Search

Sjogren’s syndrome is a chronic autoimmune disorder, characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. The syndrome can present either alone (primary Sjogren’s syndrome) or in the context of an underlying connective tissue disease (secondary Sjogren’s syndrome). Systemic features, resulting from cutaneous, respiratory, renal, hepatic, neurologic, and vascular involvement, often occur. Two types of primary Sjogren’s syndrome are currently recognized: a benign disease that affects quality of life, and a systemic syndrome associated with increased morbidity and mortality owing to a high risk of malignant transformation, and that requires close follow-up. Ocular involvement, manifested as keratoconjunctivitis sicca, is managed with local and systemic stimulators of tear secretion and supportive surgical procedures. Treatment of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes, and local and systematic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline, are helpful in patients with residual salivary function, and ciclosporin ocular drops seem to be of some benefit. Systemic immunosuppressives are reserved for treatment of severe extraglandular manifestations of Sjogren’s syndrome. Anti-B-cell therapy is a new potential therapy for the glandular and extraglandular manifestations, such as glomerulonephritis or vasculitis, in addition to the management of lymphoma associated with Sjogren’s syndrome. Induction of oral tolerance and gene-transfer modalities were recently attempted in animal models, with promising results.

Contains fulltext : 35996.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To assess the clinical implications of autoantibodies directed against different parts of the Mi-2 beta autoantigen in patients with myositis. METHODS: A systematic assessment of the clinical, laboratory, and histological characteristics of 48 anti-Mi-2 positive patients from six European centres was made. Anti-Mi-2 autoantibodies were determined with an ELISA using four overlapping fragments spanning the entire amino acid sequence of the autoantigen. Data were compared with results for a large group of anti-Mi-2 negative patients with myositis published previously. RESULTS: Anti-Mi-2 autoantibodies were found in dermatomyositis, polymyositis, and inclusion body myositis. In general, myositis with anti-Mi-2 autoantibodies was characterised by relatively mild disease, sometimes accompanied by extra-muscular symptoms, including arthralgia, arthritis, Raynaud's phenomenon, and interstitial lung disease. Cardiac disease was not seen, and treatment response was fair. No differences were found between patients with autoantibodies to different fragments of the Mi-2 beta antigen, except for a potentially increased risk of cancer in patients with antibodies directed to the N-terminal fragment of the autoantigen. CONCLUSIONS: Anti-Mi-2 autoantibodies are not a marker of a specific subtype of myositis. No significant differences between patients with autoantibodies to different fragments of the Mi-2 beta autoantigen are found, with the possible exception of an increased risk of cancer in patients with antibodies to the N-terminal fragment.

Sjogren’s syndrome (SS) is a chronic autoimmune disease affecting epithelial tissues. Exocrine glands are the primary target and their functional impairment comes as a result of immune attack of epithelial cells of the affected organs (autoimmune epithelitis). In this interplay, the role of the epithelial cell is pivotal. Extensive data point to an intrinsically activated status. Moreover, the epithelial cells possess all the features needed in order to act as non-professional antigen presenting cells. Through apoptosis and exosomes release endocellular antigens contributing to tolerance breakdown. In addition, produce cytokines and chemokines that recruit lymphocytes in the immunopathogenic lesion. Herein, we review all the aforementioned aspects of the epithelial activity that lead to the perpetuation of the lesion as well as the probable viral factors for the intrinsic activation. Finally, we propose a model for SS pathogenesis that integrates the knowledge accumulated during the last decade.

Sjogren’s syndrome (SS) is an autoimmune disorder, the principal ocular manifestation of which is decreased tear production leading to chronic irritation and damage to the corneal and conjunctival epithelium. The most important advance in the treatment of ocular manifestations of SS is the introduction of topical anti-inflammatory agents such as cyclosporine A, which increases tear production and decreases symptoms without any significant side effect. Stimulators of tear secretion, both topical, such as diquafosol, and systemic, such as pilocarpine and cevimeline, are also effective, although they have been associated with frequent side effects. Topical use of autologous serum is another new and effective form of treatment, but problems in the preparations prevent their widespread use. Additionally, nonpharmacologic treatments, such as insertion of punctal plugs, are beneficial in the dry eye of SS, whereas several other modalities, such as anti-CD4 monoclonal antibody eye drops and gene transfer, are still in experimental phases.

