Gastrointestinal manifestations of Behçet's disease: advances in evaluation and management.

Behçet's disease is a chronic, recurrent, inflammatory disorder characterized by orogenital ulcers and skin lesions; serious manifestations also include ocular, large vessel, gastrointestinal and neurological involvement. Genetic and unknown environmental factors customise the wide clinical expression of the disease. Gastrointestinal involvement is not unusual, albeit with a highly variable frequency among different ethnic populations. However, given the fact that gastrointestinal symptoms such as reflux, bleeding, diarrhoea are common in the general population, their clinical significance needs to be carefully interpreted. Apart from mouth the ileocecal area is typically involved, but inflammatory and/or vasculitic lesions may affect any part of the gastrointestinal tract. Complications such as perforation carry high morbidity rates and even mortality. Herein, we review all available information pertinent to gastrointestinal involvement of Behçet's disease and discuss the published advances in evaluation and its empirical management, including anti-TNF biologic therapies.

The presence of CD55- and/or CD59-deficient erythrocytic populations in patients with rheumatic diseases reflects an immune-mediated bone-marrow derived phenomenon.

BACKGROUND: Complement has the potential to provoke severe impairment to host tissues, as shown in autoimmune diseases where complement activation has been associated with diminished CD55 and/or CD59 expression on peripheral blood cell membranes. The aim of this study was to evaluate the presence of CD55- and/or CD59-deficient erythrocytic populations in patients with different rheumatic diseases and to investigate possible correlations with clinical or laboratory parameters. MATERIAL AND METHODS: CD55 and CD59 expression was evaluated in erythrocytes of 113 patients with rheumatic diseases, 121 normal individuals, and 10 patients with paroxysmal nocturnal hemoglobinuria (PNH) using the Sephacryl gel microtyping system. Ham and sucrose tests were also performed. RESULTS: Interestingly, the majority of patients (104/113, 92%) demonstrated CD55- and/or CD59-deficient erythrocytes: 47 (41.6%) with concomitant deficiency of CD55 and CD59, 50 (44.2%) with isolated deficiency of CD55, and 6 (6.2%) with isolated deficiency of CD59. In normal individuals, only 2 (1%) had concomitant CD55/CD59 negativity and 3 (2%) had isolated CD55 or CD59 deficiency. All PNH patients exhibited simultaneous CD55/CD59 deficiency. Positive Ham and sucrose tests were found only in PNH patients. There was no association between the CD55- and/or CD59-deficient erythrocytes and hemocytopenias or undergoing treatment. However, CD55 expression significantly influenced hemoglobin values (F=6.092, p=0.015). CONCLUSIONS: This study provides evidence supporting the presence of erythrocytes with CD55 and/or CD59 deficiency in patients with rheumatic diseases. Moreover, CD55 deficiency on red cells influences hemoglobin concentration. Further studies using molecular techniques will clarify the exact pathophysiological mechanisms of this deficiency.

The lung in the spectrum of antiphospholipid syndrome.

Patients with antiphospholipid syndrome may develop various lung manifestations. The lung complications that have been described so far are pulmonary thromboembolic disease, pulmonary hypertension, acute respiratory distress syndrome, primary thrombosis of large and small lung vessels, diffuse alveolar haemorrhage, fibrosing alveolitis and postpartum syndrome. Clinicians should be aware of these conditions as in most of these cases, timely diagnosis and treatment is needed.

Giant Cell Arteritis: Focusing on Current Aspects From the Clinic to Diagnosis and Treatment.

Giant cell arteritis (GCA) is a granulomatous arteritis involving large arteries, particularly the aorta and its major proximal branches, including the carotid and temporal arteries. GCA involves individuals over 50 years old. The etiopathogenesis of GCA may involve a genetic background triggered by unknown environmental factors (eg infections), the activation of dendritic cells as well as inflammatory and vascular remodeling. However, its pathogenetic mechanism still remains unclear, although progress has been made in recent years. In the past, inflammatory markers and arterial biopsy were considered as gold standard for the diagnosis of GCA. However, emerging imaging methods have been made more sensitive and specific for the diagnosis of GCA. Treatment includes biological and other modalities including interleukin-6 (IL-6) inhibitors.

