Showing papers in "Clinical and Experimental Rheumatology in 1996"

A study of sixty pregnancies in patients with the antiphospholipid syndrome.

Abstract: Objective To study the maternal and fetal outcome in treated antiphospholipid syndrome (APS) pregnancies. Methods Sixty pregnancies in 47 APS patients (11 primary and 36 secondary) were followed in a multidisciplinary clinic. Patients testing antiphospholipid antibody positive and having a history of recurrent miscarriages were treated with low-dose aspirin (75 mg) daily. Patients with APS and a previous history of thrombotic events were treated with subcutaneous unfractionated or low molecular weight heparin and low-dose aspirin (75 mg) daily. Results The live birth rate increased from 19% of their previous non-treated pregnancies to 70% despite a high incidence of obstetric and fetal complications: pre-eclampsia (18%), prematurity (43%), fetal distress (50%) and intrauterine growth retardation (31%). Two predictors of fetal outcome were observed: the previous obstetric history and the presence of thrombocytopenia. Seven pregnancies (12%) were complicated by thrombotic events during pregnancy or during the puerperium. There were no thrombotic events in those receiving a low molecular weight heparin regimen. Conclusion Close obstetric monitoring by a multidisciplinary team and the use of antithrombotic therapy was effective in reducing the fetal wastage in APS pregnancies despite a high incidence of obstetric and fetal complications.

Different cytokine profiles in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthropathies.

Abstract: OBJECTIVE Cytokines play a critical role in the pathogenesis of arthritis. The aim of this study was to compare the amounts of IL-1 alpha, IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-alpha, TGF-beta 1 and IFN-gamma in the synovial fluid of 30 patients with rheumatoid arthritis (RA), 40 patients with osteoarthritis (OA) and 13 patients with seronegative spondylarthropathies (SpA). METHODS Since some samples exhibited non-specific activities, all cytokines were measured by ELISA in the presence or absence of cytokine specific neutralizing antibodies. RESULTS Our data show that these cytokines can be detected in OA, RA and SpA. Compared to patients with OA, all cytokines were found in higher levels in patients with RA and SpA. Surprisingly, higher levels of IL-4, IL-10 and TGF-beta 1 were not associated with lower cytokine levels. In contrast, higher levels of IFN-gamma were associated with elevated monokine concentrations. CONCLUSIONS Our data indicate that the immunosuppressive effects of IL-4, IL-10 and TGF-beta 1 predicted from in vitro studies may not be active in vivo. Different monokine profiles could be observed in patients with IL-4 and/or IFN-gamma, indicating that the T cells involved in these diseases may have different immunoregulatory properties.

Methotrexate in primary Sjögren's syndrome.

Abstract: Objective To determine the safety and efficacy of methotrexate (MTX) in the treatment of primary Sjogren's syndrome (SS). Methods An open, one-year pilot study of MTX (0.2 mg/kg body weight taken weekly) for the treatment of SS was performed. Seventeen patients with primary SS according to EEC criteria were enrolled in the study. Outcome was determined on the basis of clinical and laboratory parameters. Results Weekly administration of MTX resulted in improvement of the main subjective symptoms (dry mouth and eyes) as well as in the frequency of parotid gland enlargement, dry cough and purpura. However, no improvement in the objective parameters of dry eyes and dry mouth were observed. Persistent asymptomatic elevation of the hepatic transaminase levels led to a dosage reduction in 7 patients (41%). Conclusions Weekly MTX may be an acceptable form of therapy for SS patients. Double-blind trials are needed to substantiate the efficacy of this therapeutic modality.

Long-term prognosis of 69 patients with dermatomyositis or polymyositis.

Abstract: Objectives : To assess the long-term prognosis of dermatomyositis and polymyositis. Methods : 69 patients with dermatomyositis or polymyositis were selected according to the diagnostic criteria of Bohan and Peter and were followed up for a minimum of 6.3 years (for surviving patients ) (mean 11.6 years). Clinical and biological features, and pulmonary and muscle parameters were considered as prognostic factors for death. Functional disability was assessed using a 4-stage grading system. Results : 30 deaths (43.5%) occurred, mainly due to cardiovascular (8), pulmonary (8), carcinomatous (5) and iatrogenic complications (5). Survival rates were 82.6% at 1 year, 73.9% at 2, 66. 7% at 5 and 55.4% at 9. Significant prognostic factors for death (Cox model with time-dependent covariates ) were old age (p < 0.0001) dysphonia (p < 0. 001 ), pulmonary interstitial fibrosis (p < 0.02), absence of myalgia (p < 0.02), absence of dysphagia (p < 0.02) and asthenia-anorexia (p < 0.05 ). Dermatomyositis and polymyositis subgroups had slightly different significant prognostic factors for death : old age, cancer, pulmonary interstitial fibrosis and asthenia-anorexia for dermatomomyositis ; old age, failure to improve muscle strength in response to treatment after one month, and the absence of myalgia as presenting symptom for polymyositis. At the end of the follow-up, 33/39 surviving patients (84.6% ) had no or insignificant muscular disability, whereas 3 children were bedridden due to generalized calcinosis. Conclusions : High mortality occurred in the first year, and the survival rate decreased continually up to 9 years. The main prognostic factor for death is old age, but dermatomyositis and polymyositis must be considered separately. General features (pulmonary fibrosis, cancer, asthenia-anorexia) are involved in dennatomyositis, whereas muscular symptoms are the most significant in polymyositis. The long-term functional prognosis was fairly good, except for generalized calcinosis, which tended to occur in childhood dermatomyositis.

