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ObjectiveTo evaluate the potential role of Streptococcus salivarius K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction.Patients and methodsThe medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months.ResultsThe number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), p < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [p < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), p < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, p < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis (p < 0.001), oral aphthae (p < 0.001) and cervical lymphadenopathy (p < 0.001) significantly decreased following SSK12.ConclusionSSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

Purpose of the present paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients with Behçet’s disease (BD). The Registry is a clinical physician-driven non-population- and electronic-based instrument implemented for the retrospective and prospective collection of real-life data about demographics, clinical, therapeutic, laboratory, instrumental and socioeconomic information from BD patients; the Registry is based on the Research Electronic Data Capture (REDCap) tool, which is thought to collect standardised information for clinical real-life research, and has been realised to change over time according to future scientific acquisitions and potentially communicate with other existing and future Registries dedicated to BD. Starting from January 31st, 2021, to February 7th, 2022, 110 centres from 23 countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 5993 fields organised into 16 instruments, including patient’s demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. The development of the AIDA International Registry for BD patients will facilitate the collection of standardised data leading to real-world evidence, enabling international multicentre collaborative research through data sharing, international consultation, dissemination of knowledge, inclusion of patients and families, and ultimately optimisation of scientific efforts and implementation of standardised care.Trial registration NCT05200715 in 21/01/2022.

Background: Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown. Methods: Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n = 57) or non-responders (n = 28) to melphalan therapy. PBMCs from healthy controls (n = 25) were also included in the study. Results: In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P

The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P

PURPOSE: To describe the effects of the antitumor necrosis factor (TNF) monoclonal antibody Infliximab systemic therapy on choroidal neovacularisation (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Prospective, noncomparative series of three patients. METHODS: A subretinal membrane secondary to AMD was documented by fluoroangiography at baseline in three elderly patients scheduled to receive Infliximab therapy for inflammatory arthritis (infusions of 5 mg/kg at weeks 0, 2, 6, and every 8 weeks thereafter). Follow-up was performed at three months post-baseline, as well as during 18 months of continuing treatment in the first patient. RESULTS: CNV regressed partially at three months and resolved at six months in the first patient. Best-corrected visual acuity (BCVA) increased from 0.05 to 0.2; this effect was sustained at 18 months. Regression of subretinal membrane and increase of BCVA was also documented in the other patients. No ocular or extra-ocular side effects were noted. CONCLUSIONS: These findings suggest a plausible pathogenetic role of TNF in CNV secondary to AMD. Additional patients should he studied to confirm the promising clinical results. (c) 2005 by Elsevier Inc. All rights reserved.

Purpose To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). Patients and Methods The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the housekeeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m(2)) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM, Results The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). Conclusion Increased DNA damage and slower repairing capacity in the p53 gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure. (c) 2005 by American Society of Clinical Oncology.

Objective. To study the stiffness of large arteries in relation to the extent of skin and lung fibrosis, aortic distensibility was examined in patients with diffuse and limited systemic sclerosis (SSc). Methods. Consecutive patients (55 with diffuse and 51 with limited SSc) without signs and symptoms of heart failure or a previous history of arterial hypertension underwent echocardiography and lung function tests. Aortic stiffness was determined non-invasively by aortic distensibility and aortic strain measurements in all patients and in 50 healthy subjects, matched for age and gender. Results. Aortic distensibility in patients with either diffuse (2.03 +/- 0.26 x 10(-6) cm(2) dyn(-1)) or limited SSc (2.12 +/- 0.33) was similarly decreased compared with controls (2.49 +/- 0.36, P

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

Background The potential role of the adult thymus in T-cell homeostasis subsequent to lymphopenia remains the subject of debate. We examined whether thymic activity contributes to reconstitution of the peripheral T-cell pool, a critical process for patients recovering from antineoplastic therapy. Methods In selected patients with various neoplastic diseases we assessed peripheral blood lymphocyte subsets by flow-cytometry, including thymus-derived, CD4+ T cells expressing the CD45RA molecule, and thymic size rebound by CT scan before, and 3, 6 and 12 months after completion of cytotoxic therapy. Results Adult patients (n = 21, mean age of 30 years, range 18-49) had higher baseline numbers of B and lower numbers of NK cells than elderly patients (n = 15, mean age of 79 years, range 70-91), while total T-cell numbers did not differ. Despite the reduction of lymphocyte counts being comparable in the adult (mean of 45%) and elderly (mean of 49%) groups, occurring at, or near, completion of treatment, an enlargement of the previously atrophic thymus was evident in 63% of the adult, but in none of the elderly, subjects. In 22 patients who remained active disease-free during the following year, B cells and NK cells recovered to pretreatment levels as soon as at 3 months, whereas overall T-cell recovery occurred at 6 months post-treatment. Thymic rebound, observed in 11 of 22 patients who were of younger age, correlated significantly with a faster and more complete recovery of CD45RA+ CD4+ (mainly helper-naive) T cells. Conclusion The adult thymus appears capable of regeneration, at least up to middle age, contributing significantly to the reconstitution of the peripheral T-cell pool following chemotherapy-induced lymphopenia. In advanced age, however, although peripheral homeostatic pathways appear intact, regeneration of the naive repertoire is incomplete.