Kikuchi's lymphadenopathy: a relatively rare but important cause of lymphadenopathy in Greece, potentially associated with the antiphospholipid syndrome.

Kikuchi-Fujimoto disease is a form of reactive lymphadenopathy, which was firstly described in Japan, but is uncommon in the Western world. We retrospectively reviewed the medical records of nine cases of adult or adolescent Kikuchi's disease diagnosed in a single Haematology Unit in Athens, Greece between 1990 and 2006. The median age of the patients was 25 years (14-40) and 8/9 were females. All patients presented with cervical lymphadenopathy sparing the supraclavicular fossa; one had associated axillary lymphadenopathy, seven had fever and two were asymptomatic. The median duration of lymphadenopathy before presentation was 30 days (10-45). Just palpable splenomegaly was recorded in three patients. The median value of the maximal lymph node diameter was 2 cm (1-5) and only 1/9 had nodes >2 cm in their largest diameter. Lymphadenopathy was tender in two patients; hard nodes were observed in three patients. The median leukocyte count was 4.7 x 10(9)/l (2.2-4.9) with a normal differential in 7/9 patients. No infectious agent could be demonstrated. One patient had clinical and laboratory evidence of primary antiphospholipid syndrome (APLS). In conclusion, Kikuchi's disease represents a rare but important diagnostic possibility for patients presenting with lymphadenopathy in Greece and other western countries. In this setting, autoimmune disorders, mainly lupus and APLS, should be considered and excluded by the appropriate laboratory work-up.

Intervertebral disc calcification in thalassemia intermedia.

OBJECTIVES: Intervertebral disc calcification, an age-related phenomenon of variable clinical significance is described in hemochromatosis. As beta-thalassemia is characterized by excessive tissue iron deposition and secondary hemosiderosis, and skeletal abnormalities are often observed in these patients, this study is conducted to identify the prevalence of Intervertebral Disc Calcification (IDC) in thalassemia intermedia population. METHODS: We investigated all the elder than 30 years beta-thalassemia intermedia patients of our Department thalassemia unit. Patients underwent thoracic and lumbar spinal X-rays for IDC presence. Patients presenting IDC were compared to those not presenting, regarding back pain anamnesis, presence of back pain, extramedullary hemopoiesis, sex, age, Hb levels, ferritin levels, reticulocytes, bilirubin values, thyroid-parathyroid abnormalities. Student's t-test was used to compare variables between patients with and without IDC. A P-value under 0.05 was considered statistically significant. RESULTS: We investigated 30 beta-thalassemia intermedia patients (19 women) with an age range 38-61 yr (42.5 +/- 11.46 yr). Intervertebral disc calcifications were observed in seven patients (23.33%). No sex and laboratory parameters statistically significant differences were observed differences for IDC prevalence, while mean age and back pain history was statistically significantly different between the two groups. CONCLUSIONS: In thalassemia patients, the big variety of spinal deformities may hide the presence of IDC and thus, this entity may be overlooked or underestimated. The clinical significance of IDC development as well as the possible prevention by early transfusion chelation therapy should be further investigated.

Calciphylaxis: a pseudo-vasculitis syndrome.

OBJECTIVES: To report a case of fatal calciphylaxis, an uncommon condition affecting patients with chronic renal disease and calcium metabolism abnormalities, that can mimic vasculitis. METHODS: We reviewed the English literature using the Medline and Embase databases and keywords "calciphylaxis" and "calcific uremic arteriolopathy." RESULTS: A patient with end-stage renal disease and no known calcium metabolism abnormalities presented with intractable lower extremity ulcers and skin findings suggestive of small-vessel disease of the upper extremities. Biopsy of the lesions showed classic calciphylaxis without evidence of vasculitis. The patient died shortly after an above-the-knee amputation. CONCLUSION: Calciphylaxis needs to be considered in the differential diagnosis of vasculitis. Skin biopsy soon after presentation is imperative for diagnosis and to avoid potentially harmful treatments such as corticosteroids and immunosuppressive medications.

