Serum C4 levels in patients with systemic lupus erythematosus in remission.

Abstract Twenty-six patients with systemic lupus erythematosus (SLE) showing systemic lupus activity measure (SLAM) and SLE disease activity index (SLEDAI) scores ≤2, as well as a lower C4 concentration than the mean C4 levels of healthy controls, were selected to evaluate the C4 levels of SLE patients in remission. Serum complement (CH50), complement components (C4, C3, and B), complement split products (C4d, iC3b, and Bb), phenotypic expression of C4 allotype, C4 production by peripheral blood monocytes, peripheral blood lymphocyte subpopulation, and interferon-gamma (IFN-γ) production were examined. In patients with SLE in remission, the C4 consumption (C4d/C4) was found to increase, and this was considered to be the most important factor for determining the serum concentration of C4. However, the relevance of the C4 allotypic expression was minimal. The IFN-γ-stimulated production of C4 by peripheral blood monocytes in SLE patients in remission was also less than that of the healthy controls. The IFN-γ-stimulated production of C4 in SLE patients in remission correlated with the peripheral blood CD4-positive cells. Less IFN-γ was produced by lymphocytes of SLE in remission than by those of healthy adults. We conclude that the serum C4 levels in SLE patients in remission reflect the degree of C4 consumption as well as the disease state, rather than genetic influences such as a C4A defect.

Congenital diaphragmatic hernia in identical twins.

The authors present a pair of identical twins with congenital diaphragmatic hernia (CDH) diagnosed prenatally, who underwent successful surgical repair. They were diagnosed as having CDH at 32 weeks' gestation and showed respiratory distress soon after cesarean section at 33 weeks' gestation. Both survived after scheduled perinatal management followed by surgery, for which the prenatal diagnosis of CDH was valuable.

Serum interleukin-2 receptor for the early diagnosis of rheumatoid arthritis.

The value of measuring soluble interleukin-2 receptor (sIL-2R) in the sera of patients with joint pain as a predicting parameter for the future development of rheumatoid arthritis (RA) was examined. sIL-2R was measured by the ELISA method. Sixty-four patients with joint pain (suspected RA: sus-RA) but no bone or joint destruction were enrolled over 2 years and 47 were selected for the study. Eleven patients whose diagnosis was sus-RA after a year of observation were successively followed-up for 5 years. Two-thirds of the patients whose sIL-2R levels were higher than those of normal healthy adults (< 82 pmol/l; mean +2SD) developed RA within a year. On the other hand, one-quarter of the patients with normal levels of sIL-2R also developed RA within a year. The presence of two or three of the following three items in patients with joint pain without any bone and joint destruction was thus indicated to be useful for the early diagnosis of RA: elevated CRP level (> or = 1.0 mg/dl), positive rheumatoid factor (RF) (> or = 30 IU/ml) and an elevated sIL-2R level (> or = 100 pmol/l). Sensitivity and specificity were 72.7% and 96.0%, respectively. The probability of development of RA is expressed as P = 1/[1 + exp(2.673 - 0.01784 x sIL-2R - 0.4398 x CRP - 0.004835 x RF)], with R2 = 0.3083 and p<0.0005. On the other hand, the sIL-2R levels did not correlate with any future bone or joint changes within a year of observation. The above criteria may therefore hopefully justify the early treatment of patients with joint pain using drugs that can modify the patients' immune function. However, the validity of these criteria still need to be examined more thoroughly in the future.

Induction of drug resistance to gold sodium thiomalate in a monocyte cell line, THP-1.

The expression of metallothionein, an intracellular heavy-metal-binding protein, and p-glycoprotein, an energy-dependent drug efflux pump, was examined to study the mechanism of cell resistance to gold sodium thiomalate (GST). THP-1, one of the monocyte-derived cell lines, was cultured for 6 months and resistance to 25 microg/ml of GST (GST-resistant cells) was thus induced. The GST-resistant cells were then cultured with bucillamine to examine the presence of cross-resistance. The intracellular GST concentration was examined by flameless atomic absorption spectroscopy. The cell viability was determined by the uptake of 3-4,5 dimethylthiazole-2,5 diphenyl tetrazolium bromide (MTT). The expression of p-glycoprotein was detected by Western blotting using monoclonal anti-p-glycoprotein antibody. The expression of metallothionein was detected using the indirect immunofluorescence technique. GST-resistant cells did not show any cross-resistance to bucillamine. The rate of cytoplasmic GST accumulation decreased in the GST-resistant cells, while the rate of GST efflux also decreased. The expression of p-glycoprotein in the GST-resistant cells was not significantly different from that in the cells not treated with GST. On the other hand, the GST-resistant cells showed a higher expression of metallothionein than cells not treated with GST. These findings suggest that the induced resistance to GST might partly be due to an induction of metallothionein.