Administration of anti-tumor necrosis factor (anti-TNF) agents is beneficial in a variety of chronic inflammatory conditions, including psoriasis. We describe 5 patients in whom psoriasiform skin lesions developed 6-9 months after the initiation of anti-TNF therapy for longstanding, seropositive rheumatoid arthritis (etanercept or adalimumab), typical ankylosing spondylitis (infliximab), and Adamantiades-Behcet’s disease (infliximab). In all 5 patients, the underlying disease had responded well to anti-TNF therapy. Four patients developed a striking pustular eruption on the palms and/or soles accompanied by plaque-type psoriasis at other skin sites, while 1 patient developed thick erythematous scaly plaques localized to the scalp. In 3 patients there was nail involvement with onycholysis, yellow discoloration, and subungual keratosis. Histologic findings from skin biopsies were consistent with psoriasis. None of these patients had a personal or family history of psoriasis. In all patients, skin lesions subsided either with topical treatment alone, or after discontinuation of the responsible anti-TNF agent. The interpretation of this paradoxical side effect of anti-TNF therapy remains unclear but may relate to altered immunity induced by the inhibition of TNF activity in predisposed individuals.

Purpose of review To discuss the clinical effects and the immunologic consequences of transient B-cell depletion using the anti-CD20 monoclonal antibody rituximab in systemic lupus erythematosus. Recent findings A total of 100 rituximab-treated patients with severe disease, refractory to major immunosuppressive treatment, have been reported so far. Within a median follow-up period of 12 months rituximab was well tolerated, which is compatible with the experience accumulated from its use in more than 500 000 lymphoma patients. About 80% of patients achieved marked and rapid reductions in global disease activity. Because of the clinical heterogeneity, dosing differences, and concomitant treatments, including cyclophosphamide in 35% of patients, a proper evaluation of the clinical efficacy or rituximab is difficult. Variable degrees of clinical benefit have been reported for all clinical systemic lupus erythematosus manifestations, including active proliferative nephritis. Whereas 4-weekly infusions of 375 mg/m(2) of rituximab result in complete B-cell depletion lasting most often from 3 to 8 months, a prolonged depletion does not always correlate with a more favorable clinical response. Total immunoglobulin levels and protective antibodies are preserved, but anti-dsDNA antibody titers decrease, often independently of the clinical response. Summary The findings reviewed point to a growing optimism for targeting B cells in the treatment of systemic lupus erythematosus; therefore double-blind studies comparing rituximab with existing immunosuppressive therapies are needed. Moreover, careful assessments of the effects of transient B-cell depletion on distinct autoimmune pathogenetic processes will enable optimization of therapeutic single or combined therapeutic schemes.

Following administration to rats of various doses of N-nitrosodimethylamine (NDMA), O-6-methylguanine (O-6-meG) was lost from the DNA of four tissues (liver, white blood cells, lymph nodes, bone marrow) over two, sharply demarcated phases with substantially differing repair rates. Repair during each phase followed approximately first-order kinetics in O-6-meG, even after a high dose of NDMA which caused substantial depletion of O-6-alkylguanine-DNA alkyltransferase (AGT), a suicide repair protein. This is compatible with rate-determining adduct repair being brought about by a distinct, minor pool of AGT molecules which is rapidly replenished by de novo AGT synthesis. Similar biphasic repair kinetics were also observed in HepG2 cells treated in vitro with NDMA. In this case, the first phase of repair was inhibited by alpha-amanitin, an inhibitor of RNA polymerase II-mediated transcription. However, no dependence on transcriptional activity was found when O-6-meG repair in specific gene sequences with different transcriptional status in rat liver was examined, suggesting that the effects of a-amanitin in HepG2 cells did not reflect inhibition of preferential repair of transcribed sequences. Repair was also examined in rat liver hepatocytes and non-parenchymal cells separately after administration of NDMA at non-AGT depleting doses. Within each cell-population, the repair followed single phase, first-order kinetics, with adduct loss from AGT-rich hepatocytes being significantly faster than from the relatively AGT-deficient non-parenchymal cells. In conclusion, differences in the AGT content of different cell subpopulations in the liver (and probably in other tissues), as well as additional cellular factors affecting repair efficiency, appear to determine the observed variation in the kinetics of repair of O-6-meG. The additional cellular factors involved appear not to be related to the transcriptional state of the sequences being repaired, but may reflect different states of chromatin condensation. (C) 2004 Elsevier B.V. All rights reserved.

