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Background: A reliable alternative to steroids for treating polymyalgia rheumatica has not yet been identified. Although infliximab has been used occasionally in steroid-resistant cases, its efficacy has not been demonstrated in a controlled study. Objective: To compare the efficacy of prednisone plus infliximab with that of prednisone plus placebo in patients with newly diagnosed polymyalgia rheumatica. Design: Randomized, placebo-controlled trial. Setting: 7 rheumatology clinics in Italy. Patients: 51 patients with newly diagnosed polymyalgia rheumatica. Patients with associated giant cell arteritis and those who had been previously treated with steroids or biological or immunosuppressive agents were excluded. Intervention: Initial therapy with oral prednisone tapered from 15 mg/d to 0 mg/d over 16 weeks according to a standard protocol, plus infusions of placebo or infliximab, 3 mg/kg of body weight, at weeks 0, 2, 6, 14, and 22. Measurements: The primary efficacy end point was the proportion of patients without relapse or recurrence through week 52. Secondary outcomes were the proportion of patients no longer taking prednisone, the number of relapses and recurrences, the duration of prednisone therapy, and the cumulative prednisone dose. Results: Four patients (3 in the infliximab group and 1 in the placebo group) did not complete the trial. The proportion of patients who were free of relapse and recurrence at 52 weeks did not differ between groups (6 of 20 patients [30%] in the infliximal group vs. 10 of 27 patients [37%] in the placebo group; adjusted risk difference, -3 percentage points [95% CI, -31 to 24 percentage points]; P = 0.80). In a sensitivity analysis that included dropouts, the best-case scenario yielded a difference of 5 percentage points (CI, -21 to 31 percentage points) between the groups. The secondary outcomes at weeks 22 and 52 did not differ between the groups. Limitations: The study had a small sample and a short follow-up. A low dosage of infliximab was used, and the prednisone dosage was rapidly tapered. Conclusions: Although too small to be definitive, the trial provides evidence that adding infliximab to prednisone for treating newly diagnosed polymyalgia rheumatica is of no benefit and may be harmful. If there is benefit, it is unlikely to be large.

Background: Steroids are the standard treatment for polymyalgia rheumatica. The efficacy of the candidate drug methotrexate has not yet been demonstrated in controlled studies. Objective: To compare the efficacy and safety of prednisone plus methotrexate and prednisone alone in patients with polymyalgia rheumatica. Design: Multicenter randomized, double-blind, placebo-controlled trial. Setting: 5 Italian rheumatology clinics. Patients: 72 patients with newly diagnosed polymyalgia rheumatica. Measurements: The proportion of patients no longer taking prednisone, the number of flare-ups, and the cumulative prednisone dose after 76 weeks. Intervention: Prednisone dosage (25 mg/d) was tapered to 0 mg/d within 24 weeks and was adjusted if flare-ups occurred. Oral methotrexate (10 mg) or placebo, with folinic acid supplementation (7.5 mg), was given weekly for 48 weeks. Results: Twenty-eight of 32 patients in the methotrexate group and 16 of 30 patients in the placebo group were no longer taking prednisone at 76 weeks (P = 0.003). The risk difference was 34 percentage points (95% CI, 11 to 53 percentage points). Similar results were obtained after adjustment for C-reactive protein level and duration of symptoms in a multivariate model. Fifteen of 32 patients in the methotrexate group and 22 of 30 patients in the placebo group had at least 1 flare-up by the end of follow-up (P = 0.04). The median prednisone dose was 2.1 g in the methotrexate group and 2.97 g in the placebo group (P = 0.03). The rate and severity of adverse events were similar. Limitations: Follow-up was short, and a high dose of folinic acid and a relatively high starting dosage of prednisone were used. Ten of 72 patients (14%) discontinued treatment or were lost to follow-up. Conclusions: Prednisone plus methotrexate is associated with shorter prednisone treatment and steroid sparing. It may be useful in patients at high risk for steroid-related toxicity.

A classification system proposed by the European Community seems to accurately identify patients with primary and secondary Sjogren's syndrome (SS). Researchers evaluated the usefulness of the six criteria in the system by testing 157 patients with confirmed SS and 121 patients with SS-like symptoms (controls) against these proposed benchmarks. The system accurately identified 97.5% of the patients with primary SS and 94.2% of the controls using four out of six items as confirmation of disease identification. The accuracy was similar for patients with secondary SS. With the elimination of the salivary gland testing, the system accurately identified only 83.7% of the patients with primary SS.

Intravenous administration of immunoglobulins (IVIg) may relieve the symptoms of rheumatoid arthritis (RA). Researchers studied the effect of IVIg on 10 RA patients who had failed to respond to previous treatment with slow acting antirheumatic drugs. Patients received 400 mg/kg of IVIg three days in a row, and then once a month for the next 12 months. Patients showed an improvement in function and relief of symptoms after six months of therapy. Several laboratory values, measured throughout the 12 months, did not improve and some became worse. The level of tumor necrosis factor alpha decreased shortly after IVIg. The blood concentration of soluble interleukin-2 receptor (sIL-2R) dropped after eight months of treatment. IVIg may be an alternative maintenance treatment for RA.

