Is SAPHO syndrome a spondylarthropathy? A vasculopathy? Report of a case.

We describe the case of a patient who had SAPHO syndrome with mediastinal and retroperitoneal fibrosis. After several years, he developed erosive polyarthritis and systemic vasculopathy. The possible implications of these associations are discussed.

Total lymphoid irradiation in rheumatoid arthritis. A ten-year followup.

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.

Osteoporosis in rheumatoid arthritis.

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.

Expression of functional B7 and CTLA4 on rheumatoid synovial T cells.

To assess the role of B7, CTLA4, and CD28 in the pathogenesis of chronic synovitis we analyzed the expression and function of these cell surface molecules in patients with rheumatoid arthritis, osteoarthritis, and psoriatic arthritis, and in normal controls. Immunoperoxidase staining of rheumatoid synovial membranes showed reactivity of 30% of T cells with anti-B7 mAb, in contrast to osteoarthritic and normal synovial membranes, in which no such staining was seen. In addition, rheumatoid synovial fluid T cells were positive by flow cytometric analysis for B7 (mean 20%, range 0 to 96%), as measured by staining with anti-B7 mAb or the CTLA4 Ig fusion protein, whereas no B7 expression was detected on peripheral blood T cells (mean 1%). To analyze the functional importance of B7 expressed on synovial fluid T cells, we used these cells as stimulator cells in primary allogeneic MLC. Purified synovial fluid T cells were far stronger stimulator cells compared with paired peripheral blood T cells and resulted in a fivefold greater increase in allogeneic T cell proliferation. Furthermore, the proliferation induced by purified synovial T cells was markedly inhibited by addition of the CTLA4 Ig fusion protein (77%). Moreover, anti-B7 mAb (37%), anti-CTLA4 mAb (33%), and Fab fragments of anti-CD28 mAb (52%) partially inhibited the primary MLC. The expression of functional B7, together with the increased expression of MHC class II molecules, indicates that synovial T cells may serve as functional APCs and may be capable of autocrine stimulation via the CD28 activation pathway.

Expression and function of CD5 and CD28 in patients with rheumatoid arthritis.

To assess the role of CD5 and CD28 in the pathogenesis of the decreased cellular immune function in patients with rheumatoid arthritis (RA) we analysed the expression and function of these T-cell surface molecules. The expression of CD5 as well as of CD28 in synovial and peripheral blood T cells was similar to that of control T cells. Monoclonal antibodies (mAb) directed at CD28 and CD5 were able to provide an accessory signal to anti-CD3 activated T cells both from the synovial fluid and from the peripheral blood. However, the proliferation induced by anti-CD3 mAb in conjunction with anti-CD5 or anti-CD28 mAb was always higher in peripheral blood (PB) T cells compared to the paired synovial fluid T cells. After simultaneous ligation of CD5 and CD28, proliferation was induced in the PB T cells. However, when compared to control PB T cells, this proliferation was significantly lower in the RA patients. Purified normal memory (CD45RO+) T cells proliferated less strongly than naive (CD45RA+) T cells, but no difference was observed between rheumatoid and normal memory T-cell proliferative responses. However, enriched PB CD45RA+ T cells from rheumatoid patients proliferated less vigorously to CD5 and CD28 ligation when compared to normal enriched CD45RA+ T cells. Synovial fluid (SF) T cells, which are mainly of the memory cell type, did not proliferate after simultaneous ligation of CD5 and CD28. This refractory state of synovial T cells could not be explained by a difference in the surface expression of CD5 or CD28. Our data suggest that the cellular immune dysfunction in the PB from rheumatoid patients may be due to a decreased responsiveness of the naive T-cell subset to accessory signals provided by CD5 and CD28. In addition, SF T cells appear hyporesponsive to stimulating signals provided through CD5 and CD28.

Clinical applications of echocardiography in patients with acute myocardial infarction.