Purpose: Studies on mortality associated with systemic sclerosis have been limited by small sample sizes. We aimed to obtain large-scale evidence on survival outcomes and predictors for this disease. Methods: We performed a meta-analysis of individual patient data from cohorts recruited from seven medical centers in the United States, Europe, and Japan, using standardized definitions for disease subtype and organ system involvement. ne primary outcome was all- cause mortality. Standardized mortality ratios and predictors of mortality were estimated. The main analysis was based only on patients enrolled at each center within 6 months of diagnosis (incident cases). Results: Among 1645 incident cases, 578 deaths occurred over 11,521 person-years of follow-up. mortality ratios varied by cohort.(1.5 to 7.2). In multivariate analyses that adjusted for age and Standardized m sex, renal (hazard ratio [HR] = 1.9; 95% confidence interval [CI]: 1.4 to 2.5), cardiac (HR = 2.8; 95% CI: 2.1 to 3.8), and pulmonary (HR = 1.6; 95% CI: 1.3 to 2.2) involvement, and anti-topoisomerase I antibodies (HR = 1.3; 95% CI: 1.0 to 1.6), increased mortality risk. Renal, cardiac, and pulmonary involvement tended to occur together (P < 0.001). For patients without adverse predictors for 3 years after enrollment, the subsequent risk of death was not significantly different from that for the general population in three cohorts, but was significantly increased in three cohorts that comprised mostly referred patients. Analysis that included all cases in each center (n = 3311; total follow-up: 19,990 person-years) yielded larsel similar results. Conclusion: Systemic sclerosis confers a high mortality risk. but there is considerable heterogeneity across settings. Internal organ involvement and anti-topoisomerase I antibodies are important determinants of mortality. 0 2005 Elsevier Inc. All rights reserved.

Objective. Autoreactive B cells play a key role in tissue injury in systemic autoimmune disease, and therefore a treatment resulting in B cell depletion could have benefit. This open-label study was undertaken to evaluate the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of lupus nephritis. Methods. Lupus patients with active proliferative nephritis (4 with focal disease and 6 with diffuse disease) received rituximab (4 weekly infusions of 375 mg/m(2)) combined with oral prednisolone. Clinical, laboratory, and immunologic responses, including peripheral lymphocyte subsets measured by flow cytometry, were prospectively assessed at monthly intervals for 12 months. Complete remission of nephritis was defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24-hour urinary protein 50% improvement in all renal parameters that were abnormal at baseline. Results. B cell depletion lasted from I month to 7 months and was well tolerated. Partial remission was achieved in 8 of 10 patients within a median of 2 months (range 1-4 months); in 5 of them, complete remission was subsequently established (at a median of 3 months from baseline), and it was sustained at 12 months in 4.As early as I month from baseline, the expression of the costimulatory molecule CD40 ligand on CD4+ T cells was decreased by 4-fold, and it was almost blocked when partial remission was clinically evident. The expression of T cell activation markers CD69 and HLA-DR was significantly decreased at time points when partial remission was observed, and was further decreased during complete remission. In contrast, in patients who did not exhibit a response or when relapse was detected in patients in whom an initial remission had been achieved, such decreases were not prominent. Serum concentrations of double-stranded DNA autoantibodies were decreased in all patients, regardless of clinical outcome. Conclusion. Following B cell depletion, clinical remission of lupus nephritis is associated with a decrease in T helper cell activation, suggesting an additional role for B cells, independent of autoantibody production, in promoting disease. A controlled trial to confirm these promising clinical results is warranted.

Sjogren’s syndrome (SS), is a chronic autoimmune disorder, characterized by lymphocytic infiltration and destruction of the exocrine glands (mainly the salivary and the lacrimal glands) resulting in dry mouth and eyes. The symptoms of SS are chronic and sometimes devastating, compromising the quality of life at a major extent. Although SS is considered a classical autoimmune disorder, evidence for the use of immunosuppressive agents, the mainstay of therapy of diseases of autoimmune origin, is scarce. Cholinergic agents, such as pilocarpine and cevimeline are the cornerstone of current therapy of SS, while oral interferon and ciclosporine ocular drops seem to be of some benefit. In contrast, other immunosuppressive substances, such as methotrexate, azathioprine or anti-TNF agents, did not alleviate the sicca features associated with the disease. Corticosteroids, cyclophosphamide and nucleoside analogues are reserved for life threatening severe extraglandular manifestations of SS.

