Patients with antiphosholipid syndrome and thrombotic recurrences: A real world observation (the Piedmont cohort study).

BACKGROUND: Patients with antiphospholipid syndrome (APS) often have thrombotic recurrences, sometimes despite appropriate ongoing anticoagulant treatment. Identifying APS vascular patients at high risk for thrombotic recurrences is still an unsolved issue. OBJECTIVES: To report the real-life experience of thrombotic recurrences in APS patients included in the Piedmont observational cohort study, and evaluate clinical and laboratory risk factors for thrombotic recurrences. PATIENTS: A multi-centre observational study was performed by enrolling 177 patients with vascular APS (primary APS in 99 subjects (56%)); the median follow-up was five years (range 1-26 years). RESULTS: The observed thrombotic recurrence rate was about 7.5/100 patient years in the first five years after the first thrombotic event. While the first recurrence often occurred (45%) in patients who were not on oral anticoagulant therapy (OAT), the second recurrence mainly occurred despite ongoing OAT (80%). However, due to the real-life observational nature of this study, treatment was based on the treating physician's judgement, and no structured therapeutic protocol was applied. Moreover, compliance with OAT was not available. No differences in antiphospholipid antibodies (aPL) profile were observed between patients with or without thrombotic recurrences, but a high risk aPL profile (Miyakis type 1 and 2a) was present in 96% of our patients, 26% of whom had triple positivity. Diabetes (p < 0.01, OR 10), inherited thrombophilia (p < 0.0078, OR 4) and OAT withdrawal were independent risk factors for recurrences. CONCLUSIONS: With the limit of a real-life observational cohort study, the thrombotic recurrence rate in APS was as high as 7.5/100 patient years in the first five years after the first thrombotic event. OAT discontinuation, diabetes and inherited thrombophilia, when associated with a high-risk aPL profile, are risk factors for thrombotic recurrences.

Antiphospholipid syndrome in northwest Italy (APS Piedmont Cohort): demographic features, risk factors, clinical and laboratory profile.

We report the experience from the Antiphospholipid Antibodies (aPL) Regional Consortium in northwest Italy, meant to support clinical research and foster collaboration among health professionals regarding the diagnosis and management of antiphospholipid syndrome (APS) patients. This cohort-study (APS Piedmont Cohort) was designed to register the clinical characteristics at inception and associated immunological manifestations at diagnosis (if any) of patients who strictly fulfilled the current criteria for APS, all recruited at the Piedmont and Valle d'Aosta regions. Clinical and laboratory data from 217 APS patients (171 with vascular events, 33 with pregnancy morbidity and 13 with both), from 16 centres within the geographical area were collected. Venous thrombosis was recorded in 45.6% of patients, arterial thrombosis in 35%, small-vessel thrombosis in 1.12% and mixed arterial and venous thrombosis in the remaining 19.4% of the cases. Pregnancy morbidity included 19 patients with unexplained fetal death beyond the 10th week of pregnancy, 17 with premature birth before the 34th week and 10 with three or more unexplained spontaneous abortions before the 10th week of gestation. This consortium represents an instrument by which to audit clinical practice, to provide counselling to local centres and to sustain future basic and clinical APS research.

Anti-cardiolipin and anti-ß2-glycoprotein I antibodies: normal reference ranges in northwestern Italy.

Laboratory tests for anticardiolipin antibodies (aCL) and anti-ß2glycoprotein I antibodies (a-ß2GPI) face problems common to many autoantibody assays: the lack of a reference standard and the need for each laboratory to assess assay-specific cut-off values. The aims of the study were to evaluate the reference range upper limits (99th percentile) used for aCL and a-ß2GPI in the northwest of Italy and to investigate the analytical performances of these assays with the newly obtained reference ranges. We assayed aCL and a-ß2GPI in 104 serum samples from patients without a history of thrombosis, pregnancy morbidity, tumours, infections and/or autoimmune diseases (30 males and 74 non-pregnant females). We tested all the commercial assays available in our regions (i.e. Orgentec Diagnostika, Aesku Diagnostics and Inova Diagnostics ELISA; CliA Zenit-RA and EliA Phadia Laboratory Systems). A further 30 serum samples, including 10 from healthy subjects, 10 from antiphospholipid syndrome (APS) patients and 10 from septic patients were assessed to investigate the analytical performance of the obtained cut-off limits. Reference range upper limits obtained with the commercial kits differ among assays and from the values reported by the manufacturer. Moreover, normal reference ranges calculated for IgG and IgM aCL differed from the arbitrary selected laboratory classification values suggested in the guidelines of 40 GPL and MPL.