The ability of echocardiography to visualize ventricular wall motion abnormalities induced by ischaemia and infarction makes it an ideal tool in the assessment of patients with acute myocardial infarction. Echocardiographic derived measurements of infarction severity, such as the wall motion score index, correlate well with both early and late complications. Echocardiography is of considerable value in the detection of mechanical complications of myocardial infarction such as aneurysm and thrombus formation, infarction expansion, ventricular septal rupture and mitral regurgitation; Doppler echocardiography is of particular worth in the detection of the latter two complications. Serial echocardiographic imaging before and after various coronary reperfusion strategies allows useful assessment of the success of these strategies. Following a myocardial infarction, a predischarge resting or exercise 2-dimensional echocardiographic study provides valuable information regarding the likelihood of adverse cardiac events during long term follow-up.

Ligation of the CD5 or CD28 molecules on resting human T cells induces expression of the early activation antigen CD69 by a calcium- and tyrosine kinase-dependent mechanism.

The CD5 and CD28 molecules on T lymphocytes can each exert an accessory role in T-cell activation. Ligands for CD5 and CD28 have been identified as CD72 and B7/BB1 respectively. The function of, and the signal transduction pathways coupled to CD28 have been the subject of extensive studies. In contrast, it is still debated whether CD5 functions as a receptor which directly transduces an independent signal to the T cell. In this paper, it is reported that culture of purified T cells in the presence of either immobilized anti-CD5 monoclonal antibody (mAb) (OKT1, Leu-1 or 10.2) or cross-linked anti-CD28 (9.3) mAb (but not of anti-LFA-1 alpha, anti-LFA-1 beta, or anti-CD7) induces expression of CD69, an early activation marker, in the absence of other activating stimuli. CD69 expression was consistently detectable after 3-24 hr on 20-50% of T cells, within both the CD4 and CD8 subsets. CD45RO- CD45RA+ naive T cells were more responsive than CD45RO+ CD45RA- memory T cells. In the presence of recombinant (r) interleukin-2 (IL-2), anti-CD5- or anti-CD28- induced CD69 expression was further up-regulated, more sustained and, as previously shown, succeeded by IL-2 responsiveness. Simultaneous cross-linking of both CD5 and CD28 enhanced CD69 expression above the levels obtained with optimal amounts of both ligands separately. In the presence of a submitogenic dose of the protein kinase C (PKC) activating agent phorbol 12-myristate 13-acetate (PMA), co-stimulation with anti-CD5 or anti-CD28 increased CD69 expression above that induced by PMA alone. Cross-linking of CD5 or CD28 induces an early rise of cytoplasmic free calcium concentration ([Ca2+)]i) and both this rise and CD69 expression were inhibited by chelation of extracellular Ca2+ with ethyleneglycol-bis-(2-aminoethyl)-tetraacetate (EGTA). Pretreatment of the cells with the tyrosine kinase inhibitor herbimycin A also blocked CD69 expression. The data thus antigen-independent fashion. Moreover it is demonstrated that influx of Ca2+ and tyrosine kinase activity are involved in the signal transduction pathways of both receptors.

Simultaneous ligation of CD5 and CD28 on resting T lymphocytes induces T cell activation in the absence of T cell receptor/CD3 occupancy.

The T cell surface molecules CD5 and CD28 have been shown to be receptors for accessory signals in T cell activation. We here demonstrate that in the absence of any other activating stimulus, simultaneous ligation of CD5 and CD28 by mAb induces polyclonal T cell activation. Immobilization of the anti-CD28 and anti-CD5 mAb was an essential requirement for T cell stimulation. This was done either through coating of the culture plates with goat anti-mouse Ig, or by coculture with mitomycin C-treated Fc gamma R-bearing P815 mouse mastocytoma cells. Most importantly, T cells could also be stimulated with B7, the natural ligand of CD28, and anti-CD5 presented on irradiated 3T6 mouse fibroblasts co-transfected with human Fc gamma RII and with B7. Neither immobilized mAb 9.3 (anti-CD28) nor any of four different anti-CD5 mAb were mitogenic as a sole stimulus. Immobilized mAb identifying CD4, CD7, or LFA-1 were not co-mitogenic with either mAb 9.3 or one of the anti-CD5 mAb. The T cell proliferation induced by cross-linking of CD5 and CD28 is IL-2-dependent, as was demonstrated by the cell-surface expression of the p55 chain of the IL-2R, the production of IL-2, and inhibition of the proliferative response by the anti-IL-2R mAb anti-Tac. CD5/CD28 ligation induced production of TNF-alpha, but not of IL-4, and did not induce modulation of the TCR/CD3 complex. Expression of IL-2R (p55) and of CD69 preferentially occurred on CD29-low naive cells, and indicated that about 50% of the cultured cells were activated. Cell proliferation was not increased by adding monocytes to the cultures and it was inhibited by PKC inhibitors (H7 and staurosporine) and by cyclosporine A. In conclusion, our data provide evidence for a pathway of Ag-independent T cell activation via CD5 and CD28, which preferentially stimulates native T cells.