Exocrine gland epithelial cells are the target of autoimmune pathology in primary Sjogren’s syndrome (pSS). Their activated phenotype has incited the notion that they are infected by a virus. We recently presented evidence that coxsackieviruses may persistently infect the salivary glands of pSS patients. We hypothesize that coxsackieviruses may play a permissive role for the perpetuation and possibly the induction of autoimmune disease in pSS.

Sjogren syndrome (SS) is a common autoimmume disease evidenced by broad organ-specific and systemic manifestations, the most prevalent being diminished lacrimal and salivary gland function, xerostomia, keratoconjunctivitis sicca, and parotid gland enlargement. Primary SS presents alone, and secondary SS occurs in connection with autoimmune rheumatic diseases. In addition, symptoms do not always present concurrently. This diversity of symptomatic expression adds to the difficulty in initial diagnosis. Armed with the recently refined criteria for diagnosis, specialists, such as rheumatologists, primary care physicians, ophthalmologists, and dentists, who would otherwise focus only on those symptoms that encompass their areas of expertise, can get a comprehensive image of the presenting patient, leading to earlier identification and treatment of SS.

Osteonecrosis is a disease in which death of cellular elements of bone occurs as a result of diminished arterial blood supply. The pathogenetic mechanisms of osteonecrosis remain unresolved. Extravascular pressure and subsequent tamponade of the arterial vessels or an intravascular thrombosis have been suggested. Immunologic factors may also play an important role. In autoimmune disorders, small vessel vasculitis or other disease-associated features, as well as antiphospholipid antibodies, have been involved in the development of osteonecrosis.

Objective. Primary Sjogren’s syndrome (SS) is an autoimmune disease characterized by activation of minor salivary gland (MSG) epithelial cells and B and T lymphocytic infiltrates. These findings have long encouraged the hypothesis that a persistent viral infection of the MSG epithelial cells may drive the autoimmune response; however, the identity of that virus has remained elusive. The aim of this study was to test this hypothesis. Methods. We applied the differential display protocol to MSG RNA samples from patients with primary SS and healthy controls. We then used seminested reverse transcriptase-polymerase chain reaction to amplify the 5’-noncoding region (5’-NCR) of the enteroviral genome in 8 patients with primary SS, 9 patients with secondary SS, and 8 control subjects. Immunohistochemistry was performed to study the expression of the VP1 enteroviral capsid protein in MSG biopsy samples from 12 patients with primary SS, 8 patients with secondary SS, and 16 controls. Results. Differential display analysis yielded a 94-bp fragment of coxsackievirus B4 (CVB4) P2A gene in the primary SS samples. The 5’-NCR was amplified in 7 samples from patients with primary SS and in no samples from patients with secondary SS or controls. The 7 amplified products were sequenced; 4 of the sequences were found to be 98-99% identical to the 5’-NCR of CVB4, and 3 were found to be 97-98% identical to the 5’-NCR of CVA13. Immunohistochemistry for the enteroviral capsid protein VP1 revealed positive staining in epithelial cells and lymphocytic infiltrates in 11 primary SS samples, 1 secondary SS sample, and no control samples. Conclusion. We provide evidence that primary SS may be associated with coxsackievirus infection of the MSG epithelial cells and focal lymphocytic infiltrates. Our findings are formulated in a hypothesis concerning the possible role of coxsackieviruses in the induction and maintenance of autoimmunity in primary SS.

Background: The MEFV gene is responsible for familial Mediterranean fever (FMF). Several disease associated mutations have been identified. The range of genetic variation in MEFV in Greek patients has not been determined. Objective: To describe a method that facilitates the routine screening of the entire coding sequence of MEFV ( excluding exon 1). Methods: The non-isotopic RNase cleavage assay (NIRCA) was optimised and used as a first step screening method to screen exons 2 to 10 of MEFV. Exons 2 and 10 were analysed separately at DNA level, while exons 3 to 9 were analysed together at cDNA level. The sample group consisted of 26 FMF patients diagnosed using established clinical criteria, six asymptomatic relatives, 12 patients with atypical clinical manifestations, nine patients suffering from various inflammatory diseases, and three normal individuals. All were analysed by NIRCA for mutations in the MEFV gene and direct sequencing was applied subsequently to confirm the results. Results: MEFV mutations were identified in 25 of 26 typical FMF patients and in two of 12 patients with atypical manifestations. NIRCA results were in concordance with sequencing findings in all sequences analysed, suggesting that the method is highly reliable in this disease. Sixteen alterations of MEFV were identified ( eight missense mutations and eight single nucleotide polymorphisms). Conclusions: NIRCA can be used for rapid screening of the coding sequence of the MEFV gene in patients suspected of suffering from FMF.

