Second-line Drug Therapy Research Articles

Primary resistance to nivolumab plus ipilimumab therapy affects second-line treatment outcomes in patients with metastatic renal cell carcinoma.

Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.

Clinical and immunological characterisation of patients with common variable immunodeficiency related immune thrombocytopenia

Primary Immune thrombocytopenia (ITP) is an autoimmune disease. Secondary ITP occurs in patients with underlying diseases such as common variable immunodeficiency (CVID). CVID is one of the most common symptomatic primary immunodeficiencies in adults, characterised by infectious and non-infectious symptoms. Amongst CVID patients, ITP is the most frequent autoimmune manifestation. In this single-centre study, we performed a clinical and immunological characterisation of 20 patients with CVID-related ITP and 20 ITP patients without CVID to compare severity and remission rates. We found that patients with CVID-related ITP had a higher WHO Bleeding Scale at initial diagnosis yet showed higher remission rates and required less treatment. Patients with ITP needed up to seven therapy options and were often treated with second-line drug therapy, whilst only one CVID-related ITP patient required second-line drug therapy. Therefore, we show that the course of thrombocytopenia in patients with CVID-related ITP is milder. Furthermore, we show that soluble interleukin-2 receptor (sIL-2R, CD25) was higher in CVID-related ITP compared to ITP patients and could accurately classify patient cohorts with an Area Under the Receiver Operating Characteristic of 0.92. Whilst none of the ITP patients had a history of immunodeficiency, we found immunological abnormalities in 12 out of 18 patients. Therefore, we recommend screening ITP patients for CVID and other immunodeficiencies to detect immune abnormalities early, as we found patients with reduced immunoglobulin levels as well as severe lymphocytopenia in our ITP cohort.

PD09-10 AVELUMAB FIRST-LINE (1L) MAINTENANCE FOR ADVANCED UROTHELIAL CARCINOMA (UC): LONG-TERM OUTCOMES FROM JAVELIN BLADDER 100 IN SUBGROUPS DEFINED BY RESPONSE TO 1L CHEMOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023PD09-10 AVELUMAB FIRST-LINE (1L) MAINTENANCE FOR ADVANCED UROTHELIAL CARCINOMA (UC): LONG-TERM OUTCOMES FROM JAVELIN BLADDER 100 IN SUBGROUPS DEFINED BY RESPONSE TO 1L CHEMOTHERAPY Begoña Valderrama, Thomas Powles, Srikala Sridhar, Claudia Caserta, Yohann Loriot, Shilpa Gupta, Joaquim Bellmunt, Cora Sternberg, Jing Wang, Nuno Costa, Robert Laliberte, Alessandra di Pietro, Se Hoon Park, and Petros Grivas Begoña ValderramaBegoña Valderrama More articles by this author , Thomas PowlesThomas Powles More articles by this author , Srikala SridharSrikala Sridhar More articles by this author , Claudia CasertaClaudia Caserta More articles by this author , Yohann LoriotYohann Loriot More articles by this author , Shilpa GuptaShilpa Gupta More articles by this author , Joaquim BellmuntJoaquim Bellmunt More articles by this author , Cora SternbergCora Sternberg More articles by this author , Jing WangJing Wang More articles by this author , Nuno CostaNuno Costa More articles by this author , Robert LaliberteRobert Laliberte More articles by this author , Alessandra di PietroAlessandra di Pietro More articles by this author , Se Hoon ParkSe Hoon Park More articles by this author , and Petros GrivasPetros Grivas More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003240.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance+best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients with advanced UC that had not progressed with 1L platinum-based chemotherapy. We report exploratory analyses in subgroups defined by response to 1L chemotherapy (complete response [CR], partial response [PR], or stable disease [SD]) after ≥2 years of follow-up. METHODS: Eligible patients had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine+cisplatin or carboplatin. Patients were randomized 1:1 to receive avelumab+BSC (n=350) or BSC alone (n=350), stratified by best response to 1L chemotherapy (CR/PR vs SD) and visceral vs nonvisceral disease at start of 1L chemotherapy. RESULTS: At data cutoff (June 4, 2021), median follow-up in both arms was ≥38 months. OS and PFS were longer in the avelumab+BSC vs BSC alone arm in all subgroups (Table 1). Median duration of study treatment and incidence of grade ≥3 treatment-emergent adverse events (TEAEs) in subgroups are shown in the Table 1. In the avelumab+BSC vs BSC alone arm, respectively, subsequent second-line anticancer drug therapy was received by: CR subgroup, 50.0% vs 74.2%; PR subgroup, 58.3% vs 71.8%; and SD subgroup, 46.4% vs 70.4%. CONCLUSIONS: Long-term follow-up from JAVELIN Bladder 100 continues to show prolonged OS and PFS with avelumab+BSC vs BSC alone irrespective of response (CR, PR, or SD) to 1L chemotherapy and despite a higher proportion of patients in the BSC alone arm receiving subsequent therapy. Long-term safety was consistent across subgroups. These findings further support avelumab 1L maintenance as standard of care for all patients with advanced UC that has not progressed with 1L platinum-based chemotherapy. © 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved. Source of Funding: This trial was sponsored by Pfizer as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). Medical writing support was provided by Jamie Ratcliffe of ClinicalThinking and was funded by Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e244 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Begoña Valderrama More articles by this author Thomas Powles More articles by this author Srikala Sridhar More articles by this author Claudia Caserta More articles by this author Yohann Loriot More articles by this author Shilpa Gupta More articles by this author Joaquim Bellmunt More articles by this author Cora Sternberg More articles by this author Jing Wang More articles by this author Nuno Costa More articles by this author Robert Laliberte More articles by this author Alessandra di Pietro More articles by this author Se Hoon Park More articles by this author Petros Grivas More articles by this author Expand All Advertisement PDF downloadLoading ...