* Abnormalities in IgG subclass distribution were sought in serum samples and bronchoalveolar lavage fluid from 15 patients with alcoholic liver disease to explain their increased susceptibility to bacterial respiratory infections. Serum IgG4 deficiency alone or in association with low IgG2 levels was revealed in approximately 30% of patients with alcoholic liver disease. This fact prompted us to further investigate the immunoglobulin concentrations in bronchoalveolar lavage fluid, paying special attention to the distribution of IgA and IgG subclasses. IgA levels were found to be normal or slightly elevated. However, there were substantial defects in total IgG and IgG1 concentrations, often associated with reduced IgG2 and IgG4 levels, in approximately 70% of patients with alcoholic liver disease, which proved to be closely correlated with the number and type (pneumonia) of bacterial respiratory infections. A prospective study of intravenous immunoglobulin substitutive therapy involving two patients with recurrent pneumonia and very low serum IgG2 values demonstrated a reduction in the number of respiratory infectious episodes as well as an increase in both serum and, to a lesser extent, bronchoalveolar lavage fluid IgG1 and IgG2 levels. We identified immune defects that may represent an important pathogenetic mechanism that, when considered together with the alcohol-related suppression of alveolar macrophage and ciliary functions and the inhibition of leukocyte migration into the lungs, should help clarify the complex relationships between alcohol and immune defense. (Arch Intern Med. 1992;152:99-104)

Background: Adult human mesenchymal stem cells retrieved, from the post-partum human umbilical cord Wharton jelly (hUCMS), have recently gained growing interest due to their morphological and functional properties. Objective: The main purpose of our work was to examine morphology and functional properties of hUCMS retrieved from healthy women as compared to those with obesity, or gestational or type 2 diabetes mellitus, under fair metabolic control. Possible differences between groups could shed light into the potential use of these cells for the cell therapy of a variety of diseases, regardless of the obesity/ diabetes status of the donor mothers. Additionally, information on how the maternal disease may affect the cord-derived stem cells, hence possibly newborn children would be important. Methods: We have studied obese/diabetic or normal donor post-partum umbilical cord-derived hUCMS, either in basal or during differentiation protocols into several cell phenotypes and the definitive endoderm. Immunomodulatory properties of these cells, in terms of inhibition of activated lymphocyte proliferation, also was examined. Results: According to our preliminary results, there are functional differences, as assessed by cell and molecular assays, in terms of both, differentiation and immunomodulatory potential, between the cells derived from normal as compared to obese/diabetic mothers. Conclusion: The findings seemingly indicate that the uterine environment of obese/diabetic mothers is quite distant from normal, regardless of metabolic control. Hence hUCMS extracted from obese/diabetic mothers do not appear to be suitable for cell therapy clinical protocols but more studies are required.

Hypertension is highly prevalent in patients with systemic autoimmune and chronic inflammatory joint diseasesImmune-mediated mechanisms and chronic inflammation have been demonstrated to have a relevant role in the pathogenesis of hypertensionIn systemic autoimmune and chronic inflammatory diseases, hypertension is a contributing factor to subclinical atherosclerosis and cardiovascular eventsPatients with systemic autoimmune and chronic inflammatory diseases benefit from routine screening of hypertension given the evidence for underdiagnosis and undertreatment of elevated blood pressure in these patientsInternational evidence-based guidelines are needed for appropriate treatment of hypertension in patients with systemic autoimmune and chronic inflammatory diseases to reduce long-term, adverse cardiovascular outcomes

Objective.To compare systemic disease activity by validated tools, i.e., the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI) and the Clinical ESSDAI (ClinESSDAI) scores, between primary Sjögren syndrome (pSS) with positive serum cryoglobulins and pSS without serum cryoglobulins.Methods.There were 825 consecutive patients with pSS who were retrospectively evaluated.Results.The ESSDAI and the ClinESSDAI scores were significantly higher in cryoglobulin-positive patients (p < 0.0001, for both scores). Cryoglobulinemia was significantly associated with these domains: constitutional (p = 0.003), lymphadenopathy (p = 0.007), glandular (p = 0.0002), cutaneous (p < 0.0001), peripheral nervous system (p < 0.0001), hematological (p = 0.004), and biological (p < 0.0001).Conclusion.Cryoglobulin-positive patients show the highest systemic activity in pSS.

The aim was to establish how patients experience the impact of spondyloarthritis (SpA) on work disability and working life. The survey was performed in 17/20 regions in Italy (1 January to 31 March 2013). A multiple-choice questionnaire was published on the official website of the sponsor - the National Association of Rheumatic Patients (ANMAR) - and hard-copies were distributed at outpatient clinics for rheumatic patients. Respondents (n = 770) were of both sexes (56 % men), educated (62 % at high school or more), of working age (75 % aged ≤60 years), and affected by SpA. The most common types diagnosed were ankylosing spondylitis (AS) (39 %) and psoriatic arthritis (PsA) (36 %). Respondents were working full-time (45 %), part-time (8 %) or had retired (22 %); 15 % were unemployed (for reasons linked to the disease or for other reasons, students or housewives). Patients reported disability (39 %), were receiving disability benefits (34 %), were experiencing important limitations that were hindering their professional development/career (36 %) and some had to change/leave their job or lost it because of SpA (21 %). Employed respondents (n = 383) had worked on average 32.2 h in the last 7 days. More hours of work were lost over the last 7 days due to SpA (2.39 h vs 1.67 h). The indirect costs of the disease amounted to €106/week for patients reporting well-being/good physical conditions/improvement and €216/week for those reporting permanent impairment. Most patients were in the midst of their productive years and were experiencing considerable difficulties in carrying out their job because of the disease: half of them reported disability and one third were experiencing important limitations in their career perspective.