Lack of correlation among the 3 outcomes describing SLE: disease activity, damage and quality of life.

Abstract: Objective The aim of the this study was to correlate three outcome measures in patients with SLE, namely disease activity, damage, and quality of life. Methods One hundred and five SLE patients completed the Medical Outcome Survey (MOS) SF-20 during their regular clinic visit. Disease activity (SLEDAI) and damage (SLICC/ACR Damage Index) were assessed according to a standard protocol. Statistical analyses included the Pearson correlation coefficients, a logistic regression, and a linear regression analysis. Results There was no correlation between the SLEDAI and SLICC/ACR DI. There was no correlation between the SLICC/ACR DI and any of the MOS domains by Pearson correlation. Although a statistical correlation was demonstrated between the SLEDAI score and the social functioning and health perception domains of the MOS SF-20, there were not clinically important. Conclusion Thus, the three outcomes of disease activity, accumulated damage, and health status remain important independent outcome measures in the assessment of prognosis in patients with SLE.

Tumor necrosis factor-alpha (TNF-alpha) in loosening of total hip replacement (THR).

Abstract: OBJECTIVE The initially well-fixed implants of total hip replacement (THR) are in the long-term subject to aseptic loosening. Many cytokines can contribute to osteolysis due to osteoclast recruitment and/or activation. However, in this respect tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role, because it upregulates interleukin-1 and 6 and granulocyte-macrophage colony stimulating factor. The aim of this study was to assess the eventual presence, cellular localization and extent of expression of TNF-alpha in the synovial-like membrane at the implant or at the cement to bone interface compared to control synovial membrane. METHODS Twenty samples from the synovial-like membrane of the periprosthetic tissues were compared to control samples. TNF-alpha containing cells were visualized using an avidin-biotin-peroxidase complex (ABC) method and analyzed by light microscopy, double labelling and image analysis. RESULTS TNF-alpha was found in the periprosthetic tissues in fibroblasts and vascular endothelial cells, but mainly in the macrophages was it found to coincide with areas containing implant-derived debris. TNF-alpha containing cells were more numerous in the synovial-like membrane in the interface tissue from the proximal stem area (2816 +/- 318 cells) than in the control synovial membrane (565 +/- 93 cells, p < 0.01). Interestingly, similarly high TNF-alpha expression (3452 +/- 582 cells) was also seen in the synovial-like membrane of the pseudocapsule. CONCLUSION These findings suggest that the foreign body-type host reaction caused by THR is characterized by the high expression of TNF-alpha. Because such expression occurred in the interface tissue between the implant and surrounding bone, TNF-alpha, due to its pivotal direct and indirect role in the activation and recruitment of osteoclasts, may contribute to periprosthetic osteolysis and to the loosening of THR.

Shift in the incidence of rheumatoid arthritis toward elderly patients in Finland during 1975-1990.

Abstract: Objective. To obtain information on changes in the age distribution of new cases of rheumatoid arthritis (RA) in Finland. Methods. The present study covered those subjects entitled under the nationwide sickness insurance scheme to receive specially reimbursed medication for RA in 5/21 central hospital districts in Finland (population base about one million adults) in 1975, 1980, 1985, and 1990. Results. During the four study years 1321 incident cases occurred, which satisfied the American Rheumatism Association 1987 classification criteria for RA. The mean age at diagnosis increased increased by 7.6 years from 1975 (50.2 years) to 1990 (57.8 years). No appreciable differences occurred between men and women. The incidence rates declined in the younger age groups. Conclusion. The epidemiology of RA is in a dynamic state. The trends may reflect marked changes in the host-environment relationship.

Cardiac manifestations in dermato-polymyositis.

