6-methoxyphenyl-3,7-dihydroimidazo[1,2-alpha] pyrazin-3-one dependent chemiluminescence and the electron paramagnetic resonance/spin trapping methods, respectively. Since many drugs, particularly the slow-acting anti-rheumatic drugs (SARDs) used in RA, may alter O2- metabolism, the effects of SARDs on SSA were also studied. The basal O2- release and opsonized zymosan- or phorbol myristate acetate-stimulated O2- generation by PB-PMN from RA patients were significantly increased, while the SSA of PMN was decreased as compared to those from healthy controls. In addition, the SSA of PMN showed a negative correlation with their O2- generation rates. The JF-PMN showed lower SSA levels than PB-PMN. A negative correlation was also found between the SSA of the plasma and the erythrocyte sedimentation rates. The SSA of the plasma, PB-PMN, JF and JF-PMN were significantly higher in patients treated with SARDs than those without. In cell-free systems, sulfasalazine (SAP) and its metabolite, 5-amino-salicylic acid, had a direct SSA within a millimolar range. The other metabolites of SASP and D-penicillamine had an indirect SSA, since they affected the O2- generating system. Auranofin and bucillamine had no SSA. However, none of the SARDs examined could scavenge O2- at concentrations reported in patients' plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Factor V deficiency associated with rheumatoid arthritis was found in a 54-year-old woman. Hereditary factor V deficiency is very rare; only about 150 cases have been reported since its discovery in 1943. This appears to be the first case report of factor V deficiency associated with rheumatoid arthritis in the literature.

We reported a case of 64 year-old female patient of pulmonary tuberculosis associated with ARDS during corticosteroid treatment of Rheumatoid Arthritis. On admission her chief complaints were fever, fatigue and dyspnea. A chest roentgenogram showed diffuse alveolar infiltration consistent with pulmonary edema. Arterial blood gas studies showed severe hypoxemia. We clinically diagnosed so-called ARDS. Smears of sputum for acid fast bacilli were negative, but transbronchial lung brushing by bronchofiberscope revealed many acid fast bacilli. Intensive therapy with anti-tuberculosis drugs (INH, RFP, SM), high dose corticosteroid (methylprednisolone) therapy and mechanical ventilation was started. During the following 2 weeks, the PaO2 rose gradually and the alveolar infiltration on the chest roentgenogram disappeared. The experience of this case to emphasized the importance of suspecting this condition because pulmonary tuberculosis is a potentially curable cause of ARDS and it should also be emphasized that the good treatment effect could be expected with combined use of high dose corticosteroid and mechanical ventilation.

Twenty-three patients were included in this prospective study about the safety and efficacy of oral low dose methotrexate (MTX) in the treatment of refractory rheumatoid arthritis. Patients received a mean dosage of 6.6 +/- 1.8 (SD) mg weekly over a mean duration of 16.6 +/- 12.5 months. Patients improved significantly in all clinical parameters of efficacy. There were significant reductions in Lansbury joint scores (p less than 0.001), duration of morning stiffness (p less than 0.001), sedimentation rates (p less than 0.001), C-reactive protein (p less than 0.01), IgG(p less than 0.01), rheumatoid factor (p less than 0.01) and significant increase in grip strength (p less than 0.001), hemoglobin (p less than 0.05) after 17 months of treatment with MTX. Radiographic progression of joint disease were assessed using global scoring method. The mean rate of development of erosions and joint-space narrowing during MTX therapy was significantly less than the rate of radiographic progression before MTX therapy (8.1 +/- 7. 9/year vs. 1.9 +/- 3.8; p less than 0.05). Adverse reactions during MTX therapy included transient transaminase elevation (17.4%). Five patients (21.7%) were withdrawn because of leukopenia (2), interstitial pneumonitis (1), stomatitis (1), skin rash (1). We conclude that low-dose methotrexate is effective for the management of clinical disease activity in patients with refractory rheumatoid arthritis and may be a disease-modifying anti-rheumatic drugs (DMAR-Ds) by roentgenographic criteria.

Superoxide radical anion (O2-) has been suggested to mediate tissue damage associated with chronic inflammatory disorders such as rheumatoid arthritis (RA) and Behçet's disease (BD). Despite that protection from O2- is provided by superoxide dismutase (SOD), there are controversial results about SOD-like activity of polymorhonuclear cells (PMN) in RA and there are no reports about it in BD. In addition, colchicine, a potent inhibitor of phagocytosis, has been used for the treatment of BD, no report about its effect on SOD-like activity of PMN is available. The present study investigates the superoxide scavenging activity (SSA) of PMN and mononuclear cells (MNC) in both RA and BD, and it examines the effects of colchicine on SSA of PMN in BD using the electron paramagnetic resonance/spin trapping method. The SSA of PMN, but not MNC, was significantly lower in patients with either RA or BD, as compared with that in healthy controls. The SSA of PMN in both RA and BD showed a strong negative correlation with that in healthy controls. The SSA of PMN in both RA and BD showed a strong negative correlation with erythrocyte sedimentation rates and C-reactive protein levels. Colchicine treatment increased the SSA of PMN toward normal level in BD patients, and prevented the decrease of SSA in PMN obtained from healthy adults after the stimulation with opsonized zymosan in vitro. Our results suggest that the decrease of SSA in PMN is not disease specific and it is probably the results of the increased amount of O2- generated by these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