Inhibition of synovial fluid T cell proliferation by anti-CD5 monoclonal antibodies. A potential mechanism for their immunotherapeutic action in vivo.

OBJECTIVE: Monoclonal antibodies (MAb) directed against the T cell surface molecule CD5 are able to provide accessory stimulatory signals to resting T cells. The potential role of CD5 as an immunoregulatory molecule in inflammatory synovitis was examined. METHODS: Synovial fluid and peripheral blood T cells of patients with active rheumatoid arthritis (RA) were purified and stimulated with interleukin-2 (IL-2), and the effect of MAb directed against CD5 on IL-2 responsiveness was examined. RESULTS: IL-2-induced proliferation of synovial fluid T cells was strongly inhibited by anti-CD5 MAb, but not by anti-CD28 or anti-CD3 MAb. In RA peripheral blood T cells, MAb directed against CD5, CD3, and CD28 induced IL-2-dependent T cell growth, similar to findings in healthy controls. The difference in activity of anti-CD5 MAb on synovial fluid T cells compared with peripheral blood T cells was not due to different surface expression of CD5. CONCLUSION: Anti-CD5 has an inhibitory effect on in vivo-activated synovial fluid T cells. The disease-ameliorative effects of anti-CD5 immunotoxin treatment of RA may be partly due to "switching-off" of T cell activation in the joints.

Activation of gold-reactive T lymphocytes in rheumatoid arthritis patients treated with gold.

OBJECTIVE: To assess the role of T lymphocyte sensitization in the etiology of side effects of gold therapy in patients with rheumatoid arthritis (RA). METHODS: Lymphocyte proliferation induced by gold(III) and gold(I) salts was measured in 53 subjects: 30 RA patients with gold-induced side effects (17 with dermatitis, 9 with proteinuria, 3 with hematologic complications, and 1 with colitis), 9 RA patients without side effects despite prolonged chrysotherapy, 4 RA patients who had never received gold, and 10 healthy controls. Peripheral blood lymphocytes were cultured with the different gold salts and proliferation was measured by 3H-thymidine incorporation. RESULTS: Thirteen of the 17 RA patients who developed gold-induced dermatitis showed significant T lymphocyte proliferation in response to gold(III) salts, and this proliferation could be completely blocked by monoclonal antibodies directed at the HLA-DR molecule. Such proliferative responses were not seen in patients with other gold-induced side effects, in patients who had never received gold, or in healthy controls. Only 1 of 9 patients who had not developed side effects despite long-term maintenance chrysotherapy showed significant lymphocyte activation with gold(III) salts. Lymphocyte proliferation could not be induced with gold(I) salts or with other metal salts. CONCLUSION: Patients with RA who develop dermatitis following treatment with sodium aurothiomalate [gold(I)] have T cells which proliferate in an HLA-DR-restricted manner in response to HAuCl4 [gold(III)]. We believe this observation can lead to more accurate diagnosis and treatment of side effects, which currently limit the use of one of the most effective antirheumatic drugs.

Outcome following incomplete revascularisation by coronary balloon angioplasty in patients with multivessel coronary artery disease.

