Therapeutic management of idiopathic pulmonary fibrosis: an evidence-based approach. |
Thu, Jul 22,2010 |
The treatment of idiopathic pulmonary fibrosis (IPF) remains controversial. The benefits of conventional treatment with corticosteroids plus either azathioprine or cyclophosphamide have not been established in randomized, controlled trials. Other treatment strategies have been suggested as understanding of the pathogenesis of IPF has increased. Recent clinical and animal studies suggest that modulating the effects of profibrotic growth factors and cytokines holds significant promise. As additional well controlled prospective studies are completed, these trials should provide the clinical evidence necessary for identifying optimal treatment strategies for future patients who have IPF.
|
|
A double-blind clinical trial for treatment of Crohn's disease by oral administration of Alequel, a mixture of autologous colon-extracted proteins: a patient-tailored approach. |
Thu, Jul 22,2010 |
|
OBJECTIVES: In this study, we evaluated the safety and efficacy of a personalized mode of treatment for Crohn's disease (CD) by oral administration of Alequel an extract of autologous colonic proteins. METHODS: Thirty-one patients with moderate to severe CD were enrolled in a 27-wk randomized, double-blind, placebo-controlled trial. Patients were randomized to receive either a placebo or the study drug prepared from autologous colonic extract. RESULTS: Oral administration of autologous colonic proteins resulted in clinical remission (58% vs 29%; 46.6% vs 26.6%, using an intention to treat analysis, p= NS), clinical response (67% vs 43%; 53.3% vs 40%, using an intention to treat analysis, p= NS) and improved quality of life (Inflammatory Bowel Disease Questionnaire score improvement 43%vs 12%) in the drug study group, compared to placebo group. No treatment-related adverse events were noted. Only in the study-drug-treated cohort who achieved clinical remission (DR), there was a decreased number of subject-specific, antigen-directed, IFNgamma spot-forming colonies. DR subjects had a lower initial C-reactive protein level than DNOR or placebo subjects, an increased percentage of peripheral blood nature killer T cells, and an increased CD4+/CD8+ T-cell ratio throughout the period of drug administration. CONCLUSIONS: Oral administration of Alequel is a safe method for treatment of patients with moderate to severe CD, and its efficacy needs to be proven. Several markers may be applicable as surrogate markers for the clinical effect.
|
|
Rituximab as therapy for refractory polymyositis and dermatomyositis. |
Thu, Jul 22,2010 |
|
We describe response to rituximab treatment of refractory inflammatory myopathy. Three patients with long-standing polymyositis (PM) or dermatomyositis (DM) poorly responsive to prednisone combined with several immunosuppressants were given intravenous rituximab 1,000 mg on Days 0 and 14. Prior to rituximab, each had significant proximal weakness with creatine phosphokinase (CPK) elevation to>3 times the normal upper limit (range 789-3,123 U/l). Patients were receiving prednisone plus methotrexate (MTX) or azathioprine. CPK decrease was observed 1 month post-infusion, with normalization of levels averaging 4.6 months (range 2.6-7.7 mo). Muscle strength improved in all, with strength returning to normal in 2. Average daily prednisone dose decreased from 16.7 mg (range 10-20 mg) to 4 mg (range 0-7 mg) after infusion. MTX dose was tapered by 50% in 2 patients. The third patient eventually discontinued all additional therapies. Percentage of CD19+ cells in each were suppressed at 0-1% 5 to 6 months after infusion (normal 5-21%). Elevated CPK with return of clinical symptoms occurred in 2 patients 6 and 10 months post-infusion, requiring rituximab retreatment. CD19+ cells remained suppressed at 1% in one patient, but were almost normal at 4% in the other. The third patient remains disease-free 12 months after initial treatment, even though her CD19+ cells are now normal at 8%. Thus, short-term beneficial effects with rituximab were observed in patients with DM and PM. However, the need for retreatment did not correlate with levels of CD19+ cells.