Abstract: Objective. To describe the functional and anatomic heart abnormalities of patients with dermatopolymyositis. Methods. Thirty-two consecutive patients with dermato-polymyositis (DM/PM) were studied. Patient assessments included a questionnaire for cardiac symptoms, physical examination, muscular enzymes, standard electrocardiogram (EKG), chest radiographs, spirometry, Holter monitoring and color Doppler flow (CDF) studies. Features evaluated with CDF included left ventricular diastolic dysfunction (LVDD), hyperdynamic heart, mitral valve prolapse, and endomyocardial fibrosis. Results. Twenty-five patients (78%) were female. The mean age was 43 years and the mean disease duration 6 years. Twenty-six (81%) patients had dermatomyositis. Only 2 (6%) had cardiac symptoms. Spirometry was performed in 20 patients, Holter monitoring in 23 and CDF in 26 patients. Electrical disturbances detected by either EKG or Holter were present in more than half of the patients studied. LVDD was identified in 11 patients (42%) and hyperdynamic heart in 4 (15%). None of the 26 patients studied by CDF had mitral valve prolapse. No significant differences in the frequency of cardiac abnormalities, including LVDD, were observed in relation to the diagnosis of DM or PM, the presence of Raynaud's phenomenon or calcinosis, or the disease activity status at the moment of the study. Conclusions. Subclinical heart abnormalities are frequent in patients with DM/PM. LVDD appears to be common. Our findings suggest that cardiac assessment of patients should be performed in order to detect abnormalities requiring specific therapy.

Incidence of chronic juvenile rheumatic diseases in Finland during 1980-1990.

Abstract: Objective. To study trends in the incidence of juvenile rheumatoid arthritis (JRA) and to obtain information on the incidence of other juvenile rheumatic diseases in Finland. Methods. The present study covered those subjects entitled under the nationwide sickness insurance scheme to receive specially, reimbursed medication for juvenile rheumatic diseases in 5/21 central hospital districts in Finland (population base about 270,000 children < 16 years of age) in 1980, 1985 and 1990. Results. A total of 114 incident cases (34 boys, 80 girls) satisfied the criteria for JRA during the three study years : 1980, 1985 and 1990. Seven of the patients had systemic-onset disease. The incidence of JRA remained similar (14/100,000 in the population < 16 years of age). The female :male ratio was 2.4 : 1. Only one case of juvenile spondyloarthropathy was found. Seven patients had juvenile systemic lupus erythematosus and four had juvenile dermato/polymyositis. The corresponding annual incidence rates were 0.1, 0.9 and 0.5/100,000, respectively, in this population. Conclusion. The present study provides population-based figures on the occurrence of various chronic arthritics syndromes in childhood using a unified data base. The incidence of JRA remained quite similar for the three study years. The incidence figures for systemic rheumatic and connective tissue diseases were slightly higher than those reported in previous studies.

Interferon alpha-2 (IFN alpha 2) increases lacrimal and salivary function in Sjögren's syndrome patients. Preliminary results of an open pilot trial versus OH-chloroquine.

Abstract: Objective. The effect of recombinant interferon alpha-2 (IFNα2) therapy in Sjogren's syndrome (SS) was studied. Methods. An open study was performed in which 20 SS patients were given IFNα2 3.10 6 MU/3 times/week or OH-chloroquine (OH-C) 6 mg/kg/daily, for a mean period of 11 months. Results. Gland assessment showed that lacrimal and salivary funcfion improved by 67% and 61% versus 15% and 18% respectively (p < 0.01) in the patients treated with IFNα2 compared to those treated with OH-C. Immunological parameters did not change over time in either group. In 3 patients a decrease in the tissue score was observed in the IFNα2 group, while no changes were seen in the control group. Tolerability was acceptable. Conclusion. This study shows that IFN can improve tear function and dry mouth in SS, without causing significant side effects.

Autoimmune thyroid disease in systemic lupus erythematosus and Sjögren's syndrome

Abstract: Autoimmune thyroid disease is common in patients with either systemic lupus erythematosus (SLE) or Sjogren's syndrome (SS); however, whether the risk is greater than in well matched controls is not clear. Antinuclear antibodies are found in the sera of patients with autoimmune thyroid disease, but there is no evidence of autoantibodies binding antigens characteristic of SLE or SS. Autoantibodies to thyroid antigens and overt autoimmune thyroid disease are common in patients with SLE or SS. However, in SLE patients there is little or no increased risk of autoimmune thyroid disease compared to an age and sex matched population. Patients with SS are likely to be at increased risk of thyroid disease, but those with autoimmune thyroid disease are not at special risk of SS. This difference can be explained if SS is considered to be an autoimmune epitheliitis that targets polarized epithelia, including the thyroid.

Pulse cyclophosphamide in the treatment of neuropsychiatric systemic lupus erythematosus.

Abstract: Objective The effect of pulse cyclophosphamide treatment was retrospectively assessed in 25 systemic lupus erythematosus (SLE) patients with central nervous system involvement. All patients who tested positive for anti-phospholipid antibodies and/or lupus anticoagulant were excluded. Results Low-dose intravenous cyclophosphamide pulses (500 mg) were administered weekly in all patients. Twenty-four out of 25 patients attained a good response (after a mean of 11 days). Cyclophosphamide was well tolerated in all patients with only minor side effects. None of the patients experienced ovarian failure, cystitis or herpes zoster. Conclusions Weekly low-dose cyclophosphamide pulses appear to be safe and effective for the management of neuropsychiatric manifestations in SLE patients without antiphospholipid antibodies.