The impact of diacerein, an effective cartilage targeted therapy that is used in patients with osteoarthritis, on the development and progression of chronic inflammatory arthritis was evaluated in a tumor necrosis factor (TNF) transgenic mouse model (Tg197). The response to diacerein at 2, 20, or 60 mg/kg daily, as well as the comparative effects of other antiarthritis drugs including dexamethasone (0.5 mg/kg daily), methotrexate ( 1 mg/kg three times weekly) and an anti-TNF agent ( 5 mg/kg weekly), were assessed in the Tg197 mice. Treatment was initiated before the onset of arthritis and was continued for 5 weeks. A significant improvement in clinical symptoms was found in all three diacerein treated groups in comparison with untreated groups. Confirming these data, semiquantitative histopathologic analysis of the hind paws revealed a significant reduction not only in cartilage destruction but also in the extent of synovitis and bone erosion in diacerein treated groups in comparison with untreated groups. At the most effective dose tested ( 2 mg/kg daily), diacerein inhibited the onset of arthritis in 28% and attenuated the progression of arthritis in 35% of the Tg197 mice. Comparative analyses showed diacerein to be more potent than methotrexate but not as effective as dexamethasone or anti-TNF agents in suppressing the progression of the TNF mediated arthritis in this model. These results indicate that diacerein has a disease modifying effect on the onset and progression of TNF driven chronic inflammatory arthritis, suggesting that the prophylactic or therapeutic potential of diacerein in patients with RA should be further examined.

The autoimmune response is executed via cognate interactions between effector immune cells and antigen presenting cells. Cognate interactions provide the immune effectors with specific signals generated through the antigen receptor as well as with second, non-specific signals, generated from the interaction of pairs of cell-surface molecules (costimulatory molecules) present on their plasma membrane. Disruption of this second, non-specific costimulatory signal results in the interruption of the productive (auto)immune response, leading to anergy, a state of immune unresponsiveness. The CD28:137 families of molecules and the CD40:CD40L pair of molecules are considered as critical costimulatory elements. Disruption of the CD28:137 interaction using a genetically engineered soluble form of the inhibitory molecule CTLA4 in vitro, as well as in experimental models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), led to the inhibition of the autoimmune response. Similarly, promising data stem from the use of an anti-CD40L monoclonal antibody (mAb) in murine SLE. While such treatments prevent the development of autoimmunity in animal models, this preventive approach is inapplicable to human diseases. However, the rational bench-to-bed side approach led investigators to clinical trials of CTLA4-Ig and of two different humanized anti-human CD40L mAbs in patients with RA and SLE, respectively. Initial experience with the use of CTLA4-Ig in patients with RA is encouraging, since in one short-term trial the construct was well-tolerated and produced clinically meaningful improvement of the disease in a significant proportion of those treated. Surprisingly, the anti-CD40L mAb treatment approach in human lupus was not fruitful, since short-term administration of the anti-CD40L mAb ruplizumab in lupus nephritis was correlated with life-threatening prothrombotic activity despite initial encouraging data in the serology and renal function of the patients. Also, IDEC-131 anti-CD40L mAb treatment did not prove to be clinically effective in human SLE, despite being well tolerated. Precise tailoring of the administration schemes for these novel therapeutic modalities is awaited. Finally, conceptually different approaches to block costimulation by inhibiting the induced expression of costimulatory molecules or the transmission of their specific intracytoplasmic signal have already produced encouraging preliminary results.