Primary adult-onset macrophage activation syndrome with multisystemic tissue phagocytosis.

The histiocyte disorders are divided into the following 3 categories according to the specific lineage of the histiocytes involved and their biological behavior: the dendritic cell-related disorders, which include Langerhans cell histiocytosis and dermal dendrocyte disorders; the macrophage cell disorders, hemophagocytic lymphohistiocytosis being the main entity; and the malignant histiocyte disorders. We present a case of a 36-year-old woman who was referred to our hospital because of fever of unknown origin, lethargy, anemia, and impaired hepatic function. Following a thorough investigation, we diagnosed extensive histiocyte-mediated phagocytosis in many areas (skin, liver, bone marrow), without any identifiable cause. The disease was controlled by immunosuppressive therapy, and the patient remains in complete remission. This case supports the concept of idiopathic generalized histiocyte activation as a distinct entity; this putative disease entity produces massive phagocytosis, regardless of the type of histiocyte differentiation. Similar cases necessitate further study for classification and management.

Epididymo-Orchitis in Bechet's Disease: A Review of the Wide Spectrum of the Disease.

 Behçet's disease is a chronic, recurrent, inflammatory disorder characterized by orogenital ulcers and skin lesions; serious manifestations also include ocular, large vessel, gastrointestinal and neurological involvement. Genetic and unknown environmental factors modify the wide clinical spectrum of the disease. During the long clinical course of the disease, testicular and epididymal involvement has been reported, with scrotal pain and swelling being the most common symptoms. In this review, we discuss the various aspects of epididymo-orchitis in Behcet's disease patients, and we evaluate the diagnostic approaches as well as the empirical therapeutic modalities of this entity.

Analgesic activity of high-dose intravenous calcitonin in cancer patients with bone metastases.

We undertook a prospective, nonrandomized study with the objective to evaluate the efficacy of salmon calcitonin (sCT) in controlling pain secondary to bone metastases. Our study population consisted of 45 cancer patients with bone metastases (26 men) with a mean age of 64 years (range, 48-70) who had completed chemotherapy, hormonal therapy and radiation therapy at least 30 days prior to enrollment in the study, and had intractable pain despite the use of common analgesics (acetaminophen, nonsteroidal anti-inflammatory agents, opioids) and bisphosphonates. The study medication was a 300-IU dose of sCT administered intravenously daily for 5 consecutive days and repeated every two weeks until no response was noticeable. The analgesic efficacy of sCT was evaluated by means of Huskisson's visual analogue scale and Keele's pain scale; the daily consumption of analgesic drugs and performance status were also monitored. None of the patients managed to completely discontinue the use of other analgesics, but 5 patients (11% of the total number) had an analgesic response that lasted 4 weeks and less than 5% of the patients continued to respond for 6 weeks. No significant side effects were observed. Our data show that intravenous calcitonin administered in a relatively high dose has a very limited therapeutic potential as an adjuvant analgesic for a short period of time in selected cancer patients with bone metastases.

Expression, prognostic significance and mutational analysis of protein tyrosine phosphatase SHP-1 in chronic myeloid leukemia.

The protein tyrosine phosphatase SHP-1 dephosphorylates BCR-ABL1, thereby serving as a potential control mechanism of BCR-ABL1 kinase activity. Pathways regulating SHP-1 expression, which could be exploited in the therapeutics of TKI-resistant chronic myeloid leukemia (CML), remain unknown. Moreover, the questions of whether there is any kind of SHP-1 deregulation in CML, contributing to disease initiation or evolution, as well as the question of prognostic significance of SHP-1, have not been definitively answered. This study shows moderately lower SHP-1 mRNA expression in chronic phase CML patients in comparison to healthy individuals and no change in SHP-1 mRNA levels after successful TKI treatment. Mutational analysis of the aminoterminal and phosphatase domains of SHP-1 in patients did not reveal genetic lesions. This study also found no correlation of SHP-1 expression at diagnosis with response to treatment, although a trend for lower SHP-1 expression was noted in the very small non-responders' group of the 3-month therapeutic milestone.