A hallmark of autoimmune diseases is the production of autoantibodies against intracellular autoantigens. Although their pathogenetic and their etiologic relationship are not fully understood, these autoantibodies are important tools for establishing the diagnosis, classification and prognosis of autoimmune diseases. Systemic rheumatic diseases are among the most complex disorders because their clinical presentation and constellation of findings are in part reflected by the wide spectrum of autoantibodies found in the sera of patients suffering from these disorders. These autoantibodies usually target large complexes consisting of protein antigens noncovalently associated with (ribo)-nucleic acid(s), like the spliceosome or Ro/La-RNPs. In this review, we first address the main characteristics and the clinical value of several autoantibodies, with respect to their diagnostic sensitivity and specificity. Subsequently, we provide a brief overview of the antigenic determinant types that have been identified on the corresponding autoantigens. The antibody targets of autontigens include primary, secondary, tertiary and quarternary structure epitopes, as well as cryptotopes, neoepitopes and mimotopes. We next focus on antigenic structures corresponding to B-cell epitopes with high disease specificity and sensitivity for all the major autoantigens in systemic autoimmunity including the Ro/La and U1 ribonucleoprotein complexes and the Ku70/80, ribosomal P, DNA topoisomerase 1, filaggrin, Jo-1 and PM/SCl-100 autoantigens. These epitopes, defined at the peptide level, can be chemically synthesized and engineered for the development of new inexpensive and easier to perform assays and the improvement of the methods for autoantibody detection. Specific examples of newly developed assays that incorporate (i) epitopes with high disease specificity and sensitivity, (ii) modified epitopes, (iii) conformational epitopes and (iv) complementary epitopes are discussed in detail. Finally, we examine the potential of combining these synthetic epitopes for future development of multiplex diagnostic tests based on miniaturized autoantigen arrays. (C) 2003 Elsevier B.V. All rights reserved.

Objective. To determine the clinical aspects and evolution of autoimmune inflammatory manifestations (AIMs) in patients with myelodysplastic syndrome (MDS) and ascertain the prognostic implications of these manifestations in MDS. Methods. Seventy patients diagnosed for MDS were enrolled in a prospective cohort study of 4-yr duration. Thirteen patients with AIMs were identified (group A). The remaining 57 MDS patients without AIMs constituted the control group (group B). Demographic, clinical features, laboratory data, treatment and outcome of all these cases were recorded. Results. On comparing features between the two groups we were unable to identify any particular difference (P greater than or equal to 0.05) concerning bone marrow blast count [odds ratio (OR) = 0.68], international prognostic scoring system (IPSS) (OR = 1.36), favourable cytogenetic abnormalities (OR = 0.52), leukaemic transformation (OR = 1.30) and survival (P = 0.76). Furthermore there was a significant difference in survival between low vs non-low IPSS patients for both groups (P < 0.01). Conclusion. In a 4-yr prospective study the prognosis of MDS patients with AIMs appeared to be closely related to the IPSS subcategory of the underlying haematological malignancy and not to the autoimmune process.

Objective. To evaluate the safety and efficacy of mycophenolate mofetil (MMF) treatment in patients with lupus nephritis. Methods. Eighteen patients with biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean duration of nephritis 57 months; nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis, six with membranous nephropathy) were included. With five exceptions, all patients had been treated previously with cyclophosphamide and were selected because of either toxicity or inadequate clinical response to treatment. MMF was given at 2 g daily in combination with steroids for up to 31months (mean 15.3 months). The side-effects of MMF were recorded and efficacy was assessed as the renal function profile. Results. Complete remission was observed in 10/18 patients and another 4/18 went into partial remission. Both creatinine clearance and proteinuria were significantly improved during MMF treatment in patients with the proliferative forms of nephritis. MMF demonstrated a steroid-sparing effect in the whole population. Treatment failure was recorded in 4/18 patients, all with membranous nephropathy. Two patients developed gastrointestinal complaints and infectious meningitis occurred in one patient. Conclusion. MMF appears to be an efficacious and safe treatment in patients with proliferative forms of lupus nephritis who do not respond to or cannot tolerate conventional treatment. The efficacy of MMF in lupus membranous nephropathy remains unclear.