Background: Endothelial dysfunction contributes to increased cardiovascular (CV) disease in rheumatoid arthritis (RA). Angiogenic T cells (Tang) are a key regulator of vascular function via their interaction with endothelial progenitor cells (EPCs). Methotrexate (MTX) has been associated to reduced CV disease risk, but its effects on endothelial homeostasis have been poorly explored. We investigated MTX effects on endothelial homeostasis in early, treatment-naïve RA patients. Methods: Fifteen untreated, early RA patients and matched healthy controls (HC) were enrolled. RA patients with long-standing disease in remission or low disease activity treated with MTX for at least 6 months were selected as controls. Circulating CD28+and CD28nullTang cell, endothelial microparticle (EMP), EPC and soluble vascular cell adhesion molecule (sVCAM)-1 levels were measured. Results: Tang percentage was higher in early RA than in HCs and significantly increased after 3-month MTX treatment. Tang cells in RA were characterized by higher percentage of CD28nulland lower CD28-positive cells than HCs. MTX restored a Tang cell phenotype similar to HCs. Altered sVCAM-1, EMP and EPC were restored to levels similar to HCs after a 3-month MTX. Biomarker levels after 3 months of MTX were not different to those of patients with long-standing treatment. Conclusions: MTX has a positive effect on Tang, sVCAM-1, EPCs and EMPs in RA. Restoration of imbalance between CD28 + and CD28nullTang by MTX may be one of the mechanisms underlying its favourable effects on endothelial dysfunction. These effects seem to be long-lasting and independent from systemic inflammation reduction, suggesting a direct effect of MTX on the endothelium.

Background: In patients affected by connective tissue diseases (CTDs), the identification of wide autoantibody profiles may prove useful in early diagnosis, in the evaluation of prognosis (risk stratification), and in predicting response to therapy. The aim of the present study was to evaluate the utility of multiparametric autoantibody analysis performed by a new fully automated particle-based multi-analyte technology (PMAT) digital system in a large multicenter cohort of CTD patients and controls. Methods: Serum samples from 787 patients with CTD (166 systemic lupus erythematosus; 133 systemic sclerosis; 279 Sjögren’s syndrome; 106 idiopathic inflammatory myopathies; 103 undifferentiated CTD), 339 patients with other disorders (disease controls) (118 infectious diseases, 110 organ-specific autoimmune diseases, 111 other rheumatic diseases), and 121 healthy subjects were collected in 13 rheumatologic centers of the FIRMA group. Sera were analyzed with the Aptiva-PMAT instrument (Inova Diagnostics) for a panel of 29 autoantibodies. Results: Multiparametric logistic regression showed that enlarged antibody profiles have a higher diagnostic efficiency than that of individual antibodies or of antibodies that constitute classification criteria for a given disease and that probability of disease increases with multiple positive autoantibodies. Conclusions: This is the first study that analyzes the clinical and diagnostic impact of autoantibody profiling in CTD. The results obtained with the new Aptiva-PMAT method may open interesting perspectives in the diagnosis and sub-classification of patients with autoimmune rheumatic diseases.

The interferon‐inducible protein 16 (IFI16) has been detected in sera from patients with autoimmune/inflammatory diseases, but not in healthy subjects. This leaking leads to loss of tolerance toward this self‐protein and the development of autoantibodies. In this study, clinical significance of both IFI16 protein and anti‐IFI16 antibodies in rheumatoid arthritis (RA) was investigated. IFI16 protein and anti‐IFI16 antibody levels were assessed by enzyme‐linked immunosorbent assay in serum samples from 154 RA patients and 182 healthy controls, and in synovial fluid (SF) samples from 21 RA patients and 25 patients with osteoarthritis (OA). Mean serum levels for both IFI16 and anti‐IFI16 antibodies were higher in RA patients than in healthy controls, with a direct correlation between IFI16 concentration and anti‐IFI16 antibody titer. The majority of RA patients with detectable circulating IFI16 protein were also positive for rheumatoid factor (RF)/anti–cyclic citrullinated peptide antibody (anti‐CCP). The latter group was found to be positive for anti‐IFI16 antibodies as well. The mean SF concentrations of both IFI16 protein and anti‐IFI16 antibodies were higher in RA patients when compared with control OA patients. Interestingly, the presence of circulating IFI16 protein, but not anti‐IFI16 antibodies, significantly correlated with RA‐associated pulmonary disease. This correlation was not dependent on the presence of anti‐IFI16 antibodies, sex, and smoking habit. Our data demonstrate that the high levels of circulating IFI16 in RA are more frequent in RF/anti‐CCP–positive RA patients and significantly associated with pulmonary involvement. The relevance of circulating IFI16 protein as a new clinical biomarker of RA should be verified with additional studies.