Fibromyalgia syndrome: definition and diagnostic aspects.

Ever since it was first defined, fibromyalgia (FM) has been considered one of the most controversial diagnoses in the field of rheumatology, to the point that not everybody accepts its existence as an independent entity. The sensitivity and specificity of the proposed diagnostic criteria are still debated by various specialists (not only rheumatologists), whose main criticism of the 1990 American College of Rheumatology criteria is that they identify subsets of particular patients that do not reflect everyday clinical reality. Furthermore, the symptoms characterising FM overlap with those of many other conditions classified in a different manner. Over the last few years, this has led to FM being considered less as a clinical entity and more as a possible manifestation of alterations in the psychoneuroendocrine system (the spectrum of affective disorders) or the stress reaction system (dysfunctional symptoms). More recently, doubts have been raised about even these classifications; and it now seems more appropriate to include FM among the central sensitisation syndromes, which identify the main pathogenetic mechanism as the cause of skeletal and extra-skeletal symptoms of FM and other previously defined "dysfunctional" syndromes.

Etiopathogenetic mechanisms of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmental influences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the development of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supports the comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Central sensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, which leads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMS has advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.

Non pharmacological treatments in fibromyalgia.

Fibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and with substantial financial costs. Once the diagnosis is made, providers should aim to increase patients' function and minimize pain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction with and the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present, pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptom control and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjective pain with greater success than monotherapy. Physical therapies, rehabilitation and alternative therapies are generally perceived to be more "natural," to have fewer adverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitive behavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.

Fibromyalgia syndrome: preventive, social and economic aspects.

There many open questions concerning the concept of primary prevention in FM. Diagnostic or classification criteria are not universally accepted, and this leads to difficulties in establishing the onset and duration of the disease. In the case of FM, primary prevention may consist of the immediate care of acute pain or treatment for affective disturbances as we do not have any specific laboratory or instrumental tests to determine risk factors of the disease. The goal of secondary prevention is early detection of the disease when patients are largely asymptomatic and intervention improves outcome. Screening allows for identification of an unrecognized disease or risk factor, which, for potential FM patients, includes analysis of tender points, Fibromyalgia Impact Questionnaire (FIQ), pain location and intensity, and fatigue and sleep complaints. Tertiary prevention inhibits further deterioration or reduces complications after the disease has developed. In FM the aim of treatment is to decrease pain and increase function via multimodal therapeutic strategies, which, in most cases, includes pharmacological and non-pharmacological interventions. Patients with FM are high consumers of health care services, and FM is associated with significant productivity-related costs. The degree of disability and the number of comorbidities are strongly associated with costs. An earlier diagnosis of FM can reduce referral costs and investigations, thus, leading to a net savings for the health care sector. However, every social assessment is closely related to the socio-economic level of the general population and to the legislation of the country in which the FM patient resides.

Symptoms and signs in fibromyalgia syndrome.

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronic widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completely understood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions. Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervous system; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal, non-musculoskeletal, or a combination of both; and many patients will also experience a host of associated symptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms; but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Several other associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probably a part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) has a significant psychological disturbance. Psychological factors are an important determinant of any type of pain, and psychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, but psychiatric illness is not a necessary factor in the etiopathogenesis of FM.

Fibromyalgia syndrome: the pharmacological treatment options.

Pharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capable of fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definite conclusions concerning the best pharmacological approach to managing FM because results of randomized clinical trials present methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. However, a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. In this review, we will evaluate those pharmacological therapies that have produced the most significant clinical results in treating FM patients. The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and nonpharmacologic therapies seems to be the most appropriate treatment strategy to date.

The evaluation of the fibromyalgia patients.

Fibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11 of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many of the existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by an extensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treating physicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evaluation for all the patients with suspected FM. Functional neuroimaging methods have revealed a large number of supraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are used in FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. To address the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop convened a meeting to develop consensus recommendations for chronic pain clinical trials.

Seasonal effects of rotational stress on Lewis lung carcinoma metastasis and T-lymphocyte subsets in mice.

Rotational stress specifically increases the formation of spontaneous lung metastasis in mice bearing Lewis lung carcinoma, without significantly modifying the growth of primary tumor. The increase in metastasis number and volume caused by rotational stress varies in magnitude with a highly significant circannual rhythm; the acrophase approximately coincides with summer solstice. Rotational stress causes a significant reduction in the number of CD3+ and CD4+ T-lymphocyte subsets in summer, whereas in winter the number of CD3+ subset is significantly increased; the CD4+/CD8+ ratio and the number of NK 1.1 antigen positive cells are not significantly modified by rotational stress in both periods considered. The increase in metastasis formation by rotational stress thus appears to negatively correlate with the number of splenic CD3+ and CD4+ T-lymphocyte subsets. This seasonal behavior occurs in spite of the control of light cycle, temperature and humidity in the animal housing, suggesting the existence in the host of an endogenous oscillator with a circannual period. These data indicate the opportunity to consider endogenous rhythms within the host, as well as seasonal factors, in studies on stress and neuroimmunomodulation in experimental oncology.

Studies on the mechanism of cortisol inhibition of human natural killer cell activity: effects of calcium entry blockers and calmodulin antagonists.

The role of Ca2+ in mediating the inhibition by glucocorticoids of human natural killer (NK) activity was investigated using Ca2+ entry blockers (verapamil and its desmethoxy-derivatives LU46973 and LU47093) and calmodulin antagonists (pimozide and two naphthalenesulfopamide derivatives, W-7 and W-13). Peripheral blood mononuclear (PBM) cell preparations were incubated for 20 h with 1 x 10(-6) M cortisol and these agents in various combinations (concentration range: 1 x 10(-7) - 1 x 10(-5) M) and then assayed in a direct 4-h cytolytic assay using 51Cr-labeled K 562 target cells. Exposure to cortisol led to a significant reduction of NK cell activity (about 50% with respect to the spontaneous activity). Ca2+ entry blockers displayed per se a dose-dependent depressive effect on cytotoxicity and gave significant enhancement of cortisol-dependent inhibition. Calmodulin antagonists were per se minimally effective but clearly amplified the cortisol-mediated inhibition. Raising extracellular Ca2+ by CaCl2 or intracellular Ca2+ by the ionophore A23187 yelded an appreciable reduction of these effects. Our data are compatible with the view that extracellular and intracellular Ca2+ play a role in the control of human NK cell activity. Moreover, it is conceivable that the mechanisms involved in glucocorticoid inhibition of NK cell activity involve Ca2+-dependent pathways.

Thrombotic recurrences and bleeding events in APS vascular patients: a review from the literature and a comparison with the APS Piedmont Cohort.

In APS vascular patients, thrombotic recurrences are more frequent than in non-APS thrombotic patients. To better define this clinical setting, a systematic review of the literature after 1999 was performed: 8 cohort studies (including the recent APS Piedmont Cohort) and 6 intervention studies were selected and evaluated. Thrombotic recurrences, bleeding events, therapeutic strategies, antiphospholipid (aPL) profile, inherited and acquired risk factors (when present) were calculated and compared. Emerging risk factors for thrombotic recurrences include withdrawal of oral anticoagulant therapy (OAT), high intensity OAT (INR range 3-4), aPL profile (triple positivity, Miyakis types 1 and 2a profiles) and association with inherited or acquired pro-thrombotic risk factors. Moreover, there are evidences that high risk (mainly for aPL profile) APS vascular patients have a high recurrence rate in spite of correct OAT treatment. Clinical trials in this clinical setting are needed.