Objective: To search for pyrin mutations associated with familial Mediterranean fever (FMF) in Greece. Patients and methods: 62 patients fulfilling the Tel Hashomer diagnostic criteria for definite (33) or probable (29) FMF diagnosis were studied. Eight point mutations of pyrin gene were tested by standard methods. Of the 62 patients tested, 48 were Greek, four were Jewish, seven were Armenian, and three were Arab. Results: 42 patients were found to be homozygotes for pyrin mutations; 11 patients were found to carry only one of the tested mutations; in nine patients no mutations were detected. Conclusion: Molecular detection of pyrin gene mutations seems useful in confirming suspected cases, and in detecting asymptomatic cases, of Mediterranean fever in Greece. It may also be used as a screening tool within affected families.

Background: Pauci-immune necrotizing glomerulonephritis (PING) occurs in various settings and has a very variable prognosis. We investigated whether clinicopathologic findings at the time of renal biopsy may predict major disease outcomes. Methods: We evaluated 72 consecutive patients with biopsy-documented PING. Kaplan-Meier curves and Cox models assessed event rates and risk factors for death, end-stage renal disease (ESRD), and death or new ESRD (after the renal biopsy). Results: During a follow-up of 305 person-years, 11 patients died, 13 patients developed ESRD, and 16 patients died or developed new ESRD. Among patients first seen within 3 months of renal biopsy (incident cases), the 5-year mortality rate was 20%, whereas the death or new ESRD rate was 34%. In univariate analyses, older age, lower creatinine clearance, erythrocyte sedimentation rate, and percentages of abnormal glomeruli, glomeruli with fibrous crescents, and glomeruli with global sclerosis were significant predictors of mortality, whereas antineutrophil cytoplasmic autoantibodies with cytoplasmic staining conferred borderline protection. For ESRD, significant predictors included a greater creatinine level, lower hematocrit, interstitial fibrosis, tubular necrosis, greater C-reactive protein level, and percentages of abnormal glomeruli, glomeruli with extracapillary proliferation, cellular crescents, and global glomerulosclerosis. For death or new ESRD, predictors were fairly similar. Adjusting for baseline creatinine level, the risk for ESRD increased 1.78-fold (95% confidence interval [CI], 1.23 to 2.58) per each 10% increase in global sclerosis and 1.47-fold (95% CI, 1.05 to 2.07) per each 10% increase in glomeruli with cellular crescents. Conclusion: Global glomerulosclerosis and crescents in a renal biopsy are strong predictors of the long-term outcome of PING.

Objective. To evaluate whether autoantibodies in the absence of rheumatic diseases increase the risk of mortality among very elderly subjects who are otherwise in good functional condition. Methods. Autoantibodies were measured in 1987 in 156 elderly nursing home residents (median age 84 yr) who were followed subsequently over 14.6 yr. Results. Eleven subjects had anticardiolipin antibodies, 30 had rheumatoid factor and 19 had antibodies to single-stranded DNA (ssDNA). Other autoantibodies were more rare. During follow-up, 144 subjects died. Adjusting for age as a time-dependent covariate, the hazard ratio for death was 0.71 [95% confidence interval (0) 0.38-1.32] for anticardiolipin antibodies, 0.93 (95% CI 0.60-1.41) for rheumatoid factor, 1.08 (95% CI 0.65-1.79) for antibodies to ssDNA, and 0.99 (95% CI, 0.70-1.41) for any autoantibody. Hazard ratios were similar when adjusted also for sex and clinical conditions. Conclusion. Our results exclude the possibility that the autoantibodies evaluated increase substantially the risk of death among very elderly subjects in good functional condition.