There is evidence that interferon is involved in the pathogenesis of primary Sjögren’s syndrome (pSS). The interferon-inducible IFI16 protein, normally expressed in cell nuclei, may be overexpressed, mislocalized in the cytoplasm and secreted in the extracellular milieu in several autoimmune disorders. This leads to tolerance breaking to this self-protein with consequent development of anti-IFI16 antibodies. The aim of this study was to identify the pathogenic and clinical significance of IFI16 and anti-IFI16 in pSS. IFI16 and anti-IFI16 were assessed in the serum of 67 pSS patients and over 100 healthy donors by enzyme-linked immunosorbent assay. IFI16 was also evaluated by immunohistochemistry in minor salivary glands of 15 pSS patients and 10 subjects with sicca symptoms but without any clinical, serological or histological features of pSS. pSS patients display higher serum levels of both IFI16 and anti-IFI16 compared to healthy donors. IFI16 concentration was directly correlated with disease duration and focus score and inversely correlated with age at diagnosis. Moreover, IFI16 positivity was associated with concurrent positivity for rheumatoid factor. Interestingly, the direct correlation between IFI16 positivity and focus score was independent of disease duration and age at diagnosis. pSS minor salivary glands display marked expression and cytoplasmic mislocalization of IFI16 by acinar and ductal epithelial cells as well as infiltrating lymphocytes and peri/intralesional endothelium compared to minor salivary glands with normal architecture or nonspecific chronic sialadenitis. Within the mononuclear cell infiltrate, IFI16 expression appears to parallel the distribution of T lymphocytes. Our data suggest that the IFI16 protein may be involved in the pathogenesis of glandular inflammation occurring in pSS.

Idiopathic inflammatory myopathies (IIM) are a rare disease; so far standardized therapy has not been adequately defined by national or international guidelines or recommendations. Corticosteroids are the mainstay of treatment, but these drugs are burdened by several side effects. Thus, additional treatment based on immunosuppressive agents, especially azathioprine, methotrexate, mycophenolate mofetil and cyclosporine, is often needed. This combinate approach both improves the disease response and allows reduction of the dosage of corticosteroids, decreasing the risk of steroid-related long-term complications. Biological agents, particularly B cell depleting agent, are emergent therapeutic tools for refractory cases. Notably, drugs currently used for the therapy of IIM or other rheumatologic and non-rheumatologic conditions can induce myopathy. Drug-induced myopathies represent a considerable part of the complex topic of muscular disorders and should be always considered in the usual diagnostic work-up of a subject with muscle disease. Several mechanisms have been advocated to explain muscular damage induced by a number of drugs and, although a recovery after drug removal is usually observed, severe or persistent myopathy may be observed following the administration of some drugs, particularly in subjects with genetic predisposition. In this review the traditional and novel therapeutic approaches for patients with IIM, particularly biologics, will be discussed and an overview on drug-induced myopathies will also be provided.

CD4+CD25low/-GITR+T lymphocytes expressing forkhead box protein P3(FoxP3) and showing regulatory activity have been recently described in healthy donors. The objective of the study was to evaluate the proportion of CD4+CD25low/-GITR+T lymphocytes within CD4+T cells and compare their phenotypic and functional profile with that of CD4+CD25highGITR−T lymphocytes in systemic lupus erythematosus (SLE) patients. The percentage of CD4+CD25low/-GITR+cells circulating in the peripheral blood (PB) of 32 patients with SLE and 25 healthy controls was evaluated with flow cytometry. CD4+CD25low/-GITR+cells were isolated with magnetic separation, and their phenotype was compared with that of CD4+CD25highGITR−cells. Regulatory activity of both cell subsets was tested in autologous and heterologous co-cultures after purification through a negative sorting strategy. Results indicated that CD4+CD25low/-GITR+cells are expanded in the PB of 50% of SLE patients. Expansion was observed only in patients with inactive disease. Phenotypic analysis demonstrated that CD4+CD25low/-GITR+cells display regulatory T-cell (Treg) markers, including FoxP3, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), transforming growth factor-beta (TGF-β), and interleukin (IL)-10. In contrast, CD4+CD25highGITR−cells appear to be activated and express low levels of Treg markers. Functional experiments demonstrated that CD4+CD25low/-GITR+cells exert a higher inhibitory activity against both autologous and heterologous cells as compared with CD4+CD25highGITR−cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-β. Phenotypic and functional data demonstrate that in SLE patients, CD4+CD25low/-GITR+cells are fully active Treg cells, possibly representing peripheral Treg (pTreg) that are expanded in patients with inactive disease. These data may suggest a key role of this T-cell subset in the modulation of the abnormal immune response in SLE. Strategies aimed at expanding this Treg subset for therapeutic purpose deserve to be investigated.

Pulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy. Thirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A “good response” was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO)>15% and PaO2> 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved. Twenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease. Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics. ClinicalTrials.gov NCT00573326. Registered 13 December 2007.

Objective.To investigate pregnancy and fetal outcomes in patients with primary Sjögren syndrome (pSS).Methods.An obstetric history of 36 women with established diagnosis of pSS at pregnancy was obtained from a multicenter cohort of 1075 patients. In a subgroup case-control analysis, 12 deliveries in patients with pSS were compared with 96 control deliveries.Results.Thirty-six women (31 with anti-SSA/Ro and/or anti-SSB/La antibodies) with an established diagnosis of pSS had 45 pregnancies with the delivery of 40 newborns. Two miscarriages, 2 fetal deaths, and 1 induced abortion were recorded. Mean age at the first pregnancy was 33.9 years; mean number of pregnancies was 1.25; 18/40 (45%) cesarean births were delivered; mean pregnancy length was 38.5 weeks (range 32–43), with 6 preterm deliveries. The mean Apgar score at 5 min was 8.9, mean birthweight was 2920 g (range 826–4060 g). Congenital heart block (CHB) occurred in 2/40 (5%) newborns. The reported rate of breastfeeding for at least 1 month was 60.5%. In 4/40 pregnancies (10%) a flare of disease activity was observed within a year from delivery. In the case-control subgroup analysis, 12 deliveries were compared with 96 controls and no significant differences were found.Conclusion.Patients with pSS can have successful pregnancies, which might be followed by a mild relapse. CHB was the only cause of death for offspring of mothers with pSS.