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from JAVELIN Bladder 100 in subgroups defined by response to 1L chemotherapy.

4559 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with aUC that had not progressed with 1L platinum-based chemotherapy. We report exploratory analyses in subgroups defined by response to 1L chemotherapy (complete response [CR], partial response [PR], or stable disease [SD]) after ≥2 years of follow-up. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression with 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin. Pts were randomized 1:1 to receive avelumab + BSC (n = 350) or BSC alone (n = 350), stratified by best response to 1L chemotherapy (CR/PR vs SD) and visceral vs nonvisceral disease at start of 1L chemotherapy. Results: At data cutoff (June 4, 2021), median follow-up in both arms was ≥38 months. OS and PFS were longer in the avelumab + BSC vs BSC alone arm in all subgroups (Table). Median duration of study treatment and incidence of grade ≥3 treatment-emergent adverse events (TEAEs) in subgroups are shown in the Table. In the avelumab + BSC vs BSC alone arm, respectively, subsequent second-line anticancer drug therapy was received by: CR subgroup, 50.0% vs 74.2%; PR subgroup, 58.3% vs 71.8%; and SD subgroup, 46.4% vs 70.4%. Conclusions: Long-term follow-up from JAVELIN Bladder 100 continues to show prolonged OS and PFS with avelumab + BSC vs BSC alone irrespective of response (CR, PR, or SD) to 1L chemotherapy and despite a higher proportion of pts in the BSC alone arm receiving subsequent therapy. Long-term safety was consistent across subgroups. These findings further support avelumab 1L maintenance as standard of care for all pts with aUC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. [Table: see text]

Clinical Outcomes of Three or More Courses of First-line Chemotherapy for Metastatic Urothelial Carcinoma.

The current standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma (UC) is platinum-based combination chemotherapy. Recently, immune checkpoint inhibitors have been reported to be effective for UC. Knowing whether immunotherapy or chemotherapy is suitable as first-line treatment is beneficial for patients. A retrospective study was conducted on the clinical outcomes of Japanese patients who received three or more courses of first-line chemotherapy for metastatic UC to assess the outcome of conventional treatments in real clinical situation. Patients who received first-line chemotherapy between August 2009 and December 2019 were included. Progression-free survival (PFS) and overall survival (OS) were assessed. The median PFS and OS were 7.1 and 27.1 months, respectively, for patients with no disease progression at the end of three courses. Of 28 patients, 25 (89.3%) received second-line drug therapy and 10 (35.7%) received focal therapy for disease control. Patients with focal therapy had significantly longer OS than those without focal therapy (p=0.019, log-rank test). OS of metastatic UC at our Institution is relatively long, suggesting that aggressive second-line drug therapy and focal therapy may have contributed to such result.