The role of infections in the pathogenesis of autoimmune diseases.

The autoimmune diseases result from inappropriate responses of the immune system to self antigens. The etiology of autoimmune diseases remains largely unknown but candidate etiologic factors include genetic abnormalities and infections. Although there are considerable data supporting the role of infections in a variety of autoimmune diseases, this role has been unequivocally established in only a few autoimmune diseases. The difficulty in establishing the infectious etiology of autoimmune diseases stems from several factors such as the heterogeneity of clinical manifestations in individual autoimmune diseases and the time interval between infection and autoimmune disease. The data on this association derive from clinical observations, epidemiological studies and research using laboratory techniques, protein sequence database screening and animal models. Infectious agents can cause autoimmune diseases by different mechanisms, which fall into two categories: antigen specific in which pathogen products or elements have a central role e.g. superantigens or epitope (molecular) mimicry, and antigen non-specific in which the pathogen provides the appropriate inflammatory setting for "bystander activation". The most important mechanisms are molecular mimicry and superantigens. As far as molecular mimicry is concerned the recent data on the degeneracy of T cell recognition shifted the focus from searching for linear sequence homology to looking for similarity of antigenic surfaces. Special mention has to be made to retroviruses as they have some unique means of inducing autoimmunity.

The clinical spectrum of primary renal vasculitis.

BACKGROUND AND OBJECTIVES: The vasculitides are potentially severe and often difficult to diagnose syndromes. Many forms of vasculitis may involve the kidneys. This review will focus on the clinical and histopathological aspects of renal involvement in the systemic vasculitides. METHODS: We searched the MEDLINE database using as key terms the MeSH terms and textwords for different forms of vasculitis and for renal involvement, creating a database of more than 2200 relevant references. RESULTS: The frequency of renal involvement in vasculitis varies among different syndromes. It is more frequent in Wegener's granulomatosis and microscopic polyarteritis, while it is uncommon to rare in other forms of vasculitis such as Behçet's disease and relapsing polychondritis. The vessels affected include the renal artery in Takayasu arteritis, medium-size renal parenchymal artery in classic polyarteritis nodosa, and glomerular involvement in Wegener's granulomatosis and microscopic polyarteritis. The clinical expression of renal vasculitis depends on the size of the affected vessels and includes renovascular hypertension, isolated nonnephrotic proteinuria, interstitial nephritis, and glomerulonephritis, which can be rapidly progressive. Diagnosis is established by a combination of history, clinical manifestations, laboratory findings (eg, urine sediment, urine protein, antineutrophil cytoplasmic antibodies), imaging techniques (renal angiography, especially when there is a suspicion of medium-to-large vessel disease, and chest radiograph), and finally, renal biopsy. Prognosis varies from unfavorable in the rapidly progressive glomerulonephritis of microscopic polyarteritis, which can lead to renal failure, chronic dialysis, and renal transplantation, to benign, as in the case of Henoch Schonlein purpura, in which the majority of patients recover. CONCLUSIONS: The manifestations and prognosis of renal vasculitis range widely. Renal involvement greatly influences prognosis and dictates the need for early and prompt immunosuppressive therapy. Thus, the clinician should be alert for the timely diagnosis and treatment of renal vasculitis.

Diffuse Calcifications of the Spleen in a Woman with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease, which affects a wide variety of organs including the spleen. Splenic involvement in SLE includes conditions such as splenomegaly, hyposplenism, infarction, and spontaneous rupture. However, only a few cases of splenic calcifications in patients with SLE have been reported. Herein, we present a case of a 24-year-old female diagnosed with SLE, in which we found diffuse splenic calcifications. The unique pattern of splenic calcifications in SLE contributes to the differential diagnosis from other conditions such as infections and other connective tissue diseases, which also cause calcifications in the spleen.