Interleukin 6 : a possible marker of disease activity in adult onset Still's disease

Abstract: Objective. Adult onset Still's disease (AOSD) is an inflammatory disorder with elevated serum acute phase proteins. Interleukin-6 is a major contributor to the acute phase response. We therefore examined the serum levels of CRP, SAA and interleukin-6 in active and inactive AOSD. Results. Active patients had significantly elevated CRP, SAA, and interleukin-6 values. After steroid treatment a marked reduction was observed in all three parameters. There was a close kinetics on the fluctuations of CRP and SAA, but not on IL-6. Conclusion. Acute phase proteins and IL-6 are useful markers of disease activity in AOSD.

Dupuytren's disease in type 1 diabetic patients : a five-year prospective study

Abstract: Objective. To clarify which are the underlying factors in the development of Dupuytren's disease (DD) in diabetic patients and to evaluate if the presence of DD can predict the development of diabetic complications. Methods. A total of 207 type 1 diabetic patients [age (mean ± SD) : 29.9 ± 9.5 years] was studied at baseline. A followup study was performed five years later in 166 patients. The presence of DD was examined and the patients were assessed in terms of the following diabetic complications : background and proliferative retinopathy, peripheral symmetrical polyneuropathy, and clinical nephropathy. Results. The prevalence of DD was 4% at the baseline study. DD was significantly associated with the age of the patient and the duration of diabetes, but not with the age at the onset of diabetes, BMI or the control of diabetes. DD was associated with somatic peripheral symmetrical polyneuropathy (p < 0.01), a history of myocardial infarction (p < 0.01) and limited joint mobility (LJM) (p < 0.05), but all of these associations could be exclusively explained by the age of the diabetic patients and the duration of diabetes. DD developed in 17 new subjects (2% per year) during the five years of the study. The subjects' age and the duration of diabetes were associated with the development of DD. There was a predominance of the development of DD in women (p < 0.05), and in subjects with retinopathy (p < 0.05), nephropathy (p < 0.05), neuropathy (p < 0.05) or hypertension (p < 0.01), but these associations could also be exclusively explained by the time-related variables. The presence of DD at the baseline study did not predict the development of diabetic complications or hypertension when the confounding effects of age and the duration of diabetes were controlled by logistic regression analysis. Conclusion. This study shows that the patient's age and the duration of diabetes are the most important factors predicting the development of DD in diabetic patients. The associations between DD and diabetic complications were exclusively explained by the age and the duration of diabetes. The presence of DD did not predict the development of diabetic complications.

Low incidence of colorectal cancer in patients with rheumatoid arthritis.

Abstract: Objective Aspirin (ASA) and also nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a low incidence of colorectal cancer The incidence of colorectal cancer in a cohort of patients with rheumatoid arthritis (RA) is reported here Methods Cancer incidence was studied in a cohort of 9469 persons hospitalized for RA during 1970-1991 in Finland The follow-up time was about 65,400 person-years Results The incidence of colon cancer was significantly, lower than in the general population [standardized incidence ratio (SIR) 057 ; 95% confidence interval (CI) 033 - 093], and the combined SIR for colorectal cancer was 062 (95% CI 042 - 088), while the combined incidence of all malignancies (SIR 116 ; 95% CI 107 - 126) was higher in RA patients than in the general population Conclusion Chronic use of NSAIDs or ASA, including antiinflammatory doses, is probably the main explanation for the low incidence of colorectal cancer in RA patients

Juvenile onset of primary Sjögren's syndrome: report of 10 cases.

Abstract: Objective Ten new cases with primary Sjogren's syndrome (pSS) whose disease began before age 16 are described Special attention is paid both to the follow-up and treatment of this condition Methods Cases with juvenile pSS were retrospectively identified from our series of 180 pSS patients Ocular, salivary, and extraglandular manifestations as well as a full laboratory evaluation including HLA-DR typing were retrieved Results A disease prevalence of 55% (10 cases, 8 female and 2 male) was found in our series The mean age at onset was 110 years, but the disease started at the age of 4 in 2 patients At onset, parotid swelling was found in 6 cases and extraglandular manifestations in 3 Throughout the follow-up period (mean 486 months from the time of diagnosis), the clinical picture was similar to that of pSS in adults, but oral involvement was generally milder Extraglandular manifestations were always present but never severe Pertinent laboratory abnormalities (eg rheumatoid factor, polyclonal hypergammaglobulinemia, leukopenia, increased ESR, ANA and anti-SSA/SSB antibodies) were found in all patients Specifically, ANA and anti-SSA were always positive Moreover, in our cases histocompatibility antigens HLA-DR3 and DR 52 were closely associated with the disease Clinical outcome was difficult to predict; however, no serious complications have been observed so far We obtained good results with low-dose steroids and/or hydroxychloroquine, especially with regard to the extraglandular manifestations and laboratory abnormalities Conclusion We confirm that juvenile pSS is not a rare condition It closely resembles pSS in adults except for the extremely high prevalence of recurrent parotitis and immunological findings

Multidisciplinary approach to chronic back pain: prognostic elements of the outcome.