Case report of partial response on second line with Ramucirumab and FOLFIRI in treatment of 74 year old male with metastatic HER2-negative gastric adenocarcinoma

According to the data of the world statistics, gastric cancer (GC) occupies the 5th place by morbidity and the 3rd one by mortality among malignant neoplasms. A significant proportion of patients are elderly patients, the proportion of which in real clinical practice can reach up to 60%. Ramucirumab is among the standards of second-line drug therapy both in monotherapy and in combination with paclitaxel. The feasibility of prescribing ramucirumab to patients with disseminated cancer of the elderly and its satisfactory tolerability is shown in a subgroup analysis of the REGARD and RAINBOW studies. The use of paclitaxel, included in the standard first-line regimens, may be limited by persistent neurotoxicity, a side effect of platinum derivatives. In this regard, the effectiveness of the combination of ramucirumab with the FOLFIRI regimen as a second-line therapy began to be studied. The article presents a clinical case of achieving a partial effect on the second-line therapy with ramucirumab with FOLFIRI regimen in a 74-year-old patient with HER2-negative gastric adenocarcinoma while registering rapid progression after 4 courses of first-line chemotherapy in XELOX regimen. Tolerability of the second line was acceptable: asthenia grade 1, stomatitis grade 1-2, neutropenia grade 3 were observed, so the irinotecan dose was reduced to 165 mg/m2. By June 2021, there were 10 28-day cycles of treatment, which is ongoing. The duration of disease control in the second line therapy was 11+ months, of which 9+ months – on the background of FOLFIRI regimen drug therapy with ramucirumab.

Real-world treatment patterns and outcomes of patients with stage IV squamous cell carcinoma of the head and neck.

To understand the treatment patterns and outcomes for stage IV squamous cell carcinoma of the head and neck, patients receiving second-line or later drug therapy. Real-world data were collected from 1152 patients in the USA, France, Germany and the UK through a retrospective chart analysis and patient-reported outcomes were collected using validated questionnaires in a subgroup of patients. Forty-four percent of patients had stage IVA/B disease. A total of 77, 19 and 3% of patients had received two, three and four plus lines of active drug treatment. Platinum- and cetuximab-based regimens were common at early treatment lines. Time to progression was short (5.2months post first line), survival rates low and patient-reported health status poor. Novel therapies that could improve clinical and patient-reported outcomes would address a significant unmet need.

Abstract SY36-01: Optimizing neoadjuvant therapy prior to surgery: Biomarker and target discovery

Abstract SY36-01: Optimizing neoadjuvant therapy prior to surgery: Biomarker and target discovery

Cost-effectiveness of cryoballoon ablation for the management of paroxysmal atrial fibrillation

Cryoballoon ablation is an established treatment option for the management of patients with atrial fibrillation. We sought to evaluate the cost-effectiveness of cryoablation, compared with second-line anti-arrhythmic drug (AAD) therapy in patients with paroxysmal atrial fibrillation (PAF), from a UK payer perspective. We developed a state-transition (Markov) model to calculate the total costs and quality-adjusted life-years (QALYs) associated with cryoablation and AAD therapy in patients with PAF. A 5-year horizon was used for the base-case. Data from a recent study of cryoballoon ablation in patients with PAF were used to model short-term health outcomes and costs, together with longer term external evidence to populate subsequent time periods. Total discounted costs were £21 162 and £17 627 for the cryoballoon ablation and AAD arms, respectively. Total QALYs of 3.565 and 3.404 therefore led to an incremental cost-effectiveness ratio of £21 957 per QALY gained. Sensitivity analysis suggested that the key drivers of the results were the model time horizon, the costs of follow-up care in patients with recurrent AF, and the costs of the ablation procedure. Cryoballoon ablation provides increased quality-adjusted life expectancy compared with AAD at reasonable additional cost, representing good value for money in patients with PAF.

