Clinical Relapse In Patients Research Articles

Postallogeneic monitoring with molecular markers detected by pretransplant next‐generation or Sanger sequencing predicts clinical relapse in patients with myelodysplastic/myeloproliferative neoplasms

Relapse is the major cause of treatment failure after allogeneic stem-cell transplantation (AHSCT) for patients with myelodysplastic syndrome/myeloproliferative syndrome neoplasms (MDS/MPN). We evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post-transplantation. We screened 45 patients with chronic myelomonocytic leukemia (n=39 patients, including seven with transformed-acute myeloid leukemia), MDS/MPN unclassifiable (n=5), and atypical BCR-ABL1-negative CML (n=1) for mutations in ASXL1, CBL, NRAS, and TET2 genes by molecular genetics including a sensitive next-generation sequencing (NGS) technique. In 36 patients, sufficient DNA was available for molecular analyses. In particular, TET2 and CBL mutations were screened applying amplicon deep sequencing. In 89% of cases, at least one mutation could be detected: ASXL1: n=18 (50%); CBL: n=7 (19%); TET2: n=15 (42%); and NRAS: n=11 (32%). Survival after AHSCT at 5yr was 46% (95% CI 28-64%) and was not influenced by any mutation. After a median of 6months after AHSCT in 33% of the patients, one of the molecular markers was still detectable, resulting in a higher incidence of relapse than in patients with undetectable mutations (50% vs. 15%, P=0.04). In conclusion, pretransplant molecular mutation analysis can help to detect biomarkers in patients with MPN/MDS, which may be subsequently used as minimal residual disease markers after AHSCT.

Short-Term Stress, but Not Mucosal Healing Nor Depression Was Predictive for the Risk of Relapse in Patients with Ulcerative Colitis

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Psychological factors such as depression and stress are under debate to contribute to the risk of relapse. The impact of mucosal healing to reduce the risk of relapse had not been studied prospectively. The aim of this study was to identify whether depression and stress increase and mucosal healing reduces the risk of clinical relapse in patients with UC in clinical remission. Patients in clinical remission were followed prospectively for 1 year, or less if they relapsed. Endoscopy and histology score and long-term perceived stress (Perceived Stress Questionnaire) were measured at baseline. Mucosal healing was defined by a Mayo Endoscopy score of 0-1. Depression (Hospital Anxiety and Depression Scale) and acute perceived stress (Cohen Perceived Stress Scale) were measured at baseline and after 1, 3, 6, 9, and 12 months. A time-dependent multivariate Cox regression model determined the predictors of time to relapse. Seventy-five patients were included into final analysis, of which 28 (37.3%) relapsed. Short-term stress at the last visit before relapse (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.01-1.10) and male gender (HR = 2.38, 95% CI = 1.01-5.61), but not baseline mucosal healing (HR = 0.86, 95% CI = 0.35-2.11), baseline long-term stress (HR = 0.20, 95% CI = 0.01-3.31), and depression at the last visit before relapse (HR = 1.08, 95% CI = 0.95-1.22) were predictive for a relapse. Short-term stress but not depression nor mucosal healing was predictive for the risk of relapse in patients with UC in clinical remission. Larger multicentre studies are necessary to confirm our findings.

Sustained Clinical Remission and Rate of Relapse After Tocilizumab Withdrawal in Patients with Rheumatoid Arthritis

Data on when to stop use of biological agents in rheumatoid arthritis (RA) are scant. We assessed the length of remission and the rate of clinical relapse in patients with RA who had to discontinue treatment with tocilizumab (TCZ) because of the ending of longterm (5 yrs) open-label clinical trials. All patients at 2 participating centers in Mexico were in remission, defined as Disease Activity Score 28 ≤ 2.6, with no swollen joints at the time of the last TCZ infusion. Patients were followed thereafter every 8 weeks for 12 months or until relapse. Relapse was defined as the presence of ≥ 1 swollen joint. Doses of methotrexate and antiinflammatory drugs were not changed during the followup period. Forty-five patients were analyzed, 87% were women (mean age 52 yrs, mean disease duration 14 yrs). During the 12 months of followup, 44% of patients maintained remission. Relapses occurred in 56% of patients: 14 during the first 3 months after the last TCZ administration. Retreatment using other agents achieved low disease activity or remission. Longterm clinical remission is possible in a number of patients with RA after suspension of TCZ. This effect has also been reported with other biologic agents. Additional data are required to support recommendations for discontinuing a biological agent after achieving remission.

Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma

Angiogenesis is not only dependent on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for stabilization of vascular walls. Clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway is still limited to date. We hypothesized that the level of vessel maturation is critically involved in the response to antiangiogenic therapies. To test this hypothesis, we evaluated the vascular network in spontaneously developing melanomas of MT/ret transgenic mice after using PTK787/ZK222584 for anti-VEGF therapy but also analyzed human melanoma metastases taken at clinical relapse in patients undergoing adjuvant treatment using bevacizumab. Both experimental settings showed that tumor vessels, which are resistant to anti-VEGF therapy, are characterized by enhanced vessel diameter and normalization of the vascular bed by coverage of mature pericytes and immunoreactivity for desmin, NG-2, platelet-derived growth factor receptor beta, and the late-stage maturity marker alpha smooth muscle actin. Our findings emphasize that the level of mural cell differentiation and stabilization of the vascular wall significantly contribute to the response toward antiangiogenic therapy in melanoma. This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this.

Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL

AbstractPersistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell–engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome–negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively.

Post-Allogeneic Monitoring with Molecular Markers Detected by Pre-Transplant Next Generation Sequencing (NGS) Predicts Clinical Relapse in Patients with Chronic Myelomonocytic Leukemia (CMML)

AbstractAbstract 4212Allogeneic stem cell transplantation remains the only curative treatment approach for chronic myelomonocytic leukemia (CMML), but relapse is the major cause of treatment failure. Here, we evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post transplantation in patients with CMML. We screened 45 patients with a median age of 57 years (range: 24–73 years) who underwent allogeneic SCT pre transplant for molecular markers including a sensitive next-generation sequencing (NGS) technique. Of those, 7 were transformed to secondary acute myeloid leukemia, 5 were classified as MDS/MPN overlap and one patient as atypical CML. In 36 patients sufficient DNA was available for molecular analyses for ASXL1, CBL, NRAS and TET2, mutations. In particular, TET2 and CBL mutations were screened applying amplicon deep-sequencing (454 Life Sciences, Branford, CT).In 32 patients (89%) at least one mutation could be detected: ASXL1: n=18: 50%; CBL: n=7: 19%; TET2: n=15:42%; NRAS: n= 11: 32%. Allogeneic SCT was performed after reduced intensity (66%) or standard myeloablative (33%) conditioning from related (22%) or unrelated donors (78%). The overall survival at 5 years was 46% (95% CI 28–64%) and the cumulative incidence of relapse at 2 year was 35%. Neither TET2, ASXL1, CBL nor NRAS mutations influenced overall survival significantly.In 21 surviving patients with at least one positive marker pre transplantation, the corresponding marker was subsequently tested in peripheral blood after a median of 6 months (range 3–9 months) after transplantation.In 6 (33%) of the patients one of the molecular markers was still detectable: ASXL1: n=3; CBL: n= 3; TET2: n=2, NRAS: n=3) and in 66% the markers were undetectable. In patients who became negative for any molecular marker the cumulative incidence of relapse at 1 year was significantly lower than in the positive tested patients. (15% versus 50%, p = 0.04).In conclusion, this study shows that molecular monitoring post transplant with molecular markers detected also by NGS pre-transplant can help to predict the risk of relapse and may be used to guide post transplant immune-modulating therapies to prevent clinical relapse. In larger studies sequential monitoring of molecular markers after stem cell transplantation are mandatory to determine optimal timing for predicting relapse and for therapeutic intervention. Disclosures:Bacher:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

Prognostic Value of Serologic and Histologic Markers on Clinical Relapse in Ulcerative Colitis Patients With Mucosal Healing