Abstract: Objective. This study presents an evaluation of a multidisciplinary approach to patients with chronic back pain. Methods. Sixty-seven patients with back pain of more than three months duration participated in a comprehensive 4 week program which included back schooling, psychological intervention, and treatment by acupuncture, chiropractic, the Alexander technique and a pain specialist. At admission to the study, patients were asked to complete a questionnaire concerning their socio-demographic background and disease history. Patients also underwent a psychological evaluation based on a questionnaire and an interview. On the basis of this evaluation, patients were graded on three criteria : (i) predominance of psychological factors ; (ii) secondary gain ; (iii) personality features. At the end of the treatment, patients were divided into three groups according to their degree of improvement. Patients were evaluated at the end of the four week program and after 6 months of follow up. Results. Significant improvement in the pain rating, pain frequency and analgesic drug consumption was observed in the treatment group, and was maintained for a period of 6 months. Satisfactory outcome was correlated to a moderate predominance ofpsychological factors, good functioning, a high level of motivation, and family support. Poor outcome was associated with a divorced marital status and unemployment, diffuse complaints, post surgery status, a high predominance of psychological factors, and the presence of secondary gain and personality disorders. Conclusion. Patients with chronic back pain seem to benefit from this proposed multidisciplinary approach. The improvement was maintained for a period of 6 months. Outcome was clearly related to psychosocial factors.

Local corticosteroid injections in the treatment of rotator cuff tendinitis (except for frozen shoulder and calcific tendinitis). Groupe Rhumatologique Français de l'Epaule (G.R.E.P.).

Abstract: Objective : This review discusses the efficacy of local corticosteroid injections in the treatment of rotator cuff tendinitis (except for frozen shoulder and calcific tendinitis) according to the controlled studies published in the literature Study selection : All controlled studies (13) published between 1955 and 1993 have been included in this review However, this work is not a metaanalysis because these studies are not comparable Data synthesis : Several studies are open to criticism Local corticosteroid injections seem to be more effective than placebo and oral non-steroidal antiinflammatory drugs, especially for pain Several questions remain unanswered : the true position of this treatment in the therapeutic strategy of rotator cuff tendinitis, the long term efficacy, and deleterious effects of local corticosteroid injections and the optimal technique and number of injections Conclusion : Local corticosteroid injections seem to be effective in the treatment of rotator cuff tendinitis However, a controlled study more closely reflecting clinical practice is needed to confirm these data

Immunoglobulins and the regulation of autoimmunity through the immune network.

Abstract: Beneficial effects of the administration of intravenous immunoglobulins (IVIg) have now been reported in a large number of autoimmune diseases, whether mediated by autoantibodies or by autoaggressive T cells. We have proposed that the immunoregulatory effect of IVIg in autoimmune disease is dependent on the selection of the recipient's immune repertoires by the variable (V) region reactivities of infused immunoglobulins. Thus IVIg contains antibodies reactive with idiotypes of natural and disease-related autoantibodies and surface immunoglobulins of B cells; IVIg also contains antibodies reactive with the idiotype, framework and constant regions of the beta chain of the alpha beta T cell receptor. Infusion of IVIg results in transient or long lasting suppression of specific autoantibody clones in vivo and in stimulation of a distinct subset of B cells reactive with the F(ab')2 fragments of IVIg Infusion of IVIg alters the general "architecture" of the network as assessed by studying the kinetic patterns of spontaneous fluctuations of natural autoantibodies in serum. Infusion of normal mouse Ig in healthy adult mice selects expressed immune repertoire by removing late pre-B and B cells in the bone marrow, mostly those expressing D proximal Vh genes, and by activating distinct subsets of B cells and CD4+ T cells in the spleen. Although dependent on the V region reactivities (composition) or injected preparations, these effects probably also require that the infused immunoglobulin contains an intact Fc moiety. If one considers the effect of IVIg on the structure, function and dynamics of the immune network IVIg may be viewed as a substitutive therapy for the quantitative/qualitative defects in network regulation that are associated with autoimmune diseases.

Immunomodulatory effect of immunoglobulins.

Abstract: IVIG is clearly indicated as the treatment of choice on the basis of large clinical trials in a number of inflammatory and autoimmune diseases, e.g. Kawasaki disease, ITP, Guillain-Barre syndrome, etc. According to in vitro studies various mechanisms have been identified whereby IgG could modify immunologically mediated and inflammatory diseases. Fc-receptor blockade as well as true down-modulation of Fc-receptors, acting as a sump for activated complement components, have been demonstrated at the cellular level and in experimental animals. The possibility of interfering with the idiotype network has been discussed in connection with autoimmune diseases. Down-regulation of inflammatory cytokines as well as an increase in the production and release of IL-1 receptor antagonist appears to be of importance in inflammatory processes. Clinical studies have proven the efficacy of IVIG. Basic research has demonstrated its possible mechanisms of action ; however, the question of exactly which mechanisms are responsible for the clinical efficacy in certain diseases still awaits clarification.