When performing coronary angioplasty in patients with multivessel disease, there is an increasing trend to attempt balloon dilation of only ischaemia producing coronary stenoses (a strategy generally associated with incomplete revascularization) rather than attempting to dilate all anatomically significant stenoses (complete revascularization strategy). However the clinical efficacy of the former strategy has been questioned. To explore further this issue, we reviewed the records of 64 consecutive patients with multivessel coronary artery disease undergoing their first angioplasty at our centre in the 15 month period, October 1st 1987 to December 31st 1988. In 59 of these 64 patients, a strategy of incomplete revascularisation [attempted dilation of at least one stenosis > or = 70% but with one or more residual stenoses > or = 70% that were not attempted] was pursued. Of these 59 patients, 18 (31%) has three vessel coronary artery disease [stenoses > or = 70% in all three major coronary artery territories] and 19 (32%) had undergone previous coronary bypass surgery. In all 59 patients, prior to angioplasty, it was attempted to identify the ischaemia producing (so-called 'culprit') lesion(s). In the 59 patients, 66 culprit lesions in 63 vessels were identified. At angioplasty, in all patients, attempted dilation was confined to the culprit lesion(s). Clinical success (successful dilation of all attempted lesions without the occurrence of in-hospital myocardial infarction, death, or coronary bypass surgery) was achieved in 53 (90%) patients. At one year following successful angioplasty, no patient had died or suffered a myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of pregnancy on disease activity in a patient with palindromic rheumatism.

A 30-year-old woman with a 12-year history of palindromic rheumatism without progression to chronic arthritis experienced pronounced reduction of arthritic symptoms during both of her 2 pregnancies with, on each occasion, symptoms recurring 3 months after delivery. This is the first reported case suggesting an ameliorating effect of pregnancy on disease activity in palindromic rheumatism.

Treatment of complicated prosthetic aortic valve endocarditis with annular abscess formation by homograft aortic root replacement.

The outcome of 30 consecutive patients with active aortic prosthetic valve endocarditis and root abscesses treated by the technique of homograft aortic root replacement with reimplantation of the coronary arteries is detailed. The principles of this technique are the removal of all abscesses and infected areas likely to drain into the infected mediastinum, excision of infected tissues down to healthy noninfected tissue and replacement with an antibiotic-impregnated homograft aortic root. All patients had evidence of progressive cardiac failure and ongoing sepsis. Mean patient age (+/- SD) at the time of operation was 42 +/- 18 years. The mean number of previous aortic valve replacements per patient was 1.6 +/- 0.7; 14 patients (47%) had undergone greater than or equal to 2 previous replacements. At operation, aortic root abscesses were found in all patients; abscess extension to adjacent structures and partial valve dehiscence had occurred in 23. In-hospital death occurred in 9 (30%) of the 30 patients. The 21 hospital survivors have been followed up for a mean of 66 +/- 42 months (range 9 to 144). Overall, 17 (81%) of the 21 hospital survivors have remained free of major adverse events (recurrence of endocarditis, need for reoperation or death). The results of our study suggest that homograft aortic root replacement should be considered favorably in the treatment of patients with aortic prosthetic valve endocarditis and root abscesses.

Differences in the stimulating capacity of immobilized anti-CD3 monoclonal antibodies: variable dependence on interleukin-1 as a helper signal for T-cell activation.

Monoclonal antibodies to the CD3 antigen on human T lymphocytes have been shown to induce accessory cell-dependent T-cell activation. One function of the accessory cells is cross-linking of CD3 by Fc receptor-binding of the anti-CD3 antibodies. Whether additional accessory signals are still required when anti-CD3 is presented in immobilized form is controversial. In the present study we stimulated purified human T cells with several anti-CD3 monoclonal antibodies, which were immobilized by coating the culture wells with goat anti-mouse IgG. A first group of immobilized anti-CD3 antibodies (anti-Leu-4, UCHT1, anti-T3, WT32 and 64.1) induced vigorous T-cell proliferation in the complete absence of monocytes, even when anti-interleukin-1 beta antiserum was added to the cultures. Other immobilized anti-CD3 antibodies (OKT3, WT31) required interleukin-1 beta in order to induce T-cell proliferation. However, when OKT3 was immobilized by direct coating of the culture wells with OKT3, it was also able to induce accessory cell-independent production of interleukin-2 and T-cell proliferation. Interleukin-1 beta further enhanced the interleukin-2-dependent proliferative response and it could provide help to induce proliferation at doses of immobilized OKT3 which, by themselves, were insufficient for full T-cell activation. We conclude that the requirement for interleukin-1 beta to induce interleukin-2-dependent proliferation of T cells when stimulated with anti-CD3 antibodies is not absolute, but depends on the CD3 epitope recognized, on the way of antibody presentation, on the antibody concentration and on other, still undefined, characteristics of the monoclonal antibodies used.

Crosslinking of the CD5 antigen on human T cells induces functional IL2 receptors.