Objective.To evaluate 4-year retention rates of tumor necrosis factor-α (TNF-α) inhibitors adalimumab, etanercept, and infliximab among patients with longstanding rheumatoid arthritis (RA), as derived from an Italian national registry.Methods.The clinical records of 853 adult patients with RA in the GISEA (Gruppo Italiano Studio Early Arthritis) registry were prospectively analyzed to compare drug survival rates and the baseline factors that may predict adherence to therapy.Results.In 2003 and 2004, 324 patients started treatment with adalimumab, 311 with etanercept, and 218 with infliximab. After 4 years, the global retention rate of anti-TNF-α therapy was 42%. Etanercept survival (51.4%) was significantly better than that of infliximab (37.6%) or adalimumab (36.4%; p < 0.0001). Accordingly, the mean duration of therapy was significantly longer for etanercept (3.1 ± 2 yrs) than for adalimumab (2.6 ± 2 yrs) or infliximab (2.7 ± 2 yrs; p < 0.05). The use of concomitant disease-modifying antirheumatic drugs, mainly methotrexate, and the presence of comorbidities significantly predicted drug continuation (p < 0.01), whereas a high Disease Activity Score did not.Conclusion.The 4-year global drug survival of adalimumab, etanercept, and infliximab was lower than 50%, with etanercept having the best retention rate. The main positive predictor of adherence to anti-TNF-α therapy was the concomitant use of methotrexate. Our study provides further evidence that the real-life treatment of patients with RA may be different from that of randomized clinical trials.

ObjectivePrimary Sjögrens syndrome SS shares clinical and serologic features with rheumatoid arthritis and systemic lupus erythematosus, 2 diseases characterized by acceleration of atherosclerosis. Signs of precocious atherosclerosis have also been shown in SS, although the pathogenic basis of early arterial damage is unclear. The arterial wall was functionally evaluated in SS subjects with analysis of the role played by diseaserelated factors.MethodsEndotheliumdependent flowmediated vasodilation FMV and endotheliumindependent nitratemediated vasodilation NMV were evaluated in 45 women with SS and 59 agematched female controls. In addition, serum soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 VCAM1, and nitrotyrosine were detected.ResultsAlthough patient FMV values did not differ from those of control subjects mean ± SD 7.4 ± 3.6 versus 7.7 ± 1.9; not significant, NMV was lower in SS patients than in controls mean ± SD 8.1 ± 3.5 versus 10.3 ± 2.1; P≤ 0.001. Patient NMV was inversely correlated with soluble VCAM1 levels r −0.38, P 0.001 and directly correlated with leukocyte count r 0.26, P 0.03. An NMV decrease was confirmed in SS patient subsets with evidence of leukopenia, rheumatoid factor, antiSSB antibodies, and joint involvement. However, patients with joint involvement or parotid enlargement, 2 of the sites mainly affected by chronic inflammation in SS, had an FMV lower than controls and patients without these clinical features.ConclusionOur results suggest that a functional impairment of the arterial wall may sustain early phases of atherosclerotic damage in SS. A combined effect of diseaserelated chronic inflammatory and immunologic factors appears to support dysfunction of endothelium and vascular smooth muscle cells, respectively.

Regulatory T cells (Treg) are a CD4+lymphocyte subset involved in self-tolerance and autoimmunity prevention. There is evidence for a phenotypic and/or functional impairment of this cell subset during the natural history of several chronic autoimmune/inflammatory diseases, including rheumatoid arthritis (RA). Although the intracellular transcription factor FoxP3 is thought to be the master regulator of Treg cell function, a number of other molecules expressed on the cell surface have been proposed for the identification of Treg cells. This is important in order to favour their possible selective isolation and in the development of new therapeutic strategies. In the present paper, available data on phenotypic and functional characterization of Treg cells in both peripheral blood and synovial fluid from RA patients are reviewed and their possible pathogenic role in triggering and perpetuating rheumatoid joint inflammation is discussed.