PURPOSE: To assess the efficacy of the anti-TNF monoclonal antibody infliximab in uveitis patients without clinically evident ocular inflammation and impaired visual acuity because of chronic cystoid macular edema (CME). DESIGN: Prospective, noncomparative, interventional case series. METHODS: Patients with refractory CME (14 eyes, mean duration of 14 months), associated with intermediate uveitis (n = 6), Adamantiades-Behcet disease (n = 2), adult-type vascular pseudotumor (n = 1), and HLAB27+-related uveitis (n = 1) received an intravenous infliximab infusion (5 mg/kg); five patients were retreated after 1 month. RESULTS: Macular thickness, measured by ocular coherence tomography, was reduced from 428 +/- 138 mum to 219 +/- 51 mum at 2 months postbaseline (P = .0001), while visual acuity increased from 0.41 +/- 0.18 to 0.83 +/- 0.17 (P < .00001). Anatomic and functional improvement was sustained at 6 months in all. No ocular or extra-ocular side effects were noted. CONCLUSION: These promising results suggest that TNF may play an important pathogenetic role in chronic CME, thus, a controlled trial is warranted. (C) 2004 by Elsevier Inc. All rights reserved.

Controversies in the occurrence and implications of headache in patients suffering from systemic lupus erythematosus (SLE) triggered us to conduct an extensive literature search in order to answer five clinical questions. (i) Is headache prevalence higher in SLE patients than in the general population? (ii) Is ‘lupus headache’ a separate entity? (iii) Is there a distinct pathogenetic mechanism of headache in SLE? (iv) Is headache related to CNS involvement or general SLE activity? (v) Is headache related to anxiety- and depression-like symptoms in SLE? All published articles reporting data from >30 SLE patients were classified into four classes (I, IIa, IIb and III) by the quality of their evidence. We found no prospective controlled study (class I), but we identified seven controlled (class II) and 28 uncontrolled studies (class III) that retrospectively investigated the occurrence of headache in SLE patients. Eight out of 35 studies applied the International Headache Society (IHS) criteria for headache classification, whereas only four uncontrolled studies investigated paediatric SLE populations (class III). Pooled data from eight studies (controlled and uncontrolled) that used the IHS criteria show that 57.1% of SLE patients reported any type of headache (migraine 31.7% and tension-type headache 23.5%). Pooled data from seven controlled studies showed that the prevalence of all headache types, including migraine, was not different from controls. Insufficient evidence was found for the concept of ‘lupus headache’. No particular pathogenetic mechanism of headache in adult SLE patients has been identified, nor an association between headache and the disease status, including CNS involvement. There is no good evidence that headache is associated with anxiety and depression in SLE. Insufficient data (class III) do not allow safe conclusions for headache among paediatric SLE patients. These findings suggest that the occurrence of headache in adult SLE patients does not itself require further investigation and that headache in those patients should be classified according to IHS criteria and managed as primary headache if there is no specific indication of a role for SLE in the patient. These recommendations should be verified by a properly controlled and prospective study in both adult and paediatric populations.

Small bowel adenocarcinoma (SBA) is a relatively rare disease. Because of its rarity the role of chemotherapy either as adjuvant or for advanced disease has not been clearly defined. Therefore any information, including case reports, is warranted. We report on three patients with adenocarcinoma of the jejunum and ileum. Two patients with positive lymph nodes received postoperative adjuvant chemotherapy with 5-fluorouracil-folinic acid (5FU-FA) for 12 months but they developed metastatic disease 3 and 8 months later, respectively. The third patient was initially treated with the same agents but for metastatic disease. All patients were subsequently treated for tumor recurrence with irinotecan 350mg/m(2) i.v. every 3 weeks as salvage chemotherapy supported by Granulocyte Colony Stimulating Factor (G-CSF) for 5 days. Two patients achieved a minor response and had a dramatic improvement of their symptoms. Their survival times after irinotecan administration were 14 and 6 months with an overall survival after primary diagnosis of 29 and 27 months, respectively. The third patient who had a tumor refractory to 5FU-FA progressed also on irinotecan and had an 8-month overall survival. Although conclusions cannot be drawn regarding the role of adjuvant chemotherapy in SBA, it seems reasonable to extrapolate from large bowel carcinoma experience. Irinotecan seems to have some degree of activity in the treatment of SBA but further studies are warranted.