NSAID-induced gastrointestinal damage. Epidemiology, risk and prevention, with an evaluation of the role of misoprostol. An Asia-Pacific perspective and consensus.

The problem of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal toxicity was reviewed by members of the Asia Pacific League of Associations for Rheumatology (APLAR) in a consensus conference in September 1992. This paper by the participants presents the consensus conclusions incorporating knowledge from recent publications. There had been a high level of concern that much of the toxicity had resulted from extensive and indiscriminate prescribing of NSAIDs. The implementation of evidence-based guidelines was considered likely to be able to effect a substantial reduction in toxicity without significant loss of overall therapeutic benefit. The evidence from which such guidelines could be developed is critically appraised.

Syndrome of inappropriate secretion of antidiuretic hormone in elderly patients with rheumatoid arthritis associated with infections: report of two cases.

Two rheumatoid arthritis (RA) patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) during the course of infection are herein reported. One patient developed SIADH during the course of a localized cutaneous herpes zoster infection while the other developed SIADH in conjunction with Staphylococcus simulans septicemia. We consider that the development of SIADH was strongly associated with superimposed infections in the underlying RA. This is the first report discussing the association of SIADH and infections in RA patients in which SIADH is diagnosed by measurement of plasma ADH.

Human monoclonal rheumatoid factors augment arthritis in mice by the activation of T cells.

In order to investigate the in vivo role of rheumatoid factor (RF), the effects of the administration of human monoclonal (m) IgM-RF and IgG-RF on the development of arthritis in mice were examined. The administration of human mRFs into mice immunized with type II collagen (CII) markedly enhanced the clinical score and paw swelling. The severity of arthritic joint disease with a marked infiltration of lymphoid cells, proliferation of synovial membrane, pannus formation and destruction of articular cartilage was significantly enhanced in both groups receiving RF (RF-enhanced arthritis). Skin ulcers were also observed in some of these RF-enhanced arthritis mice, whereas no such signs were observed in CII-immunized mice without mRFs. Both IgM-RF and IgG-RF increased CII-specific IgG antibodies in circulation, and the severity of arthritis correlated with the production of high titres of anti-CII antibodies. In vivo treatment of RF-enhanced arthritis mice with an anti-CD4 MoAb or an anti-CD8 MoAb inhibited the induction and progression of arthritis in these mice. Administration of RF to severe combined immunodeficient (SCID) mice with arthritis developed by the transfer of spleen cells from CII-immunized mice, prolonged the arthritis and enhanced the severity. This murine model of RF-enhanced arthritis may provide a useful tool for analysing the pathogenesis of rheumatoid arthritis in RF-positive patients.

[Amyloidosis of the small intestine secondary to rheumatoid arthritis and juvenile rheumatoid arthritis: report of two cases].

We herein report two cases of gastrointestinal amyloidosis, secondary to juvenile rheumatoid arthritis (JRA) in one, and rheumatoid arthritis (RA) in the other. A 21-year-old woman, who has been suffering from JRA for the past 12 years, was transferred to our hospital due to intense pain in the epigastrium and back, diarrhea, high fever, and paralytic ileus. Treatment by corticosteroid, antibiotics, protease inhibitor, and total parenteral nutrition was not effective. The laparoscopic surgery was performed because of repeated melena followed by an episode of hypovolemic shock. The resected specimen of the ileum showed histologically marked amyloid deposition in the arteriolar walls. A 83-year-old man with RA for 14 years, was admitted to our hospital with complaints of abdominal pain, nausea, and diarrhea. He underwent an emergency operation for perforation of the ileum. The resected specimen revealed amyloid deposition and non-caseating granulomas. The fragility and impaired blood supply caused by amyloid deposition in the vascular walls may have terminated in the severe intestinal lesion. Further clinicopathological studies along this line are keenly desired in order to establish therapeutic modalities for gastrointestinal amyloidosis.

[Stromelysin-1 (MMP-3) level in the sera from patients with rheumatoid arthritis and other connective tissue diseases--clinical significances in early onset rheumatoid arthritis].