OBJECTIVE: Patients with rheumatoid arthritis (RA) display high serum concentrations of soluble CD30 (sCD30), which correlate with counter-regulatory activity of CD30+ T cells in the inflamed joint. To verify the contribution of this T cell subset to disease remission, sCD30 levels were analyzed longitudinally in patients with active RA following infliximab therapy. METHODS: Infliximab plus methotrexate were started in 39 patients with active RA, while 20 patients with inactive disease, controlled by stable doses of methotrexate, acted as controls. Serial evaluations of sCD30 concentrations and disease activity indexes were performed throughout 38 weeks. RESULTS: sCD30 levels were higher in patients than in healthy controls. Rapid infliximab-induced decrease in disease activity was associated with an overall increase of sCD30 levels. In contrast, levels remained stable in controls. An inverse correlation between sCD30 levels and Disease Activity Score 28 was observed from the 22nd week of infliximab treatment. Analysis of sCD30 levels according to American College of Rheumatology response showed, after an initial general enhancement of sCD30 concentrations, a persistent increase of sCD30 in responders, but not in nonresponders. CONCLUSION: sCD30 serum levels are enhanced by tumor necrosis factor-a (TNF-a) blockade in patients with active RA and inversely correlated with disease activity, but only after some weeks of treatment. Of interest, a sustained increase of sCD30 is present only in subjects with evidence of persistent clinical response to anti-TNF-. As sCD30 serum levels mirror antiinflammatory activity of joint T cells, the present data may suggest a role of synovial counter-regulatory CD30+ T cells in the induction of infliximab-mediated remission in RA.

OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-α (TNF-α) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF- blockers. All patients received one TNF- blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-α blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA.

Anti‐inflammatory non steroidal drugs releasing NO (NO‐NSAIDs) are a new class of anti‐inflammatory drugs to which has been added an NO‐releasing moiety. These compounds have been shown to retain the anti‐inflammatory, analgesic and antipyretic activity of the parent compound but to be devoid of gastrointestinal (GI) toxicity.Freund's adjuvant (FA) arthritis was induced in rats by a single intraplantar injection into the right hindpaw of 100 μl of mycobacterium butirricum (6 mg ml−1). The effect of equimolar doses of naproxen (1, 3 and 10 mg kg−1) and NO‐naproxen (1.5, 4.5 and 16 mg kg−1) was evaluated using two dosage regimen protocols: (i) preventive, starting oral administration of the drugs at the time of induction of arthritis and for the following 21 days (day 1–21); (ii) therapeutic, starting oral administration of the drugs 7 days after adjuvant injection and for the following 14 days (day 7–21).Hindpaw swelling (days 3, 7, 11, 14, 17, 21) and nociception (days 15 and 21) were measured. On day 22 rats were sacrificed, draining lymph nodes were removed and T cells isolated. In vitroproliferation of T cells following stimulation with concanavalin A (0.5–5 μg ml−1) was measured using a tritiated thymidine incorporation assay. IL‐2 receptor expression on T cells was measured by FACS analysis.Naproxen and NO‐naproxen showed similar activity in reducing oedema formation in the non‐injected (controlateral) hindpaw. Both drugs showed anti‐nociceptive effect. NO‐naproxen was anti‐nociceptive at a dose of 4.5 mg kg−1while naproxen showed the same extent of inhibition only at a dose of 10 mg kg−1.T cells were isolated and characterized by FACS analysis. Stimulation of isolated T cells with concanavallin A in vitrocaused a significant increase in thymidine uptake. NO‐naproxen at a dose of 4.5 mg kg−1inhibited T cell proliferation to the same extent as 10 mg kg−1of naproxen.Inhibition of T cell proliferation was well correlated with reduced IL‐2 receptor expression on T cells. In addition, NO‐naproxen reduced both IL‐1β and TNFα plasma levels whilst naproxen reduced IL‐1β levels only.In conclusion, both naproxen and NO‐naproxen reduce inflammation and nociception associated with arthritis. In addition NO‐naproxen interferes to a larger extent with cellular mechanism involved in T cell activation in rat adjuvant arthritis indicating that introduction of the NO moiety in the naproxen structure increases the effect at the level of the immune system.

Background:Thymectomy (Tx) is a common therapeutic option to treat myasthenia gravis (MG), but its effects on the immune system are still obscure in humans. Objective:We sought to evaluate long-term immunologic effects of therapeutic Tx in patients with MG. Methods:T- and B-cell subsets and T-cell repertoire were analyzed in 35 patients with MG, 16 with previous Tx (at least 8 years before), 6 with recent (<1 year) Tx, and 13 without Tx, as well as in 32 healthy subjects used as normal control subjects. Serum immunoglobulins and a variety of autoantibodies were also measured. A subsequent 3-year clinical follow-up was performed to verify the possible appearance of systemic autoimmune diseases. Results:The long-term thymectomized (Txd) patients had mild T-cell lymphopenia and an expansion of some Vβ families among circulating CD4+ and CD8+ T cells. They displayed a normal number of total B and CD5+ B-circulating lymphocytes, but they also displayed a polyclonal increase in serum IgM and IgG associated with the presence of high levels of a variety of organ- and nonorgan-specific autoantibodies, including anti-dsDNA and anticardiolipin, without clinical evidence of autoimmune disease. These serologic abnormalities were not detectable in both non-Txd and recently Txd patients. After 3 years, 2 long-term Txd patients had systemic lupus erythematosus and an undifferentiated connective tissue disease. Conclusions:The association between MG and laboratory findings of systemic autoimmune disease may be in part related to Tx rather than to MG. Tx may represent a risk for the development of systemic autoimmune disorders over years in patients with MG. (J Allergy Clin Immunol 1999;103:865-72.)