Objective. To evaluate whether premenopausal women with antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE) have increased prevalence of atherosclerosis after adjustment has been made for known cardiovascular risk factors. Methods. We evaluated premenopausal women with APS in comparison with age-matched groups of patients with SLE [positive or negative for anticardiolipin (aCL) antibodies] or rheumatoid arthritis (RA), and healthy subjects. Thirty-three subjects in each group were assessed for cardiovascular risk factors, including a detailed lipid profile. Ultrasonography of carotid and femoral arteries assessed the intima-media thickness (IMT) and the presence of atherosclerotic plaque. Results. Atherosclerotic plaques were detected in 5, 2, 4, 1 and 1 subject in the five groups respectively. APS patients had significantly more affected vessels than RA patients and healthy controls (P=0.042 and P=0.016, respectively), but not compared with SLE patients. No consistent differences in IMT, traditional cardiovascular risk factors or lipid parameters were detected among the five groups. The odds for atherosclerosis independently increased 1.19-fold per year of increasing age [95% confidence interval (CI) 1.08-1.31; P=0.001), 1.019-fold per 1 mg/dl increase in low-density lipoprotein (LDL) (95% CI 1.003-1.036; P=0.020), 1.035-fold per additional 1 g of methylprednisolone equivalent cumulative corticosteroid dose (95% CI, 0.996-1.074; P=0.074), and 4.35-fold in the presence of APS or SLE (95% CI 0.75-25.2; P=0.10). Neither aCL nor anti-beta(2)GPI antibodies were associated with atherosclerosis. Conclusion. Premenopausal APS and SLE women have an increased prevalence of carotid and femoral plaque that is not accounted for by other predictors of atherosclerosis, including age, lipid parameters and cumulative steroid dose.

Background: Autoantigen La/SSB is molecular target of humoral autoimmunity in patients with primary Sjogren’s Syndrome (pSS) and systemic lupus erythematosus (SLE). in this study, we investigated the existence and possible influence of anti-idiotypic response to anti-La/SSB antibodies. Materials and Methods: Synthetic peptide analogs (pep) of the major antigenic determinants of La/SSB (289-308aa and 349-364aa) were prepared. Based on “molecular recognition” theory, complementary peptides (cpep), derived by anti-parallel readings of the noncoding strand of La/SSB DNA encoding for its antigenic determinants, were constructed. Sera from 150 patients with anti-La/SSB antibodies, 30 patients without anti-La/SSB antibodies, and 42 normal individuals were tested against all four peptides. F(ab’)(2) fragments from anti-peptide IgG were prepared and F(ab’)(2) - IgG interactions were evaluated using a specific anti-idiotypic ELISA. Results: All four peptides were recognized by anti-La positive sera (83% and 51% for pep and cpep 349-364 and 51% and 28% for pep and cpep289-308, respectively). Anti-cpep F(ab’)(2) bound to a common idiotype (Id) located within or spatially close to the antigen combining site of anti La/SSB (anti-pep) antibodies. Homologous and cross-inhibition experiments further confirmed this relation. The anti-idiotypic antibodies inhibited the anti-La/SSB antibody binding to recombinant La/SSB by 91%. To overcome the anti-idiotypic interference in anti-La/SSB detection, a specific assay was developed. Sera were heated for dissociation of Id-anti-Id complexes, anti-Id antibodies blocked with cpep, and anti-La/SSB reactivity was recovered. Application of this method to anti-Ro positive-anti-La/SSB “negative” sera showed that all anti-Ro/SSA positive autoimmune sera also possess anti-La/SSB antibodies. This reaction was not observed in 14 anti-Ro negative- anti-Sm/RNP positive sera from patients with SLE. Conclusions: Autoimmune sera from patients with pSS and SLE contain anti-idiotypic antibodies targeting a common anti-La/SSB idiotype. These antibodies can be detected using complementary peptides of La/SSB epitopes. The antiidiotypic antibodies mask the anti-La/SSB response. Hidden anti-La/SSB antibodies can be released and detected using complementary epitope analogs.