Stromelysin-1 (MMP-3) is a metalloproteinase that degrades articular cartilage matrix in patients with rheumatoid arthritis (RA). We measured MMP-3 in the sera from patients with RA and other connective tissue diseases using specific sandwich EIA and studied its clinical significance in early onset RA. MMP-3 level in healthy control (n = 170) was significantly higher in male than in female. The level of MMP-3 in RA was significantly and dramatically higher than in healthy control, osteoarthritis, systemic lupus erythematosus, progressive systemic sclerosis, primary sjogren's syndrome, mixed connective tissue disease, gouty arthritis and traumatic arthritis. Serum MMP-3 significantly correlated with serum BUN or serum creatinine levels in SLE patients but not in RA patients. In early onset RA, serum MMP-3 level was significantly elevated. Furthermore, when the relationship between the serum MMP-3 level and X-ray findings of the joints in RA was studied, it was found that MMP-3 level was elevated even in stage I or II and that there was no statistical differences between stage I or II and stage III or IV, suggesting that serum MMP-3 level is elevated in the early stage of initial inflammatory process when only mild cartilage degradation is seen. These results suggest that measurements of serum MMP-3 is an important tool for establishing diagnosis of early onset RA, and that serum MMP-3 level may be a marker of cartilage destruction and of estimating therapeutic efficacy in early onset RA.

[Clinical studies on 14 cases of adult-onset Still's disease].

We here report fourteen patients diagnosed as adult-onset Still's disease (AOSD) in our hospital. Seven patients were males (mean age at onset was 26.6 years), and seven were females (30.6 years). All of the cases had spiking fever ( > 39 degrees C) and joint symptoms. Hepatomegaly, splenomegaly, and lymphadenopathy were noted in 50% of the patients, respectively. Skin eruption was seen in twelve patients (85.7%). Among them, nine patients (64.3%) exhibited typical rash. Pleuritis or pericarditis was seen in one case each. Only one patient revealed neurological disorder. Abdominal pain was present in 50% of the cases. The ratio of occurrence of secondary amyloidosis was 14.3%. Four patients (28.6%) were diagnosed to have the apophyseal narrowing at the cervical spine (C2-C3). Two patients (14.3%) accompanied by Sjögren's syndrome were women over 40 years of age. The levels of soluble interleukin-2 receptor were significantly elevated in the sera obtained from seven patients with AOSD and four patients with juvenile-onset Still's disease, compared with normal controls. It seems to support the notion that immunopathologic processes via T cell activation play an important role in the pathogenesis of AOSD.

The effects of Tripterygium wilfordii extract on adjuvant arthritis in rats.

The effects of the extract of Tripterygium wilfordii. (TWE) on experimental adjuvant arthritis (AA) in the rat was studied. Lewis rats induced with AA were administered with TWE at 50 mg/kg/day for 10 weeks. The paw volume, its ratio to the body weight (paw ratio) and the radiologic changes in the feet of the rats with AA taking TWE were compared with those in the rats taking indomethacin (0.5 mg/kg/day) and no additional drugs. The rats taking TWE showed a smaller paw volume, a lower paw ratio and milder radiologic changes than the rats taking no drugs, however, the beneficial effects were weaker than those of indomethacin. We concluded that the beneficial effects of TWE on rats with AA was suggested. However, these results still need to be further confirmed by additional experiments.

Increased IL-1 receptor antagonist (IL-1ra) production and decreased IL-1 beta/IL-1ra ratio in mononuclear cells from rheumatoid arthritis patients.

In order to investigate the possible role of IL-1 receptor antagonist (IL-1ra) in patients with rheumatoid arthritis (RA), this study was undertaken to measure the amounts of IL-1ra and interleukin-1 beta (IL-1 beta) protein produced by mononuclear cells (MNC) and to investigate the relationship between production of these cytokines and clinical parameters. The MNC were cultured for 24 h and the supernatants were measured for IL-1ra and IL-1 beta by ELISA kits. MNC from peripheral blood (PB) and synovial fluid of RA patients produced significantly higher amounts of IL-1ra than normal PBMNC (P < 0.01 and P < 0.05, respectively). When the IL-1 beta/IL-1ra ratio was calculated, IL-1 beta/IL-1ra ratios of RA PBMNC were significantly lower than those of normal PBMNC (P < 0.001). The IL-1 beta/IL-1ra ratio of RA PBMNC was significantly higher in active RA patients than in RA patients in remission (P < 0.02). The amounts of IL-1ra produced by stimulated RA PBMNC positively correlated with the joint score (P < 0.05), serum CRP levels (P < 0.05) and the amounts of IL-1 beta produced (P < 0.01). The amounts of IL-1ra produced by unstimulated RA PBMNC did not correlate with any of the clinical parameters studied. Gold sodium thiomalate (GST), but not auranofin, increased IL-1ra production in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Rheumatoid arthritis in the northeastern area of the People's Republic of China and western Japan.