The effects of interferon-α (IFN-α) on clinical and serologic manifestations of mixed cryoglobulinemia (MC) were investigated by randomized, crossover-controlled trial in 26 patients. The trial alternated 6 months with and 6 months without IFN-α therapy (2 × 106IU daily for a month, then every other day for 5 months). In 22 patients, pretreatment steroid dosage remained unchanged during the study. Six patients dropped out (three because of side effects), whereas another 20 patients experienced a significant improvement of purpura (P< .02) and serum transaminases (P< .005) during IFN-α treatment. The presence of clinical improvement was supported by the outcome measurements of several immunologic parameters. In particular, serum cryoglobulins were significantly reduced (P < .04) during IFN-α therapy. A rebound phenomenon of clinical and serologic parameters was observed after IFN-α discontinuation. In addition, no variations were recorded during 6 months without therapy. Hepatitis C virus (HCV) RNA was detected in 91 % (20/22) of our MC patients; in 2/13 cases HCV RNA was no longer detectable in serum samples after IFN-α therapy. Thus, IFN-α could be considered as treatment for MC in patients with HCV seropositivity.

The inhibition of cyclooxygenase does not fully account for the spectrum of activities of nonsteroidal antiinflammatory drugs. It is evident, indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation. Therefore, the effects of salicylates on T-cell adhesion to and migration through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify the expression of integrins on T cells, they blunted the increased adherence induced by the anti-ß2monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction of T-cell adhesiveness appears to be dependent on the increase in[Ca2+]i levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.

A role of CD26 surface antigen (Ag) in both CD3- and CD2-mediated T cell activation has been previously demonstrated. To analyze the functional role of CD26 in the CD3- and CD2- induced activation pathways of cord T cells, which represent the most reliable source of Ag-unprimed T cells, we employed a newly developed anti-CD26 monoclonal antibody, termed anti-1F7, which is able to modulate the molecule on the cell membrane and synergize with anti-CD3 and anti-CD2 in activating T lymphocytes. The results showed that CD26 Ag is expressed on the surface of almost all resting cord T cells and that is fluorescence intensity is enhanced by activation. The binding of anti-1F7 induced a decrease in CD26 membrane expression, with no detectable effect on the surface expression of other cord T cell-related molecules. Moreover, the modulation of CD26 resulted in an increase in anti-CD3-mediated cord T cell activation through an enhancement in intracellular calcium levels, IL-2 receptor expression, and IL-2 synthesis, whereas it had no effect on cord T cell activation induced by anti-CD2 or anti-CD2 plus exogenous IL-2. The fact that the selective involvement of CD26 in the activation pathway triggered by anti-CD3, but not anti-CD2, could be reversed by prior stimulation of cord T cells with anti-CD3 suggests that this functional feature, which resembles that of mature thymocytes, may be linked to the Ag-unprimed cell phenotype of cord T lymphocytes.

Phenotypic analysis of helper CD4 + TQ1 – cell population, the major helper T-cell subset for B-cell responses, was carried out in BAL fluid of sarcoidosis patients. Most of the BAL CD4+ cells lacked TQ1 membrane antigen. A correlation between the number of helper CD4 + TQ1 – cells and IgM and IgA levels was observed in 27 sarcoidosis patients’ BAL. A role of CD4 + TQ1 – cells in modulating lung B-cell immunoglobulin secretion in sarcoidosis was confirmed by the fact that BAL IgG level and helper T-cell number correlated well in patients with low-intensity alveolitis. Results showed an inverse correlation between symptom duration and BAL IgM levels and CD4 + TQ1 – cell number. The number of helper cells was above normal in patients who had symptoms for less than 12 months and within normal range in those who had symptoms for more than that. The pathogenic and clinical relevance of these data is discussed.

Intracytoplasmic lysozynie was studied by the peroxidase antiperoxidase (PAP) and protein A-peroxidase methods in 130 cases of various myeloproliferative and lymphoproliferative disorders and 21 lymph nodes and bone marrow metastases from solid primary tumors. This marker, which can be identified in formalin or Zenker-fixed tissues, as well as in peripheral blood and bone marrow smears, proved useful to distinguish malignant myeloid and histiocytic tumors from malignant lymphoid and undifferentiated epithelial metastases. The diagnostic application of these findings are discussed.

Summary: Allergic rhinitis due to cypress pollen is a well-recognized clinical condition that is evermore frequently diagnosed as a winter allergy in the Mediterranean area. Little is known about the allergen composition of its pollen and the dynamics of its immune response. For these reasons IgE-specific antibody distribution was determined and the allergenic pollen characterized. SDS-PAGE analysis of the whole extract revealed more than ten proteic bands ranging from 10 to 90 kD. The major allergen had a molecular weight of 36 kD and the specific IgE antibody was presene in >95% of the sera tested by immunoblotting technique. Two minor allergens were observed at the 43 and 49 kd protein bands. The results obtained with the whole extract were then compared to those of five commercially available preparations.

Cord blood samples from healthy full-term newborns were tested with antimature and antiimmature lymphoid-cell monoclonal antibodies, as well as more traditional markers, in order to identify the phenotype of circulating precursor cells. The results demonstrated that human cord blood contains a lower number of OKT3+, E-rosetting mature T cells than adult blood, very high levels of OKT10+ cells, and few OKT9+, OKT8+OKT3-, and OKT4+OKT3- cells. Although the finding of OKT9+ and OKT10+ cord circulating cells could be indicative of cell activation, double marker studies in newborn blood pointed to phenotypically immature lymphoid subsets at different stages of maturation, according to Reinherz's hypothesis. In addition, the absence of nuclear Tdt-positive and hot-rosetting cells, together with the fact that most of these are OKT3+, OKT10+, OKT4+, or OKT8+ cells, suggests that the surface phenotype of newborn lymphocytes is similar to that of mature thymocytes.