We analyzed activated T-cells in the peripheral blood (PB) of 29 patients with Sjögren's syndrome (SS: 13 I degrees-SS and 16 II degrees-SS patients) and 11 patients with rheumatoid arthritis (RA) by two-color flowcytometry using antibodies to antigens serially expressed on the cell surface after activation--interleukin-2 receptor (IL-2R), HLA-DR, T-lineage specific antigen (TLiSA-1) and very late antigen (VLA-1). The early and intermediate activation antigens, DR and TLiSA-1, were significantly increased in the PB of SS and/or RA patients. The proportions of activated T-cells were higher in CD8+ cells than those in CD4+ cells. T-cells expressing IL-2R or VLA-1, which appear in the very early or late stages of activation, were also increased in SS and/or RA patients. The results suggest that activated T-cells in the PB of both diseases might be recruited from continuously activated lymphoid organs, and that the activated cells migrate from PB into target tissues. In addition, the increase of activated T-cells in PB might be one of the causes of the deficient cell-mediated immunity reported in these patients.

A forty-eight year-old female with rheumatoid arthritis developed cough, sputum and dyspnea. Chest X-ray film demonstrated bilateral diffuse interstitial pneumonia and pulmonary fibrosis. Laboratory findings were as follows: ESR 29 mm/h, CRP 3.86 mg/dl, RA test (+), RAHA (-) and WBC 7200/mm3. Marked hypoxemia (po(2)45 Torr) was demonstrated by blood gas analysis. Asymptomatic pulmonary fibrotic lesions which preceded articular symptoms were identified on her previous chest X-ray films. Methylprednisolone-pulse therapy (1g/day, for 3 days) was repeated three times with a 2-week interval. The treatment rapidly improved both pulmonary symptoms and chest X-ray findings. Although the fibrotic shadows on chest X-ray did not completely disappear, her conditions have been maintained well under the treatment with prednisolone (10mg/day) plus D-penicillamine (200mg/day).

Lymphocyte subpopulations and functions were examined in the salivary (parotid) gland lymphocytes (SGL) obtained as a cell suspension from a patient with Sjögren's syndrome associated with rheumatoid arthritis, in comparison with peripheral blood lymphocytes (PBL). Serial studies on the lymphocyte subsets in PBL using monoclonal antibodies to helper or suppressor T cell subsets (OKT4 or OKT8) demonstrated a decreased proportion of the OKT8 subset (OKT4/OKT8 ratio: 7.1-34.0). Major infiltrating cells in the gland were surface immunoglobulin-bearing B cells, and 23-35% of the SGL were T cells by both the E-rosetting method and OKT3-monoclonal antibody reactivity. Moreover, OKT4/OKT8 ratios were definitely lower in the SGL (1.0 and 1.7) than those in the PBL of the patient. Mitogen-induced lymphocyte proliferative responses of the SGL were markedly diminished, although the possible participation of defective macrophages was considered. The autologous mixed lymphocyte reaction was low in both PBL and SGL. PBL of the patient showed normal proliferative responses to mitogens except for PWM stimulation. Suppressor effects of the SGL for the proliferative responses of autologous and allogeneic PBL were demonstrated. Con A-induced suppressor function was inducible in the SGL, whereas that function could not be demonstrated in the patient's PBL.

Some evidence indicates that ibuprofen and other prostaglandin synthetase inhibitors may have the potential for cellular immune enhancement in addition to their anti-inflammatory activity. If this is true, treatment of rheumatoid arthritis, a disorder of presumed autoimmune pathogenesis, would present a dilemma. These agents are widely used in rheumatoid arthritis for their anti-inflammatory effects. If they are found to enhance cellular immune function, however, the disease might be stimulated over the long term, rather than suppressed. Preliminary evidence from four patients with rheumatoid arthritis show that oral ibuprofen had no significant immunologic effect during sequential "on" and "off" cycles, as assessed by the following measures: delayed hypersensitivity skin testing; lymphocyte transformation to mitogen (phytohemagglutinin) or specific antigen (Candida albicans); T-cell subsets, as determined by monoclonal antibody techniques; or production of the lymphokine, human immune interferon, in response to phytohemagglutinin or to staphylococcal enterotoxin A. Early evidence, therefore, suggests that oral ibuprofen therapy may be 'immunologically safe' in patients with rheumatoid arthritis, but investigations of large series of patients also assessing local immune reaction in diseased joints may be necessary for confirmation.

Lymphocyte subsets were determined in the peripheral blood from twenty-three patients with primary Sjögren's syndrome (SS) and sixteen patients with clinically active rheumatoid arthritis (RA) by two-color flowcytometry using various monoclonal antibodies. In both diseases, T-cells (CD3+), suppressor/cytotoxic cells (CD8+) and their cytotoxic subset (CD8+CD11-) were decreased, as compared with thirty-one healthy controls. B-cells (CD 21+ and CD 3-DR+) and activated T-cells (CD 3+DR+) were increased in SS patients. Helper T-cells (CD 4+Leu8-), suppressor-inducer T-cells (CD4+Leu8+), suppressor T-cells (CD8+Leu 15+) and three natural killer (NK) cell subsets determined by both CD16 and Leu7 antibodies did not differ between controls and SS or RA, although Leu7+NK cells were significantly increased in SS patients. In addition, we found that the treatment with low-dose prednisolone decreased B-cells and suppressor-inducer T cells, and increased suppressor T-cells, cytotoxic T-cells and Leu7+NK cells. The results indicate similar changes in the proportion of lymphocyte subsets and suggest immunologically activated and deficient conditions in both diseases. Immunomodulating effects of the treatment with low-dose prednisolone on some of the lymphocyte subsets in patients with these diseases were also supported by the study.