Endoscopic mucosal healing is a key endpoint for the treatment of ulcerative colitis (UC). The role of microscopic activity in predicting disease relapse has not been fully assessed. We aimed to investigate the predictive role of serologic and histologic markers on disease relapse in UC patients with endoscopically inactive disease. Adult UC patients with endoscopically inactive disease (Mayo 0) and a 12-month follow-up between 2008 and 2011 were retrospectively included. An expert pathologist evaluated all colonic biopsies for histologic activity (Geboes score) and the presence of basal plasmacytosis. Blood samples collected around the time of endoscopy were analyzed. Disease relapse, defined as a clinical Mayo score ≥3, was documented during follow-up. The study cohort consisted of 75 patients (53% men, median age 47 years). Despite normal endoscopy, histology showed inflammatory activity with a Geboes score ≥3.1 in 40% and basal plasmacytosis in 21% of patients. At 12 months, clinical relapse was observed in 20% (n=15) of patients. Presence of basal plasmacytosis (P=0.007) and a Geboes score ≥3.1 (P=0.007) were predictive of disease relapse. Using multivariate analysis, the presence of basal plasmacytosis was predictive of clinical relapse (odds ratio (OR) 5.13 (95% confidence interval (CI): 1.32-19.99), P=0.019), whereas the use of biologicals at endoscopy favored remission (OR 0.24 (95% CI: 0.05-1.01), P=0.052). We demonstrated that the presence of basal plasmacytosis predicts UC clinical relapse in patients with complete mucosal healing. We recommend closer follow-up and optimization of medical therapy in patients with basal plasmacytosis.

Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK-19mRNA-positive circulating tumor cells: results of a randomized phase II study

Since the detection of circulating tumor cells (CTCs) which express HER2 is an adverse prognostic factor in early breast cancer patients, we investigated the effect of trastuzumab on patients' clinical outcome. Seventy five women with HER2 (-) breast cancer and detectable CK19 mRNA-positive CTCs before and after adjuvant chemotherapy, were randomized to receive either trastuzumab (n=36) or observation (n=39). CK19 mRNA-positive CTCs were detected by RT-PCR and double stained CK(+)/HER2(+) cells by immunofluorescence. The primary endpoint was the 3-year disease-free survival rate. Fifty-one (89%) of the 57 analyzed patients had HER2-expressing CTCs. After trastuzumab administration, 27 of 36 (75%) women became CK19 mRNA-negative compared to seven of 39 (17.9%) in the observation arm (p=0.001). After a median follow up time of 67.2 months, four (11%) and 15 (38%) relapses were observed in the trastuzumab and observation arm, respectively (p=0.008); subgroup analysis indicated that this effect was mainly confined to women with >3 involved axillary lymph nodes (p=0.004). The median DFS was also significantly higher for the trastuzumab-treated patients (p=0.008). Administration of trastuzumab can eliminate chemotherapy-resistant CK19 mRNA-positive CTCs, reduce the risk of disease recurrence and prolong the DFS.

Long-Term Clinical Outcomes and Factors Predictive of Relapse After 5-Aminosalicylate or Sulfasalazine Therapy in Patients With Intestinal Behcet Disease

Currently, 5-aminosalicylic acid (5-ASA)/sulfasalazine is used to empirically treat patients with intestinal Behcet disease (BD) without clear clinical evidence. In this study, we investigated long-term clinical outcomes and predictors of clinical relapse in patients with intestinal BD receiving 5-ASA/sulfasalazine maintenance therapy. We reviewed the medical records of all the patients with intestinal BD, who received 5-ASA/sulfasalazine therapy in a single tertiary academic medical center between March 1986 and January 2011. The cumulative probabilities of clinical relapse after remission were calculated using the Kaplan-Meier method. Predictors of clinical relapse were identified by univariate analysis using the log-rank test and by multivariate analysis using Cox proportional hazards regression models. Among the 143 patients enrolled, 46 (32.2%) had a clinical relapse while they were being treated with 5-ASA/sulfasalazine therapy. The cumulative relapse rates at 1, 3, 5, and 10 years after remission were 8.1%, 22.6%, 31.2%, and 46.7%, respectively. By multivariate analysis, a younger age (<35 y) at the time of diagnosis, higher C-reactive protein level (≥1.5 mg/dL), and a higher disease activity index for intestinal Behcet disease score (≥60) at the time of 5-ASA/sulfasalazine initiation were independent predictors of relapse in patients with intestinal BD receiving 5-ASA/sulfasalazine maintenance therapy. This study has shown that 5-ASA/sulfasalazine therapy has a positive effect in maintaining remission in patients with intestinal BD. However, a younger age (<35 y), higher C-reactive protein level (≥1.5 mg/dL), and a higher disease activity index for intestinal Behcet disease score (≥60) were associated with a poor response to 5-ASA/sulfasalazine therapy, making careful observation and intensive treatment necessary in these risk groups.