As cord T cells, a Model of antigen (Ag)-unprimed cell, display a functional defect when stimulated through the CD3 molecule, the role of lymphocyte function-associated antigen 1(LFA-1)/intercellular adhesion molecule 1 (ICAM-1) and CD2/lymphocyte function-associated antigen 3 (LFA-3) receptor-ligand pairs in cord CD3-triggered T-cell activation was analyzed using specific monoclonal antibodies (mAb) against each adhesion molecule. The addition of anti-CD11a, anti-CD18, or anti-CD2 to both adult and cord peripheral blood mononuclear cells (PBMC) cultures led to a decrease in CD3-induced proliferation. In contrast, CD3-stimulated cord, but not adult, PBMC proliferation was markedly enhanced when anti-CD54 or anti-CD58 were added. Despite the fact that ICAM-1 and LFA-3 molecules were virtually absent on cord resting T cells, mAb against these two molecules boosted both mitogenesis of and interleukin (IL)-2 production by purified cord T cells stimulated with plastic immobilized anti-CD3. Cord T-cell supernatant levels of interferon-γ (IFN-γ) were undetectable with CD3 stimulation, slightly raised with CD58/CD3 costimulation, but normal when T cells were preincubated with IL-2 for 24 hr before being costimulated with anti-CD3/CD58. Evidence that IL-2 and IFN-γ play a pivotal role in fully activating cord T cells came from the demonstration that IL-2 and IFN-γ are able to bypass the CD3-proliferative defect through differential up-regulation of the adhesion molecules. It would, therefore, seem that ICAM-1 and LFA-3 molecules are crucially implicated in the CD3-activation pathway of Ag-unprimed T cells. Copyright 1993, 1999 Academic Press

Aims: To determine the diagnostic value of anti-acetylated peptide antibodies (AAPA) in patients with rheumatoid arthritis (RA).Methods: Three acetylated peptides (ac-lysine, ac-lysine.inv and ac-ornithine) derived from vimentin were employed to measure AAPA by enzyme-linked immunosorbent assay (ELISA) in sera of 120 patients with early RA (eRA), 195 patients with established RA (est RA), 99 healthy controls (HC), and 216 patients with other inflammatory rheumatic diseases. A carbamylated and a citrullinated version of the vimentin peptide were used additionally. Receiver operating characteristics and logistic regression analyses were used to assess the discriminative capacity of AAPA.Results: AAPA were detected in 60% of eRA and 68.7% of estRA patients, 22.2% of HC, and 7.1– 30.6% of patients with other rheumatic diseases. Importantly, AAPA were also present in 40% of seronegative RA patients, while antibodies to the carbamylated peptide were detected less frequently. Diagnostic sensitivity of individual peptides for eRA was 28.3%, 35.8%, and 34% for ac-lysine, ac-ornithine, and ac-lysine.inv, respectively. Positive likelihood ratios (LR+) for eRA versusHC were 14.0, 7.1, and 2.1. While the presence of a single AAPA showed varying specificity (range: 84–98%), the presence of two AAPA increased specificity considerably since 26.7% of eRA, as compared with 6% of disease controls, were double positive. Thus, double positivity discriminated eRA from axial spondyloarthritis with a LR+ of 18.3. Remarkably, triple positivity was 100% specific for RA, being observed in 10% of eRA and 21.5% of estRA patients, even in the absence of RF and ACPA.Conclusion: AAPA are highly prevalent in early RA and occur also independently of RF and ACPA, thereby reducing the gap of seronegativity. Furthermore, multiple AAPA reactivity increased the specificity for RA, suggesting high diagnostic value of AAPA testing.

To the Editor.—We read with interest the article by MacGregor1 in the Sept 19 issue concerning alcohol abuse and immune defense. This excellent review summarizes clinical and laboratory aspects of various dysfunctions in the cellular, humoral, and polymorphonuclear arms of the immune system in patients with alcoholic liver disease (ALD). However, some aspects of cell-mediated dysfunction in alcoholism need clarification, because several studies on thymus-dependent lymphocytes have given conflicting results.Study.—We performed a phenotypic and functional evaluation (by using monoclonal antibodies in a double-color immunofluorescence assay and pokeweed mitogen—driven coculture experiments) of circulating T cells and helper and suppressor T-cell activity on B-cell differentiation in ALD. Our results indicate a normal absolute T-cell number with an expansion of T4+ helper T cells that also coexpress on their surface interleukin 2—receptor complex (as detected by anti-Tac monoclonal antibody). Patients with ALD had 69.9% ±3.1% (0.699 ±0.031) T4+ lymphocytes

Primary Sjögren’s syndrome (pSS) is an autoimmune disorder affecting exocrine glands; however, a subgroup of pSS patients experience systemic extra-glandular involvement leading to a worsening of disease prognosis. Current therapeutic options are mainly empiric and often translated by other autoimmune diseases. In the last few years growing evidence suggests that B-cell depletion by rituximab (RTX) is effective also in pSS. Patients with early active disease appear to be those who could benefit the most from RTX. The aim of this study was to investigate the efficacy and safety of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in early active pSS patients.

The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects.