Hematologic manifestations of connective autoimmune diseases.

Autoimmune connective tissue diseases (ACTDs) constitute a heterogeneous group of chronic immune-mediated inflammatory disorders, primarily affecting connective tissues and usually characterized by multisystem involvement with variable and frequently overlapping clinical manifestations. Abnormal immune regulation patterns and persistent inflammation are ACTD hallmarks. In such a context, autoimmunity/inflammation-associated cellular and molecular networks drive a complex of reactions that may involve hemopoietic tissue and peripheral blood cells. Hematologic abnormalities affecting one or more cellular lineages are frequent manifestations of ACTDs, and may represent an important prognostic factor, reflecting the rate of activation of autoimmune/inflammatory processes. Moreover, an increased frequency of hematologic malignancies, mainly lymphoproliferative disorders, has been observed in ACTDs, such as Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and polymyositis/dermatomyositis. A proliferative drive likely constitutes the link between chronic immune activation/dysregulation and malignant transformation, creating an increased risk for genetic aberrations that may lead to uncontrolled clonal proliferation. Revealing the nature of lymphomagenesis in relation to autoimmunity/inflammation will allow the identification of subjects at risk in order to select the appropriate diagnostic and therapeutic options. In this paper, the main hematologic manifestations of adulthood ACTDs are reviewed and discussed.

Hematologic manifestations of primary Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disorder, primarily characterized by the mononuclear cell infiltration of exocrine glands exiting in parenchymal damage and secretory impairment. The spectrum of the disease extends from an autoimmune exocrinopathy to a systemic process with extraglandular manifestations. SS is defined as primary (pSS) when isolated, or secondary when associated with another autoimmune disease. Patients with pSS may present hematologic abnormalities, such as anemia, hemocytopenias, monoclonal gammopathies and lymphoprolipherative disorders, predominantly non-Hodgkin's lymphoma of B-cell origin. The increased prevalence of B-cell malignancies suggests that SS may be a boundary disease between autoimmunity and lymphoproliferation. In this paper, the hematologic manifestations of pSS are reviewed.

Respiratory system involvement in systemic vasculitides.

The respiratory system may be involved in all systemic vasculitides (SV), although with a variable frequency. Lung disease is a very common and important feature of the antineutrophil cytoplasmic antibodies (ANCA)-associated SV (AASV), such as Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS), and microscopic polyangiitis (MPA). In WG, almost all patients have either upper airway or lower respiratory tract disease. Solitary or multiple nodules and masses are the most common findings on chest radiograph. Asthma is a cardinal symptom of CSS, often preceded by allergic rhinitis, frequently complicated by nasal polyposis and sinusitis. Pulmonary transient and patchy alveolar infiltrates are the most common radiographic findings. In MPA, diffuse alveolar hemorrhage (DAH) due to alveolar capillaritis is the most frequent manifestation of the respiratory involvement, clinically expressing with hemoptysis, respiratory distress and anemia. However, DAH may be subclinical and has to be suspected when chest radiograph demonstrates new unexplained bilateral alveolar infiltrates, in the face of falling hemoglobin levels. In giant cell arteritis, the most frequent respiratory symptom is cough, usually non-productive, persistent, and responsive to corticosteroids. In Takayasu arteritis, pulmonary involvement is frequently subclinical and detectable by non-invasive techniques. Pulmonary involvement is rare in polyarteritis nodosa, Kawasaki disease, Henoch-Schönlein purpura and cryoglobulinemic vasculitis. In conclusion, the involvement of the respiratory system is a very common and important feature of AASV, whereas is less frequent in other SV. It comprises a wide spectrum of clinical features and radiological findings, and may have a prognostic significance. The assessment of the respiratory system should be included in the work-up of all patients with SV, especially of those with AASV.

Behçet's disease: familial clustering and immunogenetics.

Behçet's disease (BD) is a relapsing, multisystemic inflammatory disorder, characterized by major symptoms consisting of recurrent orogenital ulcerations, eye and skin lesions. Other clinical features may include musculoskeletal, vascular, gastrointestinal, renal, cardiopulmonary or neurological involvement. Vasculitis affecting all types and sizes of blood vessels is the main histopathologic process, in a third of cases complicated by thrombosis. The etiopathogenesis is presently unknown, but BD likely represents the result of a peculiar immune response to hitherto unidentified environmental factors in genetically predisposed subjects. The prevalent distribution in a specific geographical area spanning the Mediterranean basin and Asia, the close association with human leukocyte antigen B*51 in different ethnic groups, and the familial clustering of BD are hallmarks accounting for the strong contribution of a genetic background. The BD familial aggregation is characterized by both genetic anticipation and higher prevalence in childhood patients, likely defining a subset with stronger immunogenetic influences. Polymorphisms in genes encoding for host effector molecules may have a supplementary role in disease susceptibility and/or severity. The contribution of prothrombotic mutations and polymorphisms in the pathogenesis of BD thrombosis is controversial. In this paper, the available reports on BD familial clustering and the evidence for the role of immunogenetic predisposing factors are reviewed.

Focus on leptin, a pleiotropic hormone.

Leptin, the product of the obese gene located on human chromosome 7 (7q31.3), is a cytokine-type hormone mainly secreted by the white adipose tissue and in a lesser extent by placenta, skeletal muscle, gastric mucosa, mammary and salivary glands. Leptin, released by the adipocytes into the bloodstream in positive correlation to the fat mass, plays a key role in the body weight control. Indeed, it suppresses the appetite and increases the metabolic rate, primarily acting through central pathways. Conversely, during starvation leptinemia rapidly falls, leading to a reduction of the energy expenditure and allowing a longer survival. Recently, pleiotropic effects of leptin have been identified, consisting in modulation of several processes, such as thermogenesis, reproduction, hemostasis, angiogenesis, hematopoiesis, osteogenesis, chondrogenesis, neuroendocrine and immune functions, as well as arterial pressure control. Leptin has been also suggested as neuroendocrinologic marker of hypervigilant state. Ultimately, it may be the signal that integrates metabolic, vascular, neuroendocrine, immune and behavioural responses. In this paper, the more recent information on leptin is reviewed and summarized.

Systemic vasculitides: immunogenetics and familial clustering.

The systemic vasculitides (SV) are a heterogeneous group of rare affections characterized by a primary process of inflammation and damage of the blood vessel wall. Their etiopathogenesis is still unknown, but a complex interaction of multiple factors, such as age, sex, ethnic background, immunogenetic mechanisms and environmental influences, is probably involved. A genetic predisposition to SV is suggested by both familial case clusters and immunogenetic studies. The available reports on familial SV via the PubMed (National Library of Medicine) and Biosis indices, as well as personal observations, are summarized here. Furthermore, the evidence for a role of genetic predisposing factors is reported. The literature review suggests that several SV such as giant cell arteritis, Takayasu arteritis, Kawasaki disease, Wegener's granulomatosis and Henoch-Schönlein purpura, are governed by multiple genes encoding host defence molecules and probably triggered by environmental agents. Genetic factors seem to be implicated not only in the susceptibility, but also in the severity and outcome of SV.

Fibromyalgia: state of the art.

Fibromyalgia (FM) is a common and complex condition, defined as long lasting, widespread musculoskeletal pain, in the presence of tender points (TPs) at specific anatomical sites. Dysautonomic and functional symptoms, such as orthostatic hypotension, tachycardia, effort intolerance, marked fatigue, sleep disorders, cognitive disturbances, psychological distress, paresthesias, headache, genitourinary manifestations, irritable bowel syndrome and bladder dyskinesia, frequently occur. The etiopathogenesis of FM is presently unknown, but nociceptor, autonomic and neuro-endocrine system dysfunctions have been found in patients. Since specific serological or instrumental markers of the syndrome are not yet identifiable, TP search is the only useful diagnostic hallmark. The development of an effective therapy of FM has hitherto been hampered by the incomplete knowledge of its pathogenic mechanisms. In this paper, the most recent information on FM is reviewed.

[The hemophagocytic syndrome (macrophage activation syndrome)]. / La sindrome emofagocitica (sindrome da attivazione macrofagica).

The hemophagocytic syndrome (HPS) is an uncommon, often misdiagnosed life-threatening disorder of immune regulation, characterized by a widespread proliferation and multisystemic infiltration of non-malignant histiocytes that undergo uncontrolled hemophagocytosis in bone marrow and/or reticulo-endothelial system. The HPS immune dysfunction consists in a low or absent cytotoxic T and natural killercell activity and in hyperactivation of T lymphocytes and macrophages, with consequent proinflammatory cytokine storm. Clinically, HPS is characterized by high fever, lymphadenopathies, hepato-splenomegaly, liver dysfunction, (pan)cytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, as well as coagulopathy and neurological manifestations in many cases. A hereditary/primary variant (familial hemophagocytic lymphohistiocytosis) and an acquired/secondary form (reactive HPS) are known. This latter may occur in several disorders, including infections, immunodeficiency states, malignancies, lymphoproliferative and autoimmune diseases. Without treatment, HPS fatally has an unfavourable prognosis. Recently, outcome improvements have been reported, due to better therapeutic strategies. The clinical and pathological features of this syndrome are reviewed.

Pachydermoperiostosis and psoriatic onychopathy: an unusual association.

A 33-year-old man, suffering from cutaneous psoriasis since the age of 16, in the last 6 years experienced slow and painless enlargement at his fingertips and later at his big toes, which resulted in digital clubbing. Since the age of 31, the patient also presented psoriatic nail changes involving all his fingernails, without joint pain or inflammation. The patient's family history was negative for psoriasis, however, his brother, a 29-year-old healthy man, also presented digital clubbing. The diagnosis of pachydermoperiostosis coexistent with ungual and cutaneous manifestations of psoriasis vulgaris was made. The differential diagnosis with psoriatic onycho-pachydermo-periostitis, as well as other clinical conditions that involve the distal interphalangeal joints is discussed.