The clinical features of 134 consecutive hospitalized patients with rheumatoid arthritis in the northeastern area of the People's Republic of China and 251 consecutive hospitalized patients from western Japan were compared. A total of 91.8% of the Chinese patients were of Han nationality, while all of the patients from Japan were Japanese. The patients in the People's Republic of China showed more inflammatory articular disease and more frequent subcutaneous nodules than did the Japanese patients in the presence of a less elevated ESR value and less radiographic joint destruction. The clinical features of the patients of Han nationality and the Japanese did not change even after adjusting the patients' age and disease duration. The reasons for the contradictory features in the Chinese patients still remain to be clarified. This study is hopefully a first step in promoting more precise studies on rheumatoid arthritis in the People's Republic of China.

Role of oxygen radicals and IL-6 in IL-1-dependent cartilage matrix degradation.

It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase and that such degradation is regulated by metalloproteinase inhibitors. In the present study, the effects of IL-6 and oxygen radical scavengers on cartilage matrix degradation were studied. Superoxide dismutase, catalase, or methionine all significantly inhibited cartilage matrix degradation both in IL-1 beta-stimulated and unstimulated experimental conditions. Both 10 mM EDTA and 100 nM tissue inhibitor of metalloproteinase (TIMP) significantly inhibited cartilage matrix degradation. The addition of methionine significantly inhibited collagenase activity produced in the culture supernatants of chondrocytes stimulated with IL-1 beta. IL-6 significantly suppressed cartilage matrix degradation produced spontaneously or by IL-1 beta stimulation in chondrocytes. IL-6 inhibited superoxide production by chondrocytes both in IL-1 beta-stimulated or unstimulated conditions. These results suggest that oxygen radicals are involved in cartilage matrix degradation mediated by both paracrine and autocrine IL-1 mechanisms and that oxygen radical-mediated activation of collagenase in chondrocytes may explain the mechanisms of how oxygen radicals are involved in cartilage matrix degradation. IL-6 inhibited superoxide production in chondrocytes and thus inhibited cartilage matrix degradation.

Analysis of the genes encoding the variable regions of human IgG rheumatoid factor.

OBJECTIVE: To better understand the immunoglobulin variable (V) region repertoire of rheumatoid factors (RF). METHODS: We characterized the heavy (H) and light (L) chain gene segments utilized in a monospecific IgG RF secreting hybridoma (AEE111F) which were derived from a patient with rheumatoid arthritis (RA). The hybridoma was established by fusion of a mouse myeloma cell line with bone marrow derived mononuclear cells from a patient with RA. First strand complementary DNA (cDNA) was generated and used for a polymerase chain reaction amplification of the H and L chain V domains. The amplified V domains were sequenced and compared with an extensive database of germline and cDNA V gene segments. RESULTS: The VH sequence was found to be 96% homologous to a previously described fetal VH3 cDNA (60P2). The VL sequence was also highly homologous to the previously described V lambda II gene (96%) derived from a patient with systemic lupus erythematosus which correlated with an 8.12 idiotype (Id), and to an antibacterial antibody against the Haemophilus influenzae type b capsular polysaccharide (94.7%). CONCLUSION: The overlap among this RF VL gene and the 2 reported V lambda sequences of antibodies that expressed anti-DNA related Id and an environmental pathogen specificity suggests that a part of the IgG RF isolated from patients with RA may thus be derived from the physiological natural antibody repertoire during an abnormal immune response and then develop high affinity, monospecific RF by the selection of an antigen driven mechanism.

Effect of cytokine-induced soluble ICAM-1 from human synovial cells on synovial cell-lymphocyte adhesion.

The present study was designed to establish (i) the effects of cytokines on soluble ICAM-1 (sICAM-1) production by human synovial cells (SC) and ICAM-1 expression on these cells, and (ii) the effects of sICAM-1 on lymphocyte-SC adhesion. sICAM-1 production was enhanced in parallel with ICAM-1 expression by IL-1 beta, TNF-alpha and IFN-gamma. IL-4 showed no effects on ICAM-1 expression. In contrast with the transient elevation of cell-associated ICAM-1 by IL-1 beta, which peaked 36 h after stimulation and declined thereafter, sICAM-1 continued to accumulate in culture supernatants even after 48 h. Purified sICAM-1 was obtained from a 48 h culture synovial cell supernatant by affinity chromatography using ICAM-1 monoclonal antibody. The purified sICAM-1 significantly inhibited adhesion of lymphocytes and monocytes to cytokine-stimulated synovial cells. These results suggest that sICAM-1 may modulate chronic synovitis by inhibiting ICAM-1-mediated cell-to-cell adhesion.