CD5 is a 67-kDa antigen that is expressed on the membrane of the majority of human T cells, and on a subset of B cells. Previous studies have demonstrated that anti-CD5 monoclonal antibodies (mAb) can provide a helper signal for T cell activation through the TCR/CD3 complex. We now demonstrate that when CD5 is crosslinked by immobilized anti-CD5 mAb in the absence of other activating stimuli, the T cells proliferate in response to recombinant interleukin 2 (rIL2) (but not to rIL4). Four different anti-CD5 mAb (anti-Leu1, 10.2, anti-T1, and OKT1) had a similar effect. IL2 responsiveness could be induced with immobilized anti-CD5 mAb in cultures of purified T cells, but was enhanced by the addition of monocytes, by monocyte culture supernatant, or by the combination of IL1 and IL6. Staining with an anti-IL2 receptor (p55) mAb demonstrated expression of IL2 receptors on about 10% of the anti-CD5-stimulated T cells. Both virgin (CD45RA+) and memory (CD45RO+) T cells were responsive. Our data provide further evidence for the involvement of CD5 in T cell activation.

Predictive value of bronchoalveolar lavage in pulmonary sarcoidosis.

We investigated whether analysis of cellular composition (including lymphocyte subsets) in bronchoalveolar lavage (BAL) fluid at the start of follow-up in patients with untreated sarcoidosis has any predictive value for further evolution of the disease. The outcome was evaluated by the chest roentgenograms, the lung volumes, and the single breath diffusing capacity for CO (DCO) after 22 to 36 months. In contrast to the general belief, patients who improved radiologically had a significantly higher T4 cell count (as percentage of BAL lymphocytes) (p less than 0.02) and a higher T4-T8 ratio in the initial BAL sample (9.3 vs 3.2; p less than 0.05) than those whose chest roentgenogram showed deterioration or remained unchanged. Total cell count and the percentage of lymphocytes in BAL fluid were not different between both groups. The change in DCO at the end of the follow-up period correlated positively with the baseline BAL T4 cells (Rs = 0.44; p less than 0.05) and with the BAL T4-T8 ratio (Rs = 0.51; p less than 0.03) and negatively with the baseline BAL T8 cells (Rs = -0.48; p less than 0.04). In only three patients progression of the disease necessitated steroid therapy, and they all had a low to normal T4-T8 ratio in the initial BAL sample. Bronchoalveolar lavage was repeated at least once in ten patients. Improvement of the chest roentgenograms in these patients was accompanied by a decrease of the BAL T4 cell count (as percentage of lymphocytes) and of the T4-T8 ratio. We conclude that a high lymphocyte count, a high T4 cell count (as percentage of lymphocytes), and a high T4-T8 ratio in BAL fluid reflect an intense alveolitis at the time of the procedure, but they are not indicators of poor prognosis on which therapeutic decisions can be based.

IL-6 is an accessory signal in the alternative CD2-mediated pathway of T cell activation.

Recent studies have demonstrated that IL-1 and IL-6 are synergistic accessory signals for activation of T cells. In this study, highly purified human T cells were cultured with either a stimulating pair of anti-CD2 mAb or with immobilized anti-CD3 mAb. Monocytes, a cellfree monocyte culture supernatant or IL-1 were required for anti-CD2-stimulated T cell proliferation, and they each strongly enhanced anti-CD3-induced T cell growth. IL-6 was synergistic with IL-1 as a helper factor for T cell growth after activation via CD2, but we could not demonstrate any effect of IL-6 in the CD3 pathway. The mechanism of the synergistic helper activity of IL-1 and IL-6 on T cell activation in the CD2 pathway was further examined. IL-1 (but not IL-6) was required for induction of IL-2 production. Both IL-1 and IL-6 enhanced IL-2R (p55) expression and the proliferative response to IL-2. T cell proliferation after stimulation with anti-CD2 and IL-1 or IL-1/IL-6 proceeded through an autocrine IL-2-dependent pathway. Moreover we found that, in the absence of IL-1, IL-6 still supported a transient and limited proliferation of anti-CD2- (but not of anti-CD3-) stimulated T cells, which apparently was independent of the autocrine growth factors IL-2 or IL-4. Our data suggest that IL-6 is important as an accessory signal for T cell growth in the CD2 pathway of T cell activation.