The aim of this study was to determine the serum levels of soluble markers reflecting different aspects of immune activation in HIV-1-infected patients, and assess their prognostic significance for occurrence of AIDS-related death before the advent of the highly active antiretroviral treatment (HAART). Serum concentrations of the soluble forms of interleukin-2 receptors (sIL-2R), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sEs) have been determined in a cohort of 64 HIV-1-infected patients, between 1990-1993. The patients were followed prospectively with regular visits at the outpatient department. Follow-up time was censored at January 1, 1997, the date after which HAART was introduced. The median follow-up time was 46 months (range, 2-78 months). By the end of follow-up, 34 subjects had died. Baseline levels of all three soluble markers were significantly lower in subjects who remained alive during the follow-up compared to subjects who died. Univariate analysis showed that individual sIL-2R and sICAM-1, but not sEs measurements, were significantly associated with time to death (p = 0.008 and 0.003, respectively). Even after adjustment for age and CD4(+) T-cell counts sIL-2R measurements remained significantly prognostic. Sensitivity analysis using follow-up time to year 2000 confirmed these results. Our data suggest that assessment of the immune activation status using the easily measured levels of circulating markers may provide additional information about the risk of AIDS-related death. Further studies are needed to assess the effect of HAART on the levels of immune activation markers and their prognostic value.

The successful introduction of antitumor necrosis factor treatments in clinical practice confirmed the biologic relevance of tumor necrosis factor function in chronic inflammatory conditions in humans, mainly in the pathogenesis of rheumatoid arthritis and inflammatory bowel disease. Studies on patients receiving antitumor necrosis factor treatments offered deeper insights into the mechanisms of antitumor necrosis factor action in arthritis and revealed a master regulatory role for tumor necrosis factor in a multitude of biologic processes underlying pathogenesis. However, within such pleiotropism of key functions, blockade of tumor necrosis factor has also led to a significant incidence of unwanted clinical complications. Experimental work in animal models is providing additional clues on the specific function of tumor necrosis factor and its receptors in disease, especially on the molecular and cellular pathways through which tumor necrosis factor orchestrates beneficial and deleterious responses. (C) 2003 Lippincott Williams Wilkins.

We report the characterization of a new gene (E4.5) that maps at chromosome band 13q14.3, a chromosomal area frequently deleted in chronic lymphocytic leukemia (CLL) and in other lymphoid malignancies. E4.5 gene encodes for a 4 kb mRNA expressed in various tissues and has an open reading frame of 531 amino acids. The predicted E4.5 protein shows strong homology with the human regulator of chromosome condensation (RCC1) protein, the principal GTP exchange factor for Ran protein. The E4.5 protein contains a BTB domain in its N-terminus, a protein-protein interaction motif. Therefore, we propose that E4.5 is a new member of the RCC1-related guanine nucleotide exchange factor (GEF) family with potent interaction with other proteins and unknown function. Until now, no tumor suppressor genes have been mapped in the 13q14.3 minimal deleted region (MDR) in patients with CLL. It has been proposed that loss of the 13q14.3 MDR may contribute to lymphoid neoplasia by altering the expression/function of genes located on 13q14.3 outside the MDR. The E4.5 is one of these genes with a potential role in the pathogenesis of CLL.

An expanded cytotoxic/memory T-cell subpopulation expressing low levels of the B-cell-specific CD20 molecule was found in peripheral blood and bone marrow of patients with multiple myeloma at the time of diagnosis, but returned to normal levels following treatment. CD3(+) CD20(dim) cells were also increased in monoclonal gammopathy of unknown significance albeit at lower levels. Lower CD3(+) CD20(dim) cell numbers at baseline may be associated with lack of response to treatment and a poor outcome. Because expansion of these T cells may be related to disease status, further studies should investigate their potentially unique function in plasma cell dyscrasias.

Behcet’s disease is a multisystemic, chronic relapsing inflammatory disease classified among the vasculitides. Recurrent mucocutaneous lesions may be the only symptoms in mild cases, but articular, ocular, vascular, and/or gastrointestinal and central nervous system involvement may occur in most of the patients. Ocular disease is the most frequent cause of morbidity leading to blindness in 25% of those affected. The various non-specific immunosuppressive drugs, used either alone or in combinations, frequently fail to control inflammation or maintain remissions. The aetiology of Behcet’s disease is unknown, however it is currently thought that a central pathogenetic role of tumour necrosis factor (TNF) in the inflammatory process is possible. Until June 2002, and according to published and anecdotal data, more than 80 patients from 10 different countries have received anti-TNF treatment. The short-term effects of the anti-TNF monoclonal antibody infliximab have been reported in several case reports and small case series, whereas the effects of etanercept have been presented in recent conferences. Preliminary results strongly suggest that infliximab is remarkably effective in inducing short-term remission of almost all manifestations of the disease, including acute, sight threatening panuveitis. A double blind, placebo controlled, one month study on the efficacy of etanercept in suppressing the mucocutaneous manifestations of the disease showed beneficial results. To date, significant side effects have not been reported. It seems that TNF block is an effective new treatment for patients with Behcet’s disease. Whether such treatment is superior to the conventional therapeutic approaches in preventing relapses and progression of the disease remains to be determined by carefully controlled studies. At least three open, long term studies, including larger numbers of patients are currently being conducted.