|
|
Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance. |
Thu, Jul 22,2010 |
|
The response to initial glucocorticoid therapy in childhood acute lymphoblastic leukaemia (ALL) reliably predicts the response to multiagent chemotherapy. Patients resistant to glucocorticoids (prednisone poor responders (PPR)) have a poorer event-free survival compared to glucocorticoid-sensitive patients (prednisone good responders (PGR)). A case-control study was performed to investigate differential protein expression in leukaemic blasts from PGR and PPR childhood ALL patients. Two-dimensional gel electrophoresis (2-DE) was used for an unsupervised screening and surface enhanced laser desorption/ionisation-time of flight mass spectrometry (SELDI-TOF MS) for the characterisation of protein spots. In difference maps of average gels for the proteomes of each responder group, differentially expressed proteins were identified after tryptic digestion and spotting onto H4-SELDI-TOF-MS chips. Proteins overexpressed in PPR were Catalase, RING finger protein 22 alpha, Valosin-containing protein (VCP) and a G-protein-coupled receptor. Proteins overexpressed in PGR were protein kinase C and malate dehydrogenase. Valosin-containing protein was chosen for validation and quantification by Western blot analysis in a second case-control group of ALL patients. In this second independent cohort, median VCP expression (P25-P75) was 0.15 (0.11-0.28) in PGR and 0.34 (0.14-0.99) in PPR patients (P = 0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.
|
|
Initial treatment of idiopathic nephrotic syndrome in children: prednisone versus prednisone plus cyclosporine A: a prospective, randomized trial. |
Thu, Jul 22,2010 |
|
Previous studies of the Arbeitsgemeinschaft fur Padiatrische Nephrologie in children with steroid-sensitive nephrotic syndrome have shown that the length of initial prednisone therapy has an impact on the subsequent relapse rate. The aim of this randomized, prospective, multicenter study was to reduce the number of relapses further by increasing the initial immunosuppression: Patients with an initial attack of nephrotic syndrome were randomly allocated to treatment with 6 wk of 60 mg/m(2) per d prednisone followed by 6 wk of 40 mg/m(2) per 48 h (Pred group) or to the same prednisone treatment plus 8 wk of cyclosporine (Pred+CsA group). The primary end point was first relapse; follow-up was truncated at 2 yr. In the Pred+CsA group (n = 49 patients), the first relapse occurred later compared with the Pred group (n = 55 patients) (median 22.8 versus 12.5 mo). After 6 mo, 10.4% of patients in the Pred+CsA group experienced a first relapse versus 31.5% in the Pred group (P = 0.01); after 1 yr, 36.5 versus 51% (P = 0.15); and after 2 yr, 51 versus 50%. The mean relapse rate per patient was 0.12 versus 0.57 after 6 mo (P = 0.01), 0.63 versus 1.03 after 1 yr (P = 0.02), and 1.03 versus 2.06 after 2 yr (not significant). The significant benefit for adding CsA was lost after 9 to 12 mo. GFR remained unchanged. The subsequent treatment rate with cyclophosphamide was lower in the CsA group (five versus 12 patients) after 2 yr. With the use of logistic regression statistics, children who were younger than 7 yr show a significantly better sustained remission rate with initial CsA treatment for the 2-yr observation time (P = 0.03). It remains questionable, however, whether the intensified initial treatment with CsA could be recommended generally.
|
|
Therapy for recurrent acute pericarditis: a rheumatological solution? |
Thu, Jul 22,2010 |
|
OBJECTIVE: To assess the efficacy of a multidrug protocol in recurrent acute pericarditis. We tried also to assess the specific role of colchicine. METHODS:We studied 58 patients (34 males) in the largest monocentric observational study. All patients received prolonged courses of non-steroidal anti-inflammatory drugs; generally we do not start a corticosteroid in recurrent acute pericarditis, but if a steroid had already been started, we planned a very slow tapering; if necessary azathioprine, hydroxychloroquine, and other immunosuppressive drugs were used; 44 patients (27 males, 61.4%) were treated also with colchicine and 14 patients (7 males, 50%) were not given this drug. RESULTS: After starting our protocol recurrences dropped from 0.48 to 0.03 attacks/patient/month (p < 0.00001) within 12 months and remained at the same level till the end of the follow-up (mean 8.1 years) in the whole cohort. In the 44 patients treated with colchicine recurrences dropped from 0.54 to 0.03 attacks/patient/month (p < 0.00001) within 12 months, and in 14 patients not given colchicine recurrences decreased from 0.31 to 0.06 attacks/patient/month (p = 0.002). In patients treated with colchicine the decrease was significantly higher (0.51) than in patients not taking this drug (0.25) (p = 0.006). Colchicine was discontinued by 16.3% of patients because of side effects. CONCLUSION: A multidrug protocol including non-steroidal anti-inflammatory drugs at high dosage, slow tapering of corticosteroid, colchicine, reassurance and close clinical monitoring is very effective in recurrent pericarditis; this improvement is more dramatic in colchicine treated patients, but also patients who do not tolerate it can achieve good control of the disease.