Incidence of anti Hsp 90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis.

Abstract: Objective. To determine the incidence of anti-hsp90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis. Methods. We utilised a previously described ELISA to detect the presence of antibodies to mammalian hsp90 and 70 in 33 children with SLE, 55 with juvenile chronic arthritis (JCA) and 11 with dermatomyositis. Sera from 19 children with non-autoimmune conditions served as controls. Results. Antibodies reactive with hsp90 and/or 70 were detected in 35% of the children with SLE, and the numbers of children with SLE who have raised IgG anti-hsp90 antibodies (24%) is very similar to our adult onset cases, although the prevalence of IgM antibodies is much smaller. However, serum antibodies to hsp70 were as infrequent in children with SLE or JCA as in adults with SLE or RA, although IgG antibodies to hsp70 were detected in 50% of the synovial fluid of JCA patients. Conclusion. The incidence of antibodies to hsp90 in childhood-onset SLE resembles that described in adult onset disease suggesting that, despite clinical differences between the two, a subset of each may share a similar pathological mechanism of disease.

Glucocorticoid-induced osteoporosis: pathogenesis, prevention and treatment.

Abstract: Glucocorticoids (GC) are widely used for anti-inflammatory and immunossupressive therapy. Thirty to 50% of GC-treated patients develop osteoporosis. Potential mechanisms of GC-induced osteoporosis (GC-OP) include abnormalities in calcium balance, vitamin D metabolism, parathyroid hormone release and activity, prostaglandin E 2 and cytokine synthesis, interference with c-fos and p-53 expression in osteoblasts, and hypogonadism. Early diagnosis and detection of patients at risk are accomplished with rapid, safe and non-invasive bone density measurements. Preventive measures include maintaining a positive calcium balance, vitamin D supplementation (if indicated) and treatment of hypogonadism. The shortest duration and the smallest doses possible of GC for a particular condition are advisable. For high-risk patients and those with established GC-OP calcitonin or bisphosphonate therapy is recommended.

Juvenile Behçet's disease in Arab children.

Abstract: Behcet's disease is a chronic, relapsing, multisystem disease characterized by the clinical triad of genital ulcers, oral ulcers and ocular involvement. Twelve Saudi children are presented, all of whom satisfied the international criteria for the classification of Behcet's disease and whose initial manifestations appeared at or before the age of 16 years. The male-to-female ratio was 1.4:1. The mean age at onset was 11.5 years (range 7-16 years) and the mean duration of disease was 6.5 years (range 3-13 years). Oral ulcers were present in all patients (100%), genital ulcers in 11 patients (91%), ocular involvement in the form of anterior and/or posterior uveitis in 6 patients (50%), skin manifestations in 10 patients (83%), musculoskeletal symptoms in 9 patients (75%), and central nervous system involvement in 6 patients (50%). One patient had thrombophlebitis and another had pulmonary artery aneurysm. No renal, cardiovascular or gastrointestinal abnormalities were detected. The pathergy test was positive in 3/7 patients. HLA B5 (W51) typing was positive in 5/10 patients. This report of juvenile Behcet's disease in Saudi children suggests that this multisystem disease has an aggressive nature and should be considered in the differential diagnosis of childhood vasculitis in endemic areas.

Virus validation studies of immunoglobulin preparations.

Abstract: Objective. A validation study of the viral safety of a new polyvalent intravenous immunoglobulin (OCTA GAM) according to EU-guideline III/8115/89-EN and the requirements of the Federal Agency for Sera and Vaccines in Germany was undertaken in May 1994. The following processing steps were analyzed. Cohn-Oncley fractionation, solvent/detergent (SD) treatment, pH 4 exposure, storage of the final product at low pH and immune neutralisation. Methods. The following virus reduction factors were obtained : Cohn-Oncley fractionation : HIV-1 >5.50 ; sindbis virus >6.36 ; pseudorabies virus >7.28 ; coxsackievirus-B6 2.70 ; poliovirus-1 >3.80 ; SV40 >5.51. Solvent/Detergent treatment : HIV-1 >6.03 ; sindbis virus >7.80 ; pseudorabies virus >8.38. pH 4 exposure : HIV-1 >8.60 ; sindbis virus >8.94 ; pseudorabies virus >5.95 ; coxsackievirus-B6 2.72 ; SV40 1.15. Immune neutralisation : coxsackievirus-B6 >4.98, polio-virus-1 >5.14, HA V >3.44, HSV-1 >5.92. The following virus reduction factors were calculated for the final product : HIV-1 >20.13 ; sindbis virus >23.10 ; pseudorabies virus >21.61 ; coxsackievirus-B6 >10.4 ; poliovirus-1 : >8.94 ; HAV >3.44 ; SV40 >6.66. Conclusion. The results of our validation studies demonstrated that in addition to Cohn fractionation and immune neutralization, the two additional steps of solvent/detergent treatment and pH 4 exposure, mainly contribute to the safety of OCTAGAM with respect to both enveloped and non-enveloped viruses.