864 Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients With Crohn's Disease in Remission After Infliximab Withdrawal. a Sub-Analysis of the Stori Study

Close Monitoring of CRP and Fecal Calprotectin is Able to Predict Clinical Relapse in Patients With Crohn's Disease in Remission After Infliximab Withdrawal. a Sub-Analysis of the Stori Study Nicolas de Suray, Julia Salleron, Gwenola Vernier-Massouille, Jean-Charles Grimaud, Yoram Bouhnik, David Laharie, Jean-Louis Dupas, Helene PillantLe Moult, Laurence Picon, Michel Veyrac, Mathurin Flamant, Guillaume Savoye, Raymond Jian, Martine De Vos, Eric Piver, Jean-Frederic Colombel, Edouard Louis

Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab

Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.

Prediction of Crohn’s disease relapse with faecal calprotectin in infliximab responders: a prospective study

Aliment Pharmacol Ther 2011; 34: 462–469 Summary Background Faecal calprotectin is a reliable tool for predicting Crohn’s disease (CD) relapse in patients with sustained remission. Prediction of relapse with faecal calprotectin has been less studied in patients with severe CD treated with anti-TNF. Aim To identify an association between faecal calprotectin concentration and CD clinical relapse in patients achieving remission with infliximab (IFX). Methods From February 2007 to October 2008, consecutive patients with refractory luminal CD were prospectively included when they received three IFX infusions (5 mg/kg at weeks 0, 2 and 6) followed by maintenance with an immunomodulator alone. Faecal calprotectin and C-reactive protein (CRP) were measured at entry and at week 14 (w14). Results Sixty-five patients (43W; median age: 30.4 years) were included, and 50 (77%) were in clinical remission off steroids at w14; twenty-three of fifty (46%) experienced CD clinical relapse during the first year of follow-up. Median faecal calprotectin level at w14 was similar in patients with and without CD clinical relapse (200 and 150 μg/g respectively). When considering two suggested faecal calprotectin cut-offs to predict CD relapse, sensitivities and specificities were 61% and 48% for 130 μg/g, respectively, and 43% and 57% for 250 μg/g. Neither faecal calprotectin nor CRP at baseline and at w14 could predict relapse even when CD location subgroup analysis was considered. Conclusion In patients responding to an infliximab induction regimen, faecal calprotectin measurement at w14 cannot predict Crohn’s disease clinical relapse at 1 year.

Prediction of Crohn’s disease relapse with faecal calprotectin in infliximab responders: a prospective study

Faecal calprotectin is a reliable tool for predicting Crohn's disease (CD) relapse in patients with sustained remission. Prediction of relapse with faecal calprotectin has been less studied in patients with severe CD treated with anti-TNF. To identify an association between faecal calprotectin concentration and CD clinical relapse in patients achieving remission with infliximab (IFX). From February 2007 to October 2008, consecutive patients with refractory luminal CD were prospectively included when they received three IFX infusions (5mg/kg at weeks 0, 2 and 6) followed by maintenance with an immunomodulator alone. Faecal calprotectin and C-reactive protein (CRP) were measured at entry and at week 14 (w14). Sixty-five patients (43W; median age: 30.4years) were included, and 50 (77%) were in clinical remission off steroids at w14; twenty-three of fifty (46%) experienced CD clinical relapse during the first year of follow-up. Median faecal calprotectin level at w14 was similar in patients with and without CD clinical relapse (200 and 150μg/g respectively). When considering two suggested faecal calprotectin cut-offs to predict CD relapse, sensitivities and specificities were 61% and 48% for 130μg/g, respectively, and 43% and 57% for 250μg/g. Neither faecal calprotectin nor CRP at baseline and at w14 could predict relapse even when CD location subgroup analysis was considered. In patients responding to an infliximab induction regimen, faecal calprotectin measurement at w14 cannot predict Crohn's disease clinical relapse at 1year.