Additive two DMARD therapy of the patients with rheumatoid arthritis.

From the beginning of 1987 to the end of 1989, 72 rheumatoid arthritis patients (RA) whose disease could not be controlled by a single disease modifying antirheumatic drug (DMARD) were selected for the trial treatment. They continued the DMARD treatment used initially at its regular dose, and then started another DMARD regimen at 1/3 to 1/2 of the regular dose as an additive DMARD treatment, which we have designated as Additive Two DMARD Therapy (ATDT). The patients were followed until the end of 1992. In the 3 months of ATDT, the effectiveness of ATDT was obtained in 42 (58.3%) patients who showed more than a 30% decrease in the initial Lansbury's activity index (AI). The rate of side effects at 3 months were 5.6%. Tiopronin, bucillamine or salazopirine added to gold sodium thiomalate or tiopronin were suggested as the recommended DMARD combinations for ATDT. The suppressive effects on AI, ESR, CRP and rheumatoid factor continued for as long as 18 to 24 months. The mean period of ATDT was 21.7 months and that at which ATDT proved useful was 31.9 months. A discontinuation of the first DMARD treatment without any following disease aggravation was obtained in 10 of 15 patients whose disease activity had been sufficiently suppressed for longer than a year. In conclusion, ATDT was suggested to be a useful way of treating RA patients whose disease activity could not be controlled by a single DMARD treatment, as well as a way of evaluating the next DMARD while the ongoing DMARD was observed to gradually lose its initial drug effect.

[Cytokines and vasculitis].

Humoral and cellular immune mechanisms are thought to be involved in various forms of vasculitis and glomerulonephritis. Recent clinical and experimental results point to a role of cytokines in ANCA-positive vasculitides. In patients with malignant rheumatoid arthritis (MRA) which is characteristically induced by vasculitis in extra-articular lesions, serum soluble IL-2 receptor level was significantly higher than in rheumatoid arthritis patients without vasculitis. In Wegener's granulomatosis, TNF-alpha, IL-1 beta and IL-2 receptor positive infiltrating cells were observed in the kidneys of these patients, and in these patients, plasma levels of TNF-alpha and soluble IL-2 receptor were markedly increased. These results suggest that in ANCA-positive vasculitis TNF-alpha and IL-1 beta are produced in situ by activated infiltrating mononuclear cells and resident renal cells. In patients with giant cell arteritis and Kawasaki disease, increased levels of leukaemic inhibitory factor (LIF) and TNF-alpha were observed, respectively. These inflammatory cytokines increased in the vascular tissues and circulation may be a result of increased production by infiltrated cells or vascular cells such as endothelial cells or may be a result of endothelial cell lysis.

Trilineage response to rhG-CSF with subsequent clonal hematopoiesis in a patient with severe bone marrow aplasia.

We treated a patient with severe aplastic anemia with long-term administration of recombinant human granulocyte-colony stimulating factor (rhG-CSF). When a trilineage response of hematopoiesis was obtained after the first treatment, a chromosomal change [45XX, -7] was observed in 20 of the 20 metaphases examined. Later, we were able to show a monoclonal X inactivation pattern in the phosphoglycerate kinase (PGK) gene in the peripheral blood polymorphonuclear leukocytes and mononuclear cells, indicating the presence of clonal hematopoiesis regardless of the disappearance of the karyotype abnormality. We suggest that it is important to pay close attention to the appearance of clonal hematopoiesis during the administration of G-CSF to patients with idiopathic severe bone marrow aplasia.

[The comparison of clinical features between early rheumatoid arthritis and established rheumatoid arthritis].

Clinical features between 69 early RA patients (within a year duration) and 79 established RA patients (more than 3 years duration) were compared retrospectively. There were no significant differences about frequencies of morning stiffness (68.2% vs 54.4%) and rheumatoid nodules (20.2% vs 15.2%) between early RA and established RA. There were also no significant differences between two groups about elevation of ESR (92.8% vs 97.4%), positivity of CRP (97.1% vs 94.9%) and rheumatoid factor (RF) (82.6% vs 93.7%), and Lansbury activity index (AI) (mean 68.8% vs 78.8%). After hospitalization and treatment, all clinical indices (ESR, CRP, RF, AI) improved significantly in both groups. There, however, were clinically more "marked improvement" (39.1% vs 16.4%) and "remission" (8.7% vs none) in early RA group. We conclude that by hospitalization and treatment, clinical improvement can be expected in both early and established RA, but to secure satisfactory improvement, early detection and intervention of RA would be recommended.