CD40 ligand (CD40L or CD154) is a costimulatory molecule expressed mainly on activated CD4(+) T cells. Concentrations of the soluble form of CD40L (sCD40L) in serum were determined for a cohort of 77 human immunodeficiency virus type 1 (HIV-1)-infected patients before and after initiation of highly active antiretroviral treatment (HAART) by a quantitative enzyme-linked immunosorbent assay. Circulating sCD40L levels were higher by twofold in untreated patients than in healthy controls (means standard deviations [SD]:1.41 +/- 1.48 versus 0.69 +/- 0.59 ng/ml; P < 0.001). HIV-1-infected patients classified as CD4 T-cell category I had significantly higher sCD40L levels than patients classified as CD4 categories 2 and 3 (mean +/- SD: 2.08 +/- 1.46 ng/ml versus 1.57 +/- 1.58 [category 2] and 0.94 +/- 1.25 ng/ml [category 3]; P = 0.046), while no correlation with clinical categories A, 13, and C was found. Individual serum sCD40L levels correlated with CD4(+) T-cell counts (P = 0.039) but not with viral load, gamma globulin levels, or acute-inflammatory-response markers. After 8 to 12 months of HAART, a further threefold increase of serum sCD40L levels, which paralleled the increase of CD4(+) T-cell counts, was observed. These novel findings suggest that sCD40L measurement in HIV-1-infected patients could serve as a new surrogate marker useful in the assessment of treatment efficacy, especially in settings where well-equipped laboratories and funding required for CD4(+) T-cell count and viral load measurements are not available.

CD40 ligand (CD40L, CD154) is overexpressed on T and B cells in systemic lupus erythematosus (SLE). Monocytes have been shown to contribute to immune-mediated pathology in SLE and to express CD40L under certain conditions. Therefore, we studied CD40L expression on lupus monocytes ex vivo, as well as after activation in vitro. A highly significant sevenfold increase in the frequency of CD40L-expressing peripheral monocytes from 23 SLE patients, compared to 16 healthy individuals (mean percentage of CD40L(+)CD14(+) among CD14(+) cells, 11.7 versus 1.6), was found by flow cytometry. Increased CD40L expression on monocytes correlated significantly with disease activity, elevated gamma-globulin serum levels, as well as increased CD40L expression on T cells. CD40L expression by lupus monocytes was verified at both the mRNA and protein levels, while LPS stimulation was found to upregulate CD40L mRNA accumulation and surface protein expression. CD40L expression on activated lupus monocytes within anti-CD3-stimulated, mononuclear cell cultures was also enhanced compared to control-derived monocytes. These novel findings underscore the multiplicity of pathways through which monocytes may contribute to SLE pathology and suggest that T cell-independent CD40L-mediated cell to cell interactions may be also involved in humoral immune activation in SLE. (C) 2002 Elsevier Science (USA).