MRI findings of neuro-Behcet’s disease

Neurological manifestations present in 5% to 30% of patients with Behçet's disease. We studied consecutive patients with relapsing--remitting or progressive neuro-Behcet's disease who referred from January 2002 to January 2009 to Nemazee Hospital, Shiraz, southern Iran. Sequential MRIs were performed during clinical relapses in patients with relapsing--remitting course or during relentless progression after first referral of patients with progressive course. We reviewed 55 MRIs of 17 patients (ten men and seven women) with age of 36.4 ± 8.1 years at the time of first MRI. Nine (53%) patients had a relapsing-remitting course and eight (47%) had a progressive course. The initial and last follow-up studies had a mean interval of 29.2 months (range, 24 to 84). Of the patients with progressive neuro-Behcet's disease, 50% had brainstem atrophy and 75% had black holes in their last follow-up MRIs. The respective prevalence rates for those with relapsing--remitting neuro-Behcet's disease were 0% and 11%. In the total population of patients with neuro-Behcet's disease, the number of lesions (p = 0.002) and MRI burden (p = 0.016) had a significant increase in the last follow-up studies in comparison to the initial studies. Incremental pattern in the number of lesions and MRI burdens in patients with parenchymal neuro-Behcet's disease in our longitudinal study may imply an ongoing pathologic process.

Relationship between Thiopurine metabolite levels and endoscopic improvement in patients with postoperative moderate to severe endoscopic recurrence of Crohn's disease

Introduction: Endoscopic recurrence of Crohn's disease (CD) after curative ileocecal resection, which is reported in up to 70% of patients within 1 year, precedes clinical relapse. Azathioprine (AZA) reduces the risk of both clinical and endoscopic recurrence. Aim: To evaluate the association between thiopurine metabolite levels and endoscopic improvement in CD patients with moderate to severe postoperative endoscopic recurrence. Methods: Patients treated with AZA within the AZT-2 study, a prospective double-blinded trial comparing 2.0–2.5mg/kg/d AZA versus 4.0g/d mesalamine for prevention of clinical relapse in patients with postoperative moderate to severe endoscopic recurrence, were included. Ileocolonoscopy was performed at baseline and at week 52 or at premature discontinuation (median 364 days, range: 176–381). Red blood cell concentrations (RBC) of 6-thioguanine nucleotides (6-TGN), 6-methyl-mercaptopurine ribonucleotides (6-MMPR), and 6-methyl-thioguanine nucleotides (6-MTGN) were measured by high-performance liquid chromatography assay. A cut-off value of 6-TGN of ≥235pmol/8×108 RBC was used as established in literature. 6-MMPR and 6-MTGN levels below and above the median were considered low and high, respectively. Endoscopic improvement was defined as a reduction of the endoscopic score according to Rutgeerts by at least one point, and mucosal healing as endoscopic score of i0 (=no lesions). Results: Endoscopic data were available on 31 patients treated with azathioprine (f/m=13/18, median age: 32 years, median AZA dose: 2.24mg/kg/d) for median 358 days. At last observation, the median levels of 6-TGN (n=26), 6-MMPR (n=27), and 6-MTGN (n=26) were 139.7, 1696.1 and 70.1pmol/8×108 RBC, respectively. Overall, endoscopic score improved from i3-i4 to i0-i2 (p=0.004). Mucosal healing was achieved in 6/31 (19.4%) of patients. High 6-TGN levels (n=8) were associated with a significantly higher drop in the Rutgeerts score than low 6-TGN (n=18) levels (median drop of 3 vs. 1, p=0.023). There was no difference concerning mucosal healing (p=0.33). Furthermore, there was no correlation between 6-MMPR and 6-MTGN levels and endoscopic improvement. Conclusion: Our data suggest that high 6-TGN levels may linked to endoscopic improvement in patients with postoperative endoscopic recurrence of CD.

Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma

Angiogenesis is not only dependent on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for stabilization of vascular walls. Clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway is still limited to date. We hypothesized that the level of vessel maturation is critically involved in the response to antiangiogenic therapies. To test this hypothesis, we evaluated the vascular network in spontaneously developing melanomas of MT/ret transgenic mice after using PTK787/ZK222584 for anti-VEGF therapy but also analyzed human melanoma metastases taken at clinical relapse in patients undergoing adjuvant treatment using bevacizumab. Both experimental settings showed that tumor vessels, which are resistant to anti-VEGF therapy, are characterized by enhanced vessel diameter and normalization of the vascular bed by coverage of mature pericytes and immunoreactivity for desmin, NG-2, platelet-derived growth factor receptor β, and the late-stage maturity marker α smooth muscle actin. Our findings emphasize that the level of mural cell differentiation and stabilization of the vascular wall significantly contribute to the response toward antiangiogenic therapy in melanoma. This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this.

Traitements actuels de la sclérose en plaques

Several drugs are now available to treat multiple sclerosis. MS treatment has included immunomodulatory agents for 15 years; monoclonal antibody therapies have recently been added. IFN beta and Glatiramer acetate are effective in reducing relapses and lesions visible on magnetic resonance imaging (MRI) in patients with MS. Natalizumab, a monoclonal antibody, reduces the short-term risk of increasing disability and the rate of clinical relapse in patients with relapsing MS. Clinical trials are currently underway to assess the efficacy of other monoclonal antibodies and immunosuppressors. In the future, remyelinating and neuroprotective approach offers new perpectives.

Serum levels of complement C4 fragments correlate with disease activity in multiple sclerosis: Proteomic analysis

To detect serum biomarkers associated with disease activity in relapsing–remitting multiple sclerosis (MS). We studied serum low-molecular peptide profiling of MS patients and normal controls comprehensively by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Serum level of 1741 Da peptide was increased at the time of clinical relapse in patients than in normal controls and returned toward normal during remission. Tandem mass spectrometry analysis revealed that the peptide was a fragment of complement C4 (NGFKSHALQLNNRQI). This fragment peptide could be a possible marker of disease activity. It may reflect complement activation in the pathogenesis of MS.

Mitoxantrone: benefits and risks in multiple sclerosis patients

Mitoxantrone (MTX) is a synthetic antineoplastic cytotoxic drug, active both on proliferative and non-proliferative cells. The efficacy of MTX has been suggested by many open-label or observational studies and demonstrated in four randomized controlled clinical trials (RCTs). It is indicated for reducing neurological disability and the frequency of clinical relapses in patients with progressive relapsing and worsening relapsing-remitting MS patients. The short-term most frequent adverse events observed in RCTs have been nausea/vomiting, alopecia, an increased risk of urinary and respiratory tract infections, phlebitis, transitory leukopenia, amenorrhea in female patients and infertility. However, the most serious risks of the drug are represented by potential cardiotoxicity and leukaemia, whose incidence seems to be higher than previously reported. Therefore, all potential serious adverse events should be carefully considered against the potential relevant benefits of MTX treatment on every single MS patient.

Curcumin has Bright Prospects for the Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life. While the aetiology of IBD is not understood well, it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines. Curcumin is a bioactive substance present in the rhizomes of the herb "Curcuma longa" which has been used for centuries in Asia, both in traditional medicine and in cooking as turmeric which gives food an exotic natural yellow color. Further, in recent years, a large number of research papers have reported intriguing pharmacologic effects associated with curcumin. These include inhibitory effects on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-alpha, interferon gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-kappaB), in addition to a strong anti-oxidant effect. NF-kappaB is a key factor in the upregulation of inflammatory cytokines that have a high profile in inflammatory diseases, suggesting that curcumin could be a novel therapeutic agent for patients with IBD. Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles, from the pro-inflammatory Th1 to the anti-inflammatory Th2 type. In human IBD, up to now, only one open study has achieved encouraging results. In this study, patients were given curcumin (360 mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD. The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-alpha, IFN-gamma, NF-kappaB and its unrivalled safety profile suggest that it has bright prospects in the treatment of IBD. However, randomized controlled clinical investigations in large cohorts of patients are needed to fully evaluate the clinical potential of curcumin.