Objectives. To determine the incidence of serious myelotoxicity from intravenous cyclophosphamide (IC) in systemic lupus erythematosus (SLE). Methods. In a retrospective study, white blood cell (WBC) counts with differential and platelet counts were determined in 92 SLE patients (96 courses) given 1623 doses of IC. Results. Only one patient developed a total leucocyte count

Classification criteria for Sjogren’s syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Background: The prevalence of psychiatric symptoms and hostility factors in patients with scleroderma, although a matter of clinical interest, it is rather poorly studied. Methods: Thirty female patients with scleroderma were investigated. Thirty-three healthy women were used as a comparison group. The applied psychometric instruments were the Hostility and Direction of Hostility Questionnaire (HDHQ), the Delusions Symptoms States Inventory/states of Anxiety and Depression (DSSI/sAD) and the Symptom Check List-SOR (SCL-90R). Results: The scleroderma patients reported significantly increased depression and anxiety, somatization, interpersonal sensitivity and obsessive-compulsiveness. Paranoid ideation and psychotic symptoms scores were also increased. On hostility, they presented significantly higher scores predominantly on guilt. Conclusions: Psychiatric symptomatology in the form of anxiety, depression, obsessive-compulsiveness, somatization and feeldings of guilt were reported by the majority of the patients with scleroderma. Copyright (C) 2001 S. Karger AG, Basel.

Objective. Pulmonary capillary endothelium-bound angiotensin-converting enzyme (PCEB-ACE) activity is a sensitive and quantifiable index of endothelial function in vivo. Systemic sclerosis (SSc) is characterized by endothelial damage and excess collagen formation, causing mainly pulmonary hypertension (PH) in the limited cutaneous SSc (IcSSc) subset and interstitial lung disease with pulmonary interstitial fibrosis (PIF) in the diffuse cutaneous SSc (dcSSc) subset. This study was undertaken to investigate the hypothesis that PCEB-ACE activity is reduced early in SSc, in the absence of PH or PIF. Methods. Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis and percent metabolism (%M) of a synthetic ACE substrate and calculated functional capillary surface area (FCSA) in 25 SSc patients and 11 controls. Substrate hydrolysis and %M reflect ACE activity per capillary; FCSA reflects ACE activity per vascular bed. Results. PCEB-ACE activity was decreased in both SSc subsets. Among patients without PH, substrate hydrolysis and %M were decreased in patients with IcSSc and more profoundly in those with dcSSc; loss of FCSA normalized to body surface area (FCSA/BSA) was observed in dcSSc, but not in IcSSc. High-resolution computed tomography of the lung, performed in all SSc patients, revealed no correlation between substrate %M, hydrolysis, or FCSA/BSA and the degree of PIF; 5 dcSSc and 5 IcSSc patients with no detectable PIF exhibited decreases in hydrolysis and %M, while FCSA/BSA was decreased only in dcSSc. Conclusion. Depression of PCEB-ACE activity, indicating pulmonary endothelial dysfunction, occurs early in SSc, in the absence of PH or PIF, and is more pronounced, at this early pulmonary disease stage, in dcSSc than in IcSSc.

Background In female patients with systemic lupus erythematosus (SLE), we identified estrogen receptor ERa, ERb and ERa variant transcripts in peripheral blood mononuclear cells (PBMC). Exon 1 and 2 of ERa gene was subjected to mutation analysis to assess whether possible nucleotide alterations are linked to the disease. Methods The whole coding sequence of ERa was analysed by reverse transcription polymerase chain reaction (RT-PCR) and cDNA sequencing in PBMC prepared from 19 SLE patients and 12 healthy females. ERa exon 1 and exon 2 were subjected to mutation analysis using DNA isolated from whole blood of 21 SLE patients and 29 healthy females. The aminoterminal coding sequence of ERb was also analysed by RT-PCR. Results Wild type ERa and ERa splicing variants with deletions in exons 2, 5 and 7 were detected both in healthy individuals and in SLE patients, with no qualitative difference in their expression among the two populations. In ERa exon 1, the polymorphisms identified codon 10 and codon 87, both in patients and in healthy individuals who were not associated with the disease. No other mutations were present in ERa exon 1 or ERa exon 2 in all subjects studied. ERb was expressed in both populations. Conclusion: PBMC of SLE patients express wild type ERa, ERb and the same ERa variants as do healthy individuals. Genetic alterations in exon 1 and exon 2 of the ERa gene are not linked with SLE disease.