Circadian variations of interferon-induced enhancement of human natural killer (NK) cell activity.

We searched for circadian changes in the enhancement of the NK activity after exposure to IFN-gamma of peripheral blood mononuclear (PBM) cells obtained serially throughout the 24-h cycle. In August-October 1986, blood was drawn from 7 healthy, diurnally active and nocturnally resting male volunteers (22-34 yr) at 4-h intervals for 24 h starting at 08:00. PBM cells were immediately separated and assayed for NK cell activity, using K 562 cultured cells as a target in a 4-h 51Cr release assay after prior incubation for 20 h with buffer or 300 IU rIFN-gamma. Circadian variations of the spontaneous NK cell cytotoxicity were apparent; the activity was at its maximum at the end of the night or in the early morning and then declined in the afternoon. The 24-h rhythmic pattern was validated with statistical significance by the Cosinor method (p less than 0.02; acrophase 04:22). Maximum enhancement by IFN-gamma was attained in the second part of the night or in the early morning, i.e. in phase with the peak of the spontaneous NK cell activity. A significant circadian rhythm of the percent increase above control levels was validated by the Cosinor method (p less than 0.01; acrophase 04:03). Our findings may be of relevance to a better understanding of the mechanisms of control of human NK activity and warrant consideration as an approach to improve the effectiveness of time-qualified immunotherapy.

Altered circadian rhythms of natural killer (NK) cell activity in patients with autoimmune rheumatic diseases.

Natural Killer (NK) cells are a lymphocyte subset actively involved in cytotoxicity against tumor-transformed and virus-infected cells; they are a reliable model for the study of neuroendocrine-immune interactions. In previous works we demonstrated that in healthy subjects NK activity of peripheral blood mononuclear cells (PBMC) and susceptibility to endogenous modifiers display statistically validated circadian rhythms. In rheumatoid arthritis (RA) and in other autoimmune rheumatic diseases abnormalities of the circadian rhythm of serum cortisol and altered levels of NK cell activity have been reported. We evaluated the circadian pattern of NK cell activity in 7 hospitalized patients with autoimmune rheumatic diseases (4 RA, 1 scleroderma, 2 mixed connective tissue disease). Temporal variations of in vitro responses to either positive recombinant (immune interferon, r IFN-gamma IFN-gamma: 650 IU/ml; recombinant interleukin-2, r IL-2 IL-2: 100 IU/ml) or negative (cortisol: 10(-6) M) modifiers were also studied. Blood was drawn at 4h intervals for 24 h, starting at 0800. PBMC preparations were immediately separated and incubated for 20h in the presence or absence of modifiers. NK activity was assessed with a direct non-radiometric 4h cytolytic assay, using K 562 cells as targets. Significant circadian variations of spontaneous NK activity were documented only in women with RA, with a peak in the evening hours and a minimum in the night or in the early morning (p < 0.05, PR 51.5%, phi 1829). Population-mean cosinor analysis did not yield detection of significant circadian variations of in vitro responsiveness to modifiers.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by cortisol of human natural killer (NK) cell activity.