Cellular and molecular bases of B-cell clonal expansions.

Abstract: The concept that lymphomagenesis is a multistep process is now widely accepted. Various factors are involved in the development and malignant progression of B-cell lymphoproliferative disorders. The most frequently recognized alterations in these disorders are chromosomal translocations which lead to the activation of proto-oncogenes (c-myc) or genes encoding for proteins involved in the control of the cell cycle (cyclin D1), differentiation (bcl-6) and apoptosis (bcl-2). In addition, genetic changes that inactivate tumor suppressor genes (p53, Rb, p16) have recently been identified. Infectious agents may also play a role in lymphomagenesis either by directly driving B-cell proliferation (EBV) or by inducing a chronic antigenic stimulation (EBV, HCV, HBV, helicobacter pylori). Finally, several data indicate that local cytokine networks and, in particular, autocrine (IL-6, IL-10) and/or paracrine (IL-2, IL-4, IL-6) loops probably play a contributory role in the development and evolution of B-cell lymphoproliferation. In the last few years, the advent of molecular biology techniques has allowed important advances in the definition of the events involved i the earlier phases of lymphoma development. This has been made possible, in particular, by the study of a series of oligoclonal or monoclonal lymphoproliferative disorders characterized by an indolent or "smoldering" clinical course, such as follicular lymphoma and the lymphoproliferation associated with autoimmune diseases, which are at high risk of evolution to a highly malignant lymphoma. In nearly all of these conditions, the clonal B-cells responsible for the early stages of the disease are probably not fully transformed and retain various degrees of responsiveness to a wide variety of microenvironmental stimuli (antigen or autoantigen stimulation, interactions with "reactive" T lymphocytes, local cytokine networks). These latter in turn may induce the regression of pathological lesions, maintain the disease in an active state or contribute to the evolution towards an overtly malignant lymphoma. These findings open new avenues for the design of unconventional strategies of intervention aimed at preventing the malignant evolution of pre-lymphomatous lesions and controlling the clinical course of certain low-grade B-cell lymphomas.

Glycosaminoglycans in autoimmunity.

Abstract: Alteration of the distribution pattern and composition of glycosaminoglycans (GAG) and proteoglycans may play an important role in the development of autoimmune diseases. Recent experiments indicate that anti-DNA antibodies cross-reacting with hyaluronic acid, heparan sulphate and chondroitin sulphate are present in patients with systemic lupus erythematosus. Furthermore, elevated hyaluronic acid antibody levels correlating with the disease score have been found in the sera of patients with autoimmune thyroid disease in comparison to controls. In vitro, T lymphocytes from patients with this disease increased the production of hyaluronic acid by cultured human retroorbital fibroblasts. Fibroblast stimulation, as well as elevated collagen and GAG production, could be shown in chicken cell lines which spontaneously develop an autoimmune syndrome analogous to human scleroderma. To analyse the structure and distribution pattern of different GAG compounds in the tissues and body fluids of patients with autoimmune diseases a highly specific HPLC method was developed, which revealed increased urinary chondroitin sulphate and dermatan sulphate concentrations in patients with autoimmune thyroid disease in comparison to controls, concentrations which were positively correlated with disease severity and disease activity. Furthermore, the renal GAG excretion in patients with autoimmune diabetes mellitus was studied, and markedly higher excretion in patients compared to healthy controls was found, which was correlated with the duration of the disease and diabetic late complications. Thus, GAG polysaccharides not only appear to play a major role in the pathogenesis of autoimmune diseases, but have been successfully introduced as an activity marker of the disease

International survey on the management of patients with SLE. I. General data on the participating centers and the results of a questionnaire regarding mucocutaneous involvement