Nuclear grade plus proliferation grading system for invasive ductal carcinoma of the breast: validation in a tertiary referral hospital cohort.

OBJECTIVES: For patients with invasive breast cancer, management decisions are informed by tumor grade according to the Nottingham Grading System (NGS), either on its own or as part of the Nottingham Prognostic Index (NPI). A system retaining the nuclear grade element but substituting the two subjective components, mitosis count and tubule formation, of the NGS with a proliferation index based on Ki-67 (MIB-1) has been proposed (nuclear grade plus proliferation [N+P] grading). METHODS: We validated the prognostic value of this grading system on a population of 322 women. RESULTS: N+P grading resulted in more grade I tumors (47.9% vs 4.5%) and fewer grade II (32% vs 51.5%) and grade III (20.1% vs 44%) tumors compared with NGS. The NPI calculated based on N+P grade had a similar association with survival (P < .001; odds ratio, 1.729) as the NPI calculated on the basis of the NGS grade (P < .001; odds ratio, 1.668). CONCLUSIONS: The N+P system seems equivalent to the NGS system.

Cytomegalovirus meningoencephalitis after rituximab treatment for primary central nervous system lymphoma.

The efficacy and safety of rituximab against B-cell lymphomas is well established. However, there has been an increased incidence of infectious complications after rituximab treatment, mostly hepatitis B reactivation and progressive multifocal leukoencephalopathy. This is the case of a 67-year-old patient with primary central nervous system lymphoma, who developed cytomegalovirus meningoencephalitis after receiving high-dose chemotherapy and rituximab. As there was no evidence of lymphoma relapse or additional immunosuppression, besides his previous treatment, an association between rituximab and cytomegalovirus meningoencephalitis cannot be ruled out.

High Frequency of Thyroid Disorders in Patients Presenting With Neutropenia to an Outpatient Hematology Clinic STROBE-Compliant Article.

Granulopoiesis abnormalities have been described in association with thyroid disorders (TD). However, data regarding systematic evaluation of adult neutropenia and concurrent or prior TD are scarce. To investigate the frequency of TD among patients presenting with neutropenia, and the immunophenotypic and immunologic profile of neutropenic patients with concomitant thyroidopathy. Two hundred eighteen consecutive neutropenic patients were prospectively evaluated in our outpatient Hematology Clinic, with a detailed laboratory screen, including thyroid function tests, antineutrophil antibodies, blood lymphocytes immunophenotyping, and detection of T-cell clonality by PCR. Among 218 patients with neutropenia, 95 (43.6%) had TD, 65 chronic immunologic neutropenia, 20 clonal proliferation of T-large granular lymphocytes (T-LGL), 5 autoimmune disorders, and 33 other diagnoses. TD-patients had an increased frequency of recurrent infections compared with other patients (P = 0.045). The following correlations were found: negative correlation between FT3 and absolute neutrophil count (ANC) (r²â€Š= -0.274, P = 0.007), negative correlation between TPO-Abs/TG-Abs and C4 (r²â€Š= -0.16, P = 0.045; r²â€Š= -0.266, P = 0.001), and CD4⁺ counts were inversely correlated to T4 and positively to TSH (r²â€Š= -0.274, P = 0.024; r²â€Š= 0.16, P = 0.045). In addition, TD-patients had significantly higher percentages of CD4⁺ lymphocytes (P = 0.003). Among TD-patients, 23.4% had Hashimoto thyroiditis (HT), 4.1%, Graves disease (GD), 8.2% nontoxic multinodular goiter (NTMG), 5% subclinical hypothyroidism, and 2.8% had undergone total thyroidectomy associated with nodules (TTM). Thirteen TD-patients displayed T-LGL. Patients with autoimmune thyroidopathy had an increased frequency of concomitant autoimmune manifestations (P = 0.03). Significant differences between the different thyroidopathies included: HT-patients had higher percentages of B-lymphocytes, while the opposite was evident for the TTM-subgroup (P = 0.009, 0.02); GD-patients showed an increase of the proportion of NK cells and a decrease in the percentage of TCRγδ+ lymphocytes (P = 0.001, 0.045); and NTMG-patients had significantly higher ANC (P = 0.004) compared to other thyroidopathies. Antineutrophil antibodies were found in 37.2% of TD-patients tested. Anti-TPO titers were significantly higher in patients with positive antineutrophil antibodies (P = 0.04). The frequency of TD among neutropenic patients may be higher than previously reported. The existence of antineutrophil antibodies, as well as the different distribution of lymphocyte subsets among patients with different TD, suggests both humoral and cellular mechanisms in the pathophysiology of thyroid disease-associated neutropenia.