Objective. Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). Thr aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms: and (ii) the number of patients that eventually developed full SLE. Methods. Outcome parameters were the ACR criteria, the SLE: disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least yr were included in the study. All 122, patients who were included in the study were evaluated annually during 3 yr of follow-up. Results. Our results are confined to a patient cohort defined by disease duration of at least yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43%, of the patients. On recruitment to the study, 22 of the 112 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. Tn the 3 yr of follow-up only three patients developed SLE. Conclusions, A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

Backround Cryoglobulinemia has been reported in several chronic infectious and autoimmune diseases, and in patients with HIV-1 infection, Cryoglobulinemia associated with hepatitis C virus infection is considered a risk factor for the development of neoplasia, especially B-cell non-Hodgkin lymphoma. This study was undertaken to investigate whether the presence of circulating cryoglobulins is associated with survival or development of neoplastic disease in HIV-1 infection. Design We evaluated 87 unselected consecutive HIV-1 infected patients for the presence of cryoglobulinemia and they were prospectively followed up for a median of 34 months, with clinic visits at 4-month intervals. None of the patients had neoplasia at study entry. Time-to-event analysis for death, neoplasm and B-cell lymphoproliferative disorder were performed with Cox proportional hazards models. Results Mixed cryoglobulinemia (types II and III) was detected in 24 (28%) of the 87 patients. During the follow up, 12 patients died and 8 developed neoplastic disease. Multivariate analysis showed that circulating cryoglobulins were an independent predictor of death (relative risk (RR), 4.97; 95% confidence intervals (CI), 1.26-19.63] and development of neoplasia (RR, 5.18; 95% CI, 1.23-21.83). In addition, cryoglobulinemia reached borderline significance as a predictor of lymphoproliferative disorder of B-cell origin (P = 0.08; RR, 4.53; 95% CI, 0.83-24.75). Conclusions Our results suggest that cryoglobulinemia is associated with an increased risk for death, neoplasia or development of lymphoproliferative disorder of B-cell origin, in HIV-1 infected patients.

We hypothesized that B-cell epitope mapping of DNA Topoisomerase I (type-I topoisomerase, or Topo I) may define epitopes strongly associated with pulmonary interstitial fibrosis (PIF) in systemic sclerosis (SSc). B-cell epitope mapping of Topo I was performed using 63 20-mer peptides overlapping by eight residues and spanning the entire length of the Topo I sequence. These peptides, coupled to polystyrene pins, were tested for antibody binding by enzyme-linked immunosorbent assays (ELISAs) using immunoglobulin G fractions from anti-Topo I, anticentromere, anti-U3RNP-positive, and normal sera. Four major epitopes were recognized by anti-Topo I sera, but not from the control sera: WWEEERYPEGIKWKFLEHKG (205-224, epitope I), RIANFKIEPPGLFRGRGNHP (349-368, epitope II), PGHKWKEVRHDNK-VTWLVSW (397-416, epitope III), and ELDGQEYVVEFDFLGKDSIR (517-536, epitope IV), Peptide-epitopes were then synthesized in their soluble forms and ELISA systems were developed. Epitopes II to IV are localized at highly exposed sites of the Topo I tertiary structure, whereas epitope I is localized at a less accessible site. In a cohort of 81 patients with SSc with clinical data on the evolution of their disease, patients with antibodies in their sera recognizing at least three of the four epitopes had 3.1 times (P = 0.02) the hazard of developing PIF compared with patients whose sera recognized no epitopes or only one or two of the four epitopes. The discrimination was much stronger than that achieved by the simple determination of Topo I antibodies by counterimmunoelectrophoresis and immunoblot (hazard ratio 1.7, P = 0.30) in the same patients. B-cell epitope mapping of the anti-Topo I response has identified four major epitopes which cumulatively show a strong association with the development of PIF in SSc.

Autoantibodies to cellular autoantigens are usually found in sera of patients with systemic autoimmune rheumatic diseases. Patients with Sjogren’s syndrome (SS) frequently present autoantibodies to both organ and non-organ-specific autoantigens. The most commonly detected autoantibodies are those directed against the ribonucleoproteins Ro/SSA and La/SSB. The presence of the antibodies in SS is associated with early disease onset, longer disease duration, parotid gland enlargement, higher frequency of extraglandular manifestations and more intense lymphocytic infiltration of the minor salivary glands. Over the past several years, the structure and function of these autoantigens have been extensively studied. Several centers, using different techniques, have investigated the B cell epitopes on the protein components Po 60 kD, Ro 52kD, and La 48 kD. Finally, increased evidence of direct involvement of anti-Ro/SSA and anti-La/SSB autoantibodies in the pathogenesis of tissue injury has been contributed by several studies. Copyright(C) 2000 S. Karger AG, Basel.