We have retrospectively evaluated and characterized the hypersensitivity reactions associated with carboplatin administration in ovarian cancer patients treated mainly on an outpatient basis at the Laikon Hospital from 1988 to 1998. A total of 240 patients, who had never been exposed to platinum compounds previously, received carboplatin plus cyclophosphamide (n = 58) or paclitaxel (n = 136) intravenously, and intraperitoneal carboplatin plus intravenous cyclophosphamide (n = 46). The median number of carboplatin courses was 6 (range 3-12) and 5 (range 4-6) for the intravenous and intraperitoneal treatment regimens, respectively. Thirty-two of 194 patients (16%) who were on intravenous carboplatin treatment developed symptoms compatible with a hypersensitivity reaction to carboplatin, that was always verified by manifestation of at least similar symptoms on rechallenging. In contrast, in the group of 46 patients on intraperitoneal carboplatin treatment, no hypersensitivity reaction was ever noticed. Hypersensitivity reactions always occurred after administration of the first 4 intravenous courses of carboplatin; 4, 19, 4, and 5 reactions occurred at the 5th, 6th, 7th, and 8th courses, respectively. These reactions could be distinguished in: (a) mild hypersensitivity reactions in 20 of 194 patients, which manifested as itching (20 patients) and small area erythema plus erythema of the palms and soles (12 patients), occurring either during intravenous injection when most of the drug scheduled had been administered, or within 3 days, and (b) in severe reactions in 12 of 194 patients, which manifested acutely as itching, diffuse erythroderma, rigor, facial swelling, throat and chest tightness, tachycardia (12 patients) and bronchospasm (2 patients), and hypertension or hypotension in 8 and 4 patients, respectively. With appropriate symptomatic management, discontinuation of carboplatin treatment was not required in patients with mild hypersensitivity reactions, but none of the 12 patients with severe reactions was able to receive a full subsequent dose of carboplatin on rechallenging. However, in 4 of these 12 patients carboplatin was replaced by cisplatin, which was given for 4-6 courses without side effects. These findings indicate that although hypersensitivity reactions are common in general, occurring in almost 1 of every 6 patients treated intravenously with carboplatin, their clinical picture is variable, leading to discontinuation of treatment in only 6% of patients. This is not the case when the intraperitoneal route of carboplatin administration is used when indicated. Copyright (C) 2001 S. Karger AG, Basel.

Permanent loss of vision resulting from relapsing ocular inflammation occurs frequently in patients with Behcet’s disease, despite intensive, chronic Immunosuppressive therapy. Since tumour necrosis factor (TNF) might have an Important pathogenetic role in Behcet’s disease, we decided to give a single Infusion of infliximab-a monoclonal antibody against TNF-to five patients with relapsing panuveitis, at the immediate onset of last relapse. Remission of ocular Inflammation was evident within the first 24 h, and complete suppression was seen 7 days after treatment In ail patients. No side-effects were noted. We suggest that Infliximab is a rapid and effective new therapy for sight-threatening ocular inflammation in Behcet’s disease.

Objective: To investigate the response and toxicity of a salvage regimen in patients with advanced breast cancer whose tumours became resistant to fluorouracil-epirubicin-cyclophosphamide (FEC). By substituting doxorubicin for epirubicin and ifosfamide for cyclophosphamide, we aimed to evaluate the possible lack of cross-resistance between the two anthracyclines and the two alkylating agents. Patients and Participants: The study included 37 evaluable patients with histologically or cytologically proven breast cancer and evidence of progressive metastatic disease whose disease had progressed under FEC chemotherapy (15 patients) or had recurred within 6 months after FEC chemotherapy (22 patients). Interventions: A regimen of intravenous doxorubicin 50 mg/m(2) on day 1 plus intravenous ifosfamide 5 g/m(2) delivered over 2 days with mesna plus intravenous fluorouracil 600 mg/m(2) on day 1 was administered every 4 weeks. Nonresponding patients after two courses of treatment received intravenous paclitaxel 175 mg/m(2) over 3 hours. Results: Objective response was achieved by eight patients, with one complete and seven partial responses (21%; 95% confidence interval 10 to 38%). Median response duration was 3 months (range 2 to 7 months), time to progression was 5 months (3 to s months) and survival was 8 months (4 to 20 months). Myelotoxicity was significant, with five episodes of neutropenic fever, and 10 patients developed congestive heart failure. Cardiac toxicity developed in patients who received a median cumulative dose of >200 mg/m(2) of epirubicin plus 400 mg/m(2) of doxorubicin. Conclusion: Administration of doxorubicin plus ifosfamide in patients with tumour recurrence after FEC chemotherapy represents a moderately effective regimen, suggesting that the two anthracyclines and the two alkylating agents sequential administration of anthracyclines precludes use of this regimen in patients with impaired cardiac function and in those who have received a cumulative dose of anthracyclines >600 mg/m(2).