Abstract: Objective The diagnosis and treatment of the mucocutaneous (MC), neuropsychiatric (NP), and renal (RN) manifestations of systemic lupus erythematosus (SLE) remain unsolved issues. To shed light on these issues, a questionnaire was prepared and sent to 153 lupus centres around the world, in order to determine the level of agreement between experts in their approach to these complex aspects of the disease. Methods The first section of the questionnaire was designed to collect information on the characteristics of the responding lupus centres. The second section was dedicated to MC manifestations, with questions focusing on: (i) the frequency of MC manifestations as a whole and of the single clinical MC entities; (ii) clinical features, outcome and therapy of subacute cutaneous lupus erythematosus (SCLE); (iii) the utility of the lupus band test (LBT); and (iv) the use of various therapeutic protocols to treat MC manifestations. Results Sixty-one questionnaires from 19 countries were analysed. Out of these, 37 were completed by Departments of Rheumatology, 21 by Departments of Internal Medicine or Clinical Immunology, and 3 by Departments of Nephrology. About 66% of these centres stated that they were currently following more than 100 lupus cases, 95% had an in-patient ward and 82% had their own laboratory. The American College of Rheumatology classification criteria and various scales for disease activity assessment were regularly used by 87% and 57% of centres respectively. The overall prevalence of MC manifestations was judged to be over 30% by 82% of the respondents (Rs), and over 60% by 36% of the Rs. Among the different MC manifestations, malar rash was reported to be the most frequent (40%), followed by alopecia (24.1%) and oral ulcers (18.6%). In reporting the prevalence of each MC manifestation, the Rs showed a low level of agreement, the coefficient of variation (CV) being > 0.75 for all of the manifestations listed with the exception of malar rash (CV = 0.54). Poor agreement among centers was also found for the reported association of various MC manifestations with SCLE (15 different answers), and on the prognostic factors for SCLE (17 different answers). There was agreement on the best procedure (up to 70% of the Rs preferred a non-UV exposed skin area) and on the utility of the LBT (83% using it only for diagnostic purpose). Hydroxychloroquine was the most popular therapeutic protocol, being used by 85% of the Rs for a wide variety of MC manifestations. Among other therapies, azathioprine was used by 59%, dapsone by 41%, and thalidomide by 35% of the Rs, all to treat a wide spectrum of MC manifestations. Pulse steroid, cyclosporin A and pulse cyclophosphamide were less commonly employed (by 27%, 22% and 13% of the Rs, respectively), and were reserved for the most severe MC manifestations, particularly vasculitis. Conclusion The present survey indicates that, although most of the participating centres had extensive experience in the management of SLE, their approach to the MC manifestations was not homogeneous, and collaborative studies are clearly needed, particularly to optimise the therapeutic protocols.

In vitro effects of methotrexate on polyamine levels in lymphocytes from rheumatoid arthritis patients.

Abstract: Objective : Several studies have documented increased levels of polyamines in rheumatoid arthritis (RA). We have suggested that one of the mechanisms of action of methotrexate (MTX) involves the inhibition of polyamine synthesis in lymphocytes. In this study, we sought to establish the inhibitory effect of MTX on polyamine synthesis and its specificity. Methods : Polyamine levels were determined in stimulated RA lymphocytes incubated in vitro with MTX and compared to levels in lymphocytes incubated with hydrocortisone, D-penicillamine, or medium alone. Lymphocyte polyamine levels were correlated with IgM-rheumatoid factor (RF) synthesis. Results : Incubation with MTX resulted in concentration-dependent decreased intracellular levels of spermidine and spermine, while putrescine levels were not affected. Addition of folinic acid or S-adenosyl-methionine (SAM) prevented this MTX-induced inhibition. Incubation with D-penicillamine or hydrocortisone had no significant effect on polyamine levels. There was a positive correlation between intracellular polyamine levels and the inhibition of IgM-RF synthesis by MTX. Conclusion : These data suggest that MTX inhibits the synthesis of spermidine and spermine in stimulated RA lymphocytes through inhibition of the SAM-dependent pathway. This inhibition may be related to the immune-modulating properties of MTX.

Parvovirus B19 infection in Behçet's disease.

Abstract: Objective. To investigate whether parvovirus B19 infection is associated with Behcet's disease (BD). Methods. Serum samples from 41 patients with BD and from 40 age- and sex-matched controls were studied. An ELISA assay was used to detect antibodies against parvovirus B19. Results. Six patients with BD (15.7%) had anti-B19 IgM antibodies in their serum samples indicating a recent infection, while no positivity for IgM antibodies was detected in the control group (p = 0.03). Conclusion. Although there have been several reports of B19 infection associated with vasculitis, our findings do not strongly support the involvement of B19 in the pathogenesis of BD. The serological evidence of acute infection in 6 BD patients may be purely coincidental. There was also no positive correlation with the articular and vascular manifestations of BD.

Lipoproteins, anticardiolipin antibodies and thrombotic events in rheumatoid arthritis

Abstract: Objective To investigate lipoprotein levels in rheumatoid arthritis (RA) patients with and without anticardiolipin antibody (aCL) positivity and to evaluate whether an abnormal lipid profile might be associated with an altered risk of vascular disorders. Methods 137 female patients were evaluated for their aCL levels (isotypes IgG and IgM); concentrations of plasma lipids, lipoproteins, and apolipoproteins; and for the occurrence of thrombotic events. The patients were grouped according to their aCL positivity. Results Higher rates of venous and/or arterial thrombosis were diagnosed in all the RA patients compared to the controls (p = 0.01). Lower levels of the high density lipoprotein cholesterol, apolipoprotein AI, were found in these patients (p = 0.001). Higher levels of lipoprotein (a) were observed in RA patients when compared to controls in both aCL positive and negative RA patients (P = 0.001 and p = 0.01, respectively). Conclusion The presence of aCL and an altered lipid profile may represent an important risk factor for thrombotic events in patients affected by RA.