[Adult onset Still's disease]. / Malattia di still dell'adulto.

Adult onset Still's disease (AOSD), the adult variant of the systemic form of the juvenile rheumatoid arthritis, is an uncommon disorder of unknown origin. Although the pathogenesis has not yet been clarified, an immunologically mediated inflammation occurs in active AOSD. High spiking fever, evanescent maculo-papular skin rash, arthralgias/arthritis, neutrophilic leukocytosis, negative rheumatoid factor and antinuclear antibodies, as well as a marked hyperferritinemia are the major features of AOSD. Sore throat, lymphadenopathies, hepato-splenomegaly, abdominal pain, polyserositis, respiratory distress syndrome, multiple organ dysfunction and disseminated intravascular coagulation may also occur. The clinical course of AOSD is extremely variable and unpredictable and can be divided into three main patterns: a self-limited or monocyclic pattern, a polycyclic or intermittent course, with one or more flares of the disease and complete remission among the episodes, and a chronic course, characterized by persistently active disease, usually due to a chronic, destructive arthritis. Since there are not pathognomonic laboratory parameters or histological findings, the diagnosis of AOSD requires the exclusion of infectious, malignant and autoimmune disorders. Some sets of criteria for classification have been proposed, but so far not validated. The prognosis of AOSD is usually considered relatively benign, although a destructive arthritis may cause severe disability and the multisystemic life-threatening complications of the disease may determine a fatal outcome. Treatment usually consists in nonsteroidal anti-inflammatory drugs and corticosteroids, but a more aggressive approach with disease modifying antirheumatic or immunosuppressive drugs may be required.

[Mondor's diseases. Spectrum of the clinical and pathological features]. / La malattia di Mondor. Spettro delle manifestazioni clinico-patologiche.

Mondor's disease is an uncommon disorders, occurring mostly in middle-aged women, and characterized by superficial thrombophlebitis classically involving the thoraco-epigastric veins and/or their confluents. Rare cases have been reported in atypical sites (upper arms, abdomen, groin and penis). The most common clinical features include lateral chest wall tension and pain, as well as the presence of a tender subcutaneous linear or winding cord-like structure, corresponding to the affected vessel, often with skin redness, edema or retraction. The etiology is unknown. Mondor's disease may be primary or secondary to local trauma, surgical procedures, bandaging, tight clothes and infections; it may also be associated with breast cancer. This condition is usually a benign and self-limited process, requiring only symptomatic treatment. Surgery is indicated when it is associated with malignancies or severe local pain and retraction. The clinical and pathological spectrum of this disease are reviewed.

Remitting seronegative symmetrical synovitis with pitting oedema in a patient with myelodysplastic syndrome and relapsing polychondritis.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) may be the inaugural manifestation of different rheumatic diseases of the elderly, malignancies and myelodysplastic syndromes (MDS). Relapsing polychondritis (RP) is a rare systemic disorder characterised by an inflammatory process involving predominantly cartilaginous structures, the cardiovascular system and organs of special sense. We report on a 72-year-old man with RS3PE and MDS, refractory anaemia subtype, diagnosed at the same time as RS3PE. Several months later the patient presented a clinical and pathological picture compatible with RP. Although the association between RP and MDS is well known, no previous cases of RS3PE preceding RP have been reported. This case confirms that RS3PE may herald many diseases, among others autoimmune disorders such as RP.

Coexistent Marfan's syndrome and ankylosing spondylitis: a case report.

We report on a 46-year-old man with a 4-year history of predominantly nocturnal pain at the thoracic and lumbar spine as well as accompanying morning stiffness and episodes of alternating buttock pain. At physical examination the patient presented with the typical traits for Marfan's syndrome (MFS), along with limitation of both chest expansion and movement in all planes of the lumbar spine. Pelvic and lumbar spine radiographs showed findings consistent with ankylosing spondylitis (AS). Laboratory tests were consistent with an inflammatory state and HLA typing was positive for the B27 antigen. Transthoracic echocardiography showed prolapse of the posterior mitral leaflet and mild aortic insufficiency. We diagnosed co-existent MFS and AS. The association of these two pathologies is particularly interesting, owing to the co-existence of hypermobility of peripheral joints due to MFS ligamentous hyperlaxity, and the reduction of both axial skeleton motility and chest expansion related to AS. As both of these diseases may damage the cardiovascular system over time, follow-up with echocardiography monitoring is indispensable.

Antioxidant activity of bull semen in relation with aging.

This paper reports on the findings of an antioxidant activity in whole semen from bull and its components, washed spermatozoa and seminal fluid. The antioxidant activity has been evaluated as the ability of semen or its components to inhibit the spontaneous autooxidation of epinephrine a pH 10, 2, which involves the production of superoxide radicals (0(2)). This preliminary study provides further evidence on the role of free radicals, which are well known to be dangerous to cellular life, and points to the need of a better understanding of the role of antioxidant activities as a cellular protective mechanism.