Background: To better understand the molecular background of B-cell overactivity characterizing systemic lupus erythematosus (SLE), we examined the expression of the CD22 co-receptor and of kinase Lyn, which are involved in signaling inhibitory pathways, in B cells from patients with SLE. Methods: Two-color flow cytometry was used to study the expression of surface antigens on freshly isolated peripheral B cells from patients with SLE, disease-control patients, and healthy volunteers. Intracellular kinases Lyn and Syk were analyzed using Western immunoblots, and differences at the messenger RNA (mRNA) level were evaluated using semiquantitative polymerase chain reaction (PCR). Results: Expression of B-cell surface CD22 was intact in patients with SLE, but expression of the B-cell kinase Lyn was significantly decreased in resting, as well as in anti-sIgM-stimulated B-cell-enriched cell lysates obtained from 66% of patients with SLE, Lyn deficiency was disease-specific and unrelated to disease activity, Expression of B-cell kinase Syk was similar in all study groups. Semiquantitative PCR revealed that Lyn mRNA was significantly decreased in lupus patients with decreased Lyn protein expression, suggesting that Lyn deficiency may be caused at least in part by defects at the transcription level. Conclusions: Decreased expression of Lyn in some patients with SLE represents a B-cell defect that may enhance our understanding of SLE molecular pathogenesis by providing rational therapeutic targets.

Deletions in the 5q14 region have been described in a variety of neoplasms, such as testicular germ cell tumors, ovarian, gastric and lung cancer. The high frequency of allelic losses observed in this region implies the presence of putative tumor suppressor gene(s) (TSGs). In the present study, we investigated in a series of 56 non-small cell lung carcinomas (NSCLCs) the allelic imbalance (Alm) within the 5q14 region, employing the D5S644 marker, and its relationship with p53 abnormalities, the kinetic parameters [proliferation index (PI) and apoptotic index (AI)] and the ploidy status of the carcinomas. AI at D5S644 was found at a frequency of 51.2%. The rather high percentage of Alm in stage I tumors suggests an early involvement in NSCLC development. LOH at 5q14 was associated with decreased AR in lung tumors insinuating the presence of a putative TSG(s) (P = 0.008). Simultaneous alterations of both p53 and D5S644 locus were the most frequent pattern observed (37.5%). Cases demonstrating this profile also exhibited a marked decrease in AI (P = 0.001). These findings imply a synergistic mechanism of co-operation between different TSGs. However, proliferation activity was dependent only on p53 status, leading to the assumption that the putative TSG(s) present at 5q14 may probably be involved in normal apoptotic procedures. Further studies are needed to identify the candidate gene(s). (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

Adhesion molecules expressed on the surface of immune cells transduce a variety of cell-activating signals and mediate important interactions by binding to multiple specific counter-receptors expressed on other cells or on extracellular matrix components. A large number of aberrations in the expression of cell-bound molecules at the mRNA and protein level in vivo have been described in patients with autoimmune connective tissue diseases, In vitro studies suggest the presence of functional abnormalities of adhesive pathways, at least at some points of the disease. Increased circulating levels of isoforms of several adhesion molecules have also been demonstrated in these patients. The possible involvement in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome and systemic sclerosis of E-, P- and L-selectins, of some integrins and of several adhesion molecules of the immunoglobulin superfamily that in addition participate in lymphocyte costimulation will be discussed in this review. Further studies on migration and recruitment patterns of immune cells into inflamed tissues, as well as on possible defects of lymphocyte activation in these patients, are expected to expand our knowledge on systemic autoimmune responses and identify targets for specific immunotherapy.

Objective: We investigated the double biochemical modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA) for the treatment of 65 patients with advanced colorectal cancer. In particular, we studied the response and toxicity of the regimen. Methods: A combination of MTX 130 mg/m(2) intravenously at day 0, followed 24 hours later by FA orally as MTX rescue, and FA 300 mg/m2 intravenously daily (days 1 to 4) followed by 5-FU 500 mg/m(2) intravenously daily (days 1 to 4) was administered. Results: Objective response was achieved by 23 patients, with three complete and 20 partial responses [35%: 95% confidence interval (CI) 23 to 48%]. Median survival of the group was 12 months (range 6 to 36 months). Conclusion: According to these results, double biochemical modulation of 5-FU : with MTX and FA led to a significantly higher response rate followed by considerable toxicity.

A large array of heterogeneous aberrations of the immune system have been described in systemic lupus erythematosus (SLE). Since the function and the fate of the immune system cells are governed principally by the biochemical events that follow ligation of specialized cell-surface receptors, we will review in this article recent developments in our understanding of abnormalities in the biochemistry of signals generated either by the antigen-receptor complex or by systems of costimulatory cell-surface molecules, like the CD28/CTLA4:CD80/CD86 and the CD40:CD40L pairs found on the surface membrane of lupus immune cells.