Suboptimal erythropoietic response to hypoxemia in idiopathic pulmonary fibrosis.

BACKGROUND AND STUDY OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory process characterized by severe derangement of gas exchange in the advanced stages of disease. However, erythrocytosis is infrequent in IPF. The aim of this study was to investigate the potential relation between the blunted erythropoietic response and the chronic inflammation. SUBJECTS: Nine patients (6 men and 3 women) with IPF and profound hypoxemia (PO(2) < 65 mm Hg) and 34 sex- and age-matched healthy volunteers participated in the study. METHODS: We evaluated the hematologic parameters, serum erythropoietin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 levels. We also studied the development of burst-forming unit-erythroid (BFU-E)-derived colonies in semisolid methylcellulose cultures in blood samples from all patients. RESULTS: Hemoglobin and serum erythropoietin levels were almost comparable between the two studied groups. On the contrary, serum TNF-alpha, IL-6, and IL-8 values were significantly higher in patients with IPF (p < 0.05, p < 0.01, and p < 0.001, respectively). IPF sera induced a significant growth inhibition of erythroid bursts arising from mononuclear cells of either patients or control subjects compared with heat-inactivated AB serum (p < 0.05 and p < 0.01, respectively). Moreover, there was an apparent increment in the number of BFU-E colonies when patients' mononuclear cells were cultured in comparison with those of healthy subjects (p < 0.05). CONCLUSIONS: Our findings suggest that in IPF there is an increased number of primitive erythroid progenitors, which fail to proliferate and differentiate in vivo, suggesting a kind of ineffective erythropoiesis. As a consequence, hemoglobin levels do not rise in proportion to the severity of hypoxemia. Cytokines released from alveolar macrophages seem to have not only local but also systemic effects, since the serum of these patients directly suppressed erythropoiesis; however, the suboptimal erythropoietic response to hypoxia cannot be entirely attributed to this suppression. It is possible that several other factors interfere, synergistically or additively.

Leukemogenic risk of hydroxyurea therapy as a single agent in polycythemia vera and essential thrombocythemia: N- and K-ras mutations and microsatellite instability in chromosomes 5 and 7 in 69 patients.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative diseases that carry intrinsically the potential for leukemic transformation. The aims of this study were (1) to detect involvement of N- and K-ras mutations in codons 12 and 13 in the pathogenesis of the chronic and blastic phases of PV and ET, (2) to study the occurrence of microsatellite instability (MSI) in chromosomes 5 and 7 during the chronic phase and blastic transformation of the disease, and (3) to examine the incidence of leukemia in patients treated with hydroxyurea (HU). Samples of PV and ET patients were analyzed with a polymerase chain reaction. No N- or K-ras mutations were detected. A positive score for MSI in chromosome 7 was found in 1 patient with PV during leukemic transformation. Three of 69 patients developed acute myelogenous leukemia, 2 with PV and 1 with ET. As of this report, the overall incidence of leukemic transformation is 5.7% (2/35 patients) in PV and 3.3% (1/30 patients) in ET patients treated with HU. These results indicate that (1) MSI is a genetic marker that can be detected, even in a small group of patients, at the blastic phase of the disease and (2) no increased leukemogenicity was noted in this group of patients treated with HU.