Cyclosporine A for the treatment of refractory nephrotic syndrome with renal dysfunction

Cyclosporine A (CsA) is an immunosuppressant agent and is utilized as a second-line drug therapy for refractory nephrotic syndrome (RNS). In general, the use of CsA is strictly controlled in patients with an estimated glomerular filtration rate (eGFR) <30–40 ml/min/1.73 m2, and little is known about the safety and efficacy of CsA treatment in patients with RNS complicated by renal dysfunction. In the present study, the clinical data of 10 patients with RNS and renal dysfunction, who received CsA treatment between 2000 and 2009 in the Kidney Institute of PLA, were reviewed retrospectively. Pathologically, these patients included six cases with minimal change, two cases of diffuse mesangial proliferation and two cases of focal segmental glomerulosclerosis. Six months subsequent to the initiation of the CsA treatment, six patients achieved complete remission, two patients achieved remarkable remission and two patients achieved partial remission. Renal function was improved in all patients as represented by the improvement in the eGFR (28.6±3.8 ml/min/1.73 m2 prior to treatment versus 99.3±21.9 ml/min/1.73 m2 6 months subsequent to treatment). Few adverse CsA-related events were observed. These results suggest that renal dysfunction is not an absolute contraindication for CsA treatment in patients with RNS. The use of CsA is safe and efficacious and may, in certain cases, improve renal function in patients with RNS and renal impairment.

P355 Efficacy and safety of oral tacrolimus for the treatment of severe steroid-resistant ulcerative colitis

Background: Ulcerative colitis (UC) that occurs in childhood is usually an extensive colitis or pancolitis and is most often associated with severe steroid-refractory flares. Tacrolimus is a second-line drug therapy indicated in patients with severe flare that is unresponsive to steroid therapy. Objective: to describe our experience of the efficacy and safety of oral tacrolimus treatment in children with steroid-resistant severe ulcerative colitis. Methods: We conducted a retrospective study that included all patients under 18 years suffering from serious flares of ulcerative colitis treated with oral tacrolimus during the period between January 1998 and October 2011. All patients received an oral dose of 0.12mg/kg/day. The drug dosage was adjusted to achieve a plasma trough level of tacrolimus between 5 and 10 ng/mL. For statistical analysis and preparation of the survival curves we used the SPSS version 17.0 for Windows program. A p value <0.01 was considered as significant. Results: A total of 10 patients, 7 women were included. Seven patiens were in their first attack of the disease. The mean age was 9.4±4.9 years-old, and the time course of the disease of 1.3 months (IQR, 1 to 5.7m). The initial clinical response was achieved in 6 patients. All nonresponders required colectomy within one month after initiation of treatment. In the subgroup that responded initially, 2 of 6 patients required colectomy, one at 10 months after starting treatment and the other one at 6 years and 4 months after the immunomodulatory therapy was stopped. Plasma trough levels of tacrolimus were 4 13 ng/ml. The median duration of treatment in the responder group was 4.7 months (IQ, 3.7 to 6) versus 0.23 months in the nonresponders (IQ 0.13 to 0.8m), p = 0.01. Tacrolimus was well tolerated in all cases. Conclusions: Tacrolimus is useful in inducing remission in patients with acute, severe steroid-resistant flares of ulcerative colitis. It can change the course of the disease, and it can prevent or delay surgery allowing to prepare the patient and his family for a probable surgery.

Ethionamide-induced gynecomastia.

Gynecomastia is very rare during antituberculosis chemotherapy. We describe a 38-year-old male patient who developed a painful gynecomastia following second-line drug therapy for multidrug-resistant pulmonary tuberculosis. Gynecomastia disappeared after stopping the ethionamide. A published literature on antituberculosis-induced gynecomastia is also briefly discussed.