|
|
An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens. |
Thu, Jul 22,2010 |
|
Algorithms for grading acute graft-versus-host disease (GVHD) are inaccurate in assessing mortality risk. We developed a method to predict mortality by using data from 386 patients with acute GVHD. From the onset of GVHD to day 100, GVHD manifestations were scored for the skin, liver, and upper and lower gastrointestinal tract, and data were recorded for immunosuppressive treatment, performance, and fever. Logistic regression models predicting nonrelapse mortality (NRM) at day 200 were developed with data from 193 randomly selected patients and then validated in the remaining 193 patients. Clinical parameters were grouped to optimize predictive accuracy measured as the area under a receiver-operator characteristic (ROC) curve. The optimal model included the total serum bilirubin concentration, oral intake, need for treatment with prednisone, and performance score. When the overall burden of GVHD was measured by using average Acute GVHD Activity Index (aGVHDAI) scores for each patient in training and validation data sets, areas under ROC curves were 0.87 and 0.85, respectively. Contour lines were generated to reflect the predicted NRM at day 200 as a function of current aGVHDAI scores. These results demonstrate that clinical manifestations of GVHD severity can be used to accurately predict the risk of NRM in real time.
|
|
Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies. |
Thu, Jul 22,2010 |
|
Fifty-two infants with acute lymphoblastic leukemia (ALL) enrolled in the AIEOP ALL-91 and ALL-95 studies were treated with the intermediate or high risk protocols according to their presenting features and early response to treatment. The 5-year event-free survival was 33.3% (95% CI 12.1-54.5), 53.5% (95% CI 35.7-71.3) and 45.0% (95% CI 31.3-58.7) in the ALL-91 and ALL-95 studies and in the overall cohort, respectively. In the ALL-95 high-risk group (BFM therapy intensified by three blocks and double protocol II) nine of 17 patients treated with chemotherapy only and three of four transplanted patients were alive and in complete remission. The corresponding figures for patients treated in the ALL-91 high-risk protocol (reduced induction and nine blocks) were one of seven patients treated with chemotherapy only and none of two who were transplanted.
|
|
Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. |
Thu, Jul 22,2010 |
|
BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the feasibility and toxicity of CHOP-14, with rituximab (R-CHOP-14), supported by pegfilgrastim, in untreated diffuse large B-cell lymphoma (DLBCL). DESIGN AND METHODS: This study included 50 patients with DLBCL with a median age of 55 years (range: 22-70). Sixty-two percent had an International Prognostic Index score >1, 40% had bulky disease and 52% had stage IV disease. CHOP was administered every 14 days, preceded on day 1 by rituximab (375 mg/m2) and followed on day 3 by pegfilgrastim (6 mg per cycle). Toxicity was calculated over 277 cycles administered; feasibility was calculated over 227, since the first cycle in each patient was not susceptible to delay or dose-reduction. RESULTS: Therapy was delivered on time in 92% of cycles, with the relative dose intensity being 95% for doxorubicin and cyclophosphamide. Grade 4 neutropenia developed in 19% of cycles and neutropenic fever in 4% of cycles (16% of patients), with a median duration of 3 days (range: 2-10). The program was completed in 40 of 50 patients (80%); reasons for withdrawal included progression in three patients, interstitial pneumonia in four, prolonged severe neutropenia in two and septic shock in one patient. Severe adverse events occurred on 12 occasions (4% of cycles), involving 11 patients (22% of total); the most frequent severe adverse event was interstitial pneumonia which occurred in seven patients (14% of total). In three cases, Pneumocystis carinii pneumonia was documented; no cotrimoxazole prophylaxis had been given and a correlation with hypogammaglobulinemia was observed. The complete remission rate was 74%; the 2-year event-free and overall survival rates were 72% and 68%, respectively. INTERPRETATION AND CONCLUSIONS: A single dose of pegfilgrastim per cycle of R-CHOP allowed on-time delivery of this chemotherapy in DLBCL, with a low incidence of febrile neutropenia; the risk of P. carinii pneumonia makes cotrimoxazole prophylaxis essential in this setting.
|
|
Drug induced liver injury secondary to interferon-beta (IFN-beta) in multiple sclerosis. |
Thu, Jul 22,2010 |
|
Post marketing studies of Interferon-beta (IFN beta) therapy in multiple sclerosis (MS) have demonstrated surprisingly high rates of hepatotoxicity. Grade 3 hepatotoxicity (AST and ALT > 5 to 20 upper limit normal) or higher has been observed in as many as 1.4% of MS patients on IFN beta. We report three cases of IFN beta induced hepatitis in MS and discuss the pathology findings and possible mechanisms of drug-induced liver injury.
|
|
|