The effects of cortisol on the natural killer (NK) activity of human peripheral blood mononuclear (PBM) cells were studied in vitro using a direct 4-h 51Cr-release assay and K 562 cell line as a target. Preincubation for 20 h of PBM cells drawn from healthy donors with 1 X 10(-8) to 1 X 10(-5) M cortisol resulted in a significant decrease of NK cell activity. The magnitude of the suppression was directly related to the steroid concentration and inversely related to the number of effector cells. Cortisol was able to minimize the enhancement of NK cytotoxicity obtainable in the presence of immune interferon (IFN-gamma). A significantly higher suppression was achieved after sequential exposure of PBM cells to cortisol and equimolar levels of prostaglandin E2 (PgE2). The concomitant incubation with theophylline and isobutyl-methylxanthine failed to enhance the cortisol-induced suppression, whereas PgE2-dependent inhibition significantly increased after exposure of PBM cells to methyl-xanthines. The inhibitory effect of cortisol was partially or totally prevented by the concomitant incubation with equimolar amounts of 11-deoxycortisol and RU 486 but not of progesterone. Treatment of NK effectors with a monoclonal anti-human corticosteroid-binding globulin (CBG) antibody produced an enhancement of the spontaneous NK activity and a partial suppression of cortisol-mediated effects. Our results suggest that endogenous glucocorticoids play a role in the regulation of NK cell-mediated cytotoxicity. Since the effect of cortisol was additive to that of PgE2 and was not changed by phosphodiesterase inhibitors, it is conceivable that the hormone acts at a level different from the adenylate cyclase-phosphodiesterase system. Data obtained with the use of antiglucocorticoids and the anti-CBG antibody are compatible with a role both of high-affinity glucocorticoid receptors and of CBG in mediating cortisol action on the human NK cell activity.

Circadian changes in human natural killer-cell activity.

The circadian changes in natural killer (NK) activity of peripheral blood mononuclear cells (PDM) were studied in five clinically healthy, diurnally active, nocturnally resting women. Data on spontaneous NK-cell activity were complemented by data on the chronosusceptibility to in vitro inhibition by 1 X 10(-6) M cortisol and by the rhythmometric evaluation of rectal temperature and plasma cortisol as potential circadian markers. In April-July, 1985, blood was drawn at 4-hr intervals for 24 hr starting at 0800 hr. Cells were immediately separated and assayed for NK activity using K 562 cultured cells as a target and a 4-hr 51Cr-release assay. Circadian variations of the spontaneous NK activity were apparent; the maximum of the activity occurred in the morning or in the early afternoon. In individual subjects, peak-to-through differences were 50% or more of the 24-hr mean. Chronosusceptibility to cortisol (20 hr incubation prior to the cytotoxic assay) was ecphasic with respect to the spontaneous NK-cell activity, with a maximum in the evening or night. Data obtained by immunofluorescence using specific anti-NK cell monoclonal antibodies confirm the occurrence of a higher number of phenotypically identifiable NK effectors in the morning vs. other circadian stages. Our data confirm previous findings and extend their scope to immunopharmacology emphasizing the need for time-qualified investigations on immune coordination in vivo.

Involvement of Ca2+-dependent pathways in the inhibition of human natural killer (NK) cell activity by cortisol.

The role of Ca2+ as a second messenger of the glucocorticoid inhibition of human natural killer (NK) cell activity was evaluated using Ca2+ entry blockers (verapamil and its desmethoxy derivatives LU46973 and LU47093), calmodulin antagonists (pimozide and two naphthalensulfonamide derivatives, W-7 and W-13), the Ca2+ channel agonist BAY K 8644 and the calcium ionophore A23187. Peripheral blood mononuclear (PBM) cell preparations were incubated for 20 h with 1 x 10(-6) M cortisol and these agents in various combinations (concentration range: 1 x 10(-9) -1 x 10(-5) M) and then assayed in a direct 4-h cytolytic assay using 51Cr-labeled K 562 target cells. Exposure to cortisol led to a significant reduction of NK cell activity (about 50% vs. spontaneous activity). Ca2+ entry blockers and calmodulin antagonists were per se minimally effective, but significantly enhanced cortisol-dependent inhibition of NK cell activity. Raising extracellular Ca2+ by CaCl2 or intracellular Ca2+ by the calcium channel agonist BAY K 8644 or the ionophore A23187 resulted in an appreciable reduction of these effects. Similar results were obtained when these substances were added to monocyte-depleted or NK cell-enriched suspensions exposed to cortisol. Our data are consistent with the view that extra- and intracellular Ca2+ plays a role in the control of human NK cell activity. It is also conceivable that both calcium flux into the cell and the calcium calmodulin system are involved in the cortisol-induced inhibition of natural cytotoxicity.