Discordance between physician's and parent's global assessments in juvenile idiopathic arthritis

To investigate the discrepancy between physician's and parent's global assessments of disease status and the factors explaining discordance in patients with juvenile idiopathic arthritis (JIA). The mothers of 197 patients with JIA rated the child's overall well-being on a 10 cm visual analogue scale (VAS) and the attending physician rated the child's overall disease activity on a 10 cm VAS. A discordance score was calculated by subtracting the physician's global assessment from that of the parent's, leading to the definition of three patient groups: (1) no discordance, when physician's and parent's assessments were within 1 cm of each other; (2) negative discordance, when parent's assessment was underrated relative to the physician; and (3) positive discordance, when parent's assessment was over-rated relative to the physician. Negative and positive discordance was defined as 'marked' when the difference between the two assessments was greater than 3 cm. No discordance was found in 40.6% of the patients. Negative discordance was found in 51.3% of the patients, with 34% showing marked discordance. Positive discordance was found in 8.1% of the patients, with 2% showing marked discordance. Significant differences between groups included a shorter disease duration among patients with a markedly positive discordance (P = 0.02) and a greater frequency of ongoing second-line drug therapy among patients with no discordance or with positive discordance (P = 0.008). Patients with no discordance or with marked positive discordance had a significantly lower joint counts (P = 0.02-0.004). Parents and physicians often perceive the health status of children with JIA differently, with parents providing most frequently lower rating.

Refractory convulsive status epilepticus in childhood

Refractory convulsive status epilepticus (RCSE) is life-threatening condition, with seizures lasting over one hour and not responding to first and second-line anticonvulsant drug therapy. Any mistreatment or delayed proper treatment significantly increase mortality and neurologic sequelae. First line drugs for convulsion ceasing are benzodiazepines, phenobarbital and phenytoin. In case of refractory status, infusion of midazolam and general anesthesia should be administered. The most important measures of the intensive care are control of vital functions, homeostasis, prevention and therapy for possible brain and systemic complications. Discovery of etiology of status epilepticus is highly important because symptomatic therapy should be administered. Overall mortality rate during RCSE is 13.5%, and is much higher in acute symptomatic group--28.6%. Early sequelae rate is 40.6%, 27.3% and 70% in idiopathic and acute symptomatic groups, respectively.

Predictors of an unsatisfactory response to pentavalent antimony in the treatment of American visceral leishmaniasis

Although treatment of visceral leishmaniasis with pentavalent antimony is usually successful, some patients require second-line drug therapy, most commonly with amphotericin B. To identify the clinical characteristics that predict an inadequate response to pentavalent antimony, a case-control study was undertaken in Teresina, Piaui, Brazil. Over a two-year period, there were 19 cases of VL in which the staff physicians of a hospital prescribed second-line therapy with amphotericin B after determining that treatment with pentavalent antimony had failed. The control group consisted of 97 patients that were successfully treated with pentavalent antimony. A chart review using univariate and multivariate analysis was performed. The cure rate was 90% with amphotericin B. The odds ratio for the prescription of amphotericin B was 10.2 for children less than one year old, compared with individuals aged over 10 years. Patients who presented coinfection had an OR of 7.1 while those on antibiotics had an OR of 2.8. These data support either undertaking a longer course of therapy with pentavalent antimony for children or using amphotericin B as a first-line agent for children and individuals with coinfections. It also suggests that chemoprophylaxis directed toward bacterial coinfection in small children with VL may be indicated.

Short- and Long-Term Outcomes After Status Epilepticus.

Refractory Status Epilepticus Frequency, Risk Factors, and Impact on Outcome Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons B-F Arch Neurol 2002;59:205–210 Refractory status epilepticus (RSE) is a life-threatening condition in which seizures do not respond to first- and second-line anticonvulsant drug therapy. How often RSE occurs, risk factors that predispose to this condition, and the effect of failure to control seizures on clinical outcome are poorly defined. Objective To determine the frequency, risk factors, and impact on outcome of RSE. Design Retrospective cohort study. Setting Large academic teaching hospital. Patients Consecutive sample of 83 episodes of status epilepticus in 74 patients (mean age, 63 years). Main outcome. Methods Refractory status epilepticus was defined as seizures lasting longer than 60 minutes despite treatment with a benzodiazepine and an adequate loading dose of a standard intravenous anticonvulsant drug. Factors associated with RSE were identified using univariate and backward stepwise logistic regression analyses. Results In 57 episodes (69%), seizures occurred after treatment with a benzodiazepine, and in 26 (31%), seizures occurred after treatment with a second-line anticonvulsant drug (usually phenytoin), fulfilling our criteria for RSE. Nonconvulsive SE (P = .03) and focal motor seizures at onset (P = .04) were identified as independent risk factors for RSE. Eleven (42%) of 26 patients with RSE had seizures after receiving a third-line agent (usually phenobarbital). Although mortality was not increased (17% overall), RSE was associated with prolonged hospital length of stay (P &lt; .001) and more frequent functional deterioration at discharge (P = .02). Conclusions Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability. Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE. Randomized controlled trials are needed to define the optimal treatment of RSE. Long-term Mortality After a First Episode of Status Epilepticus Logroscino G, Hesdorffer DC, Cascino GD, Annegers JF, Bagiella E, Hauser WA Neurology 2002;58:537–541 Objective To evaluate long-term mortality among people with status epilepticus (SE). Methods The authors performed a population-based retrospective cohort study to determine long-term mortality after SE. Between January 1, 1965, and December 31, 1984, all first episodes of SE receiving medical attention were ascertained through the Rochester Epidemiology Project Records-Linkage System. Cases surviving the first 30 days (n = 145) were followed until death or study termination (February 1996). Results At 10 years, cumulative mortality among 30-day survivors was 43%. The standardized mortality ratio (SMR) at 10 years was 2.8 (95% CI, 2.1–3.5). The mortality rate of those with idiopathic/cryptogenic SE was not increased (SMR = 1.1; 95% CI, 0.5–2.3). The following characteristics of SE increased long-term risk for mortality: SE ≥ 24 hours in duration vs. SE &lt; 2 hours (relative risk [RR] = 2.3; 95% CI, 1.1–5.1); acute symptomatic etiology vs. idiopathic/cryptogenic etiology (RR = 2.2; 95% CI, 1.0–5.1); myoclonic SE vs. generalized convulsive SE (RR = 4.0; 95% CI, 1.3–13). Conclusion Forty percent of subjects who survived the first 30 days after an incident episode of SE die within the next 10 years. The long-term mortality rate was threefold that of the general population over the same time period. The long-term mortality rate at 10 years was worse for those with myoclonic SE, for those who presented with SE lasting more than 24 hours, and for those with acute symptomatic SE. The long-term mortality rate was not altered in those with idiopathic/cryptogenic SE. We conclude that SE alone does not modify long-term mortality.

Refractory status epilepticus: frequency, risk factors, and impact on outcome.

Refractory status epilepticus (RSE) is a life-threatening condition in which seizures do not respond to first- and second-line anticonvulsant drug therapy. How often RSE occurs, risk factors that predispose to this condition, and the effect of failure to control seizures on clinical outcome are poorly defined. To determine the frequency, risk factors, and impact on outcome of RSE. Retrospective cohort study. Large academic teaching hospital. Consecutive sample of 83 episodes of status epilepticus in 74 patients (mean age, 63 years). Refractory status epilepticus was defined as seizures lasting longer than 60 minutes despite treatment with a benzodiazepine and an adequate loading dose of a standard intravenous anticonvulsant drug. Factors associated with RSE were identified using univariate and backward stepwiselogistic regression analyses. In 57 episodes (69%), seizures occurred after treatment with a benzodiazepine, and in 26 (31%), seizures occurred after treatment with a second-line anticonvulsant drug (usually phenytoin), fulfilling our criteria for RSE. Nonconvulsive SE (P=.03) and focal motor seizures at onset (P=.04) were identified as independent risk factors for RSE. Eleven (42%) of 26 patients with RSE had seizures after receiving a third-line agent (usually phenobarbital). Although mortality was not increased (17% overall), RSE was associated with prolonged hospital length of stay (P<.001) and more frequent functional deterioration at discharge (P=.02). Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability. Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE. Randomized controlled trials are needed to define the optimal treatment of RSE.

Second-line drug therapy for osteoarthritis

L'activite biologique des medicaments antibiotiques ou antiinflammatoires destines a traiter l'osteite est decrite, ainsi que leurs effets indesirables

The use of antimalarials in combination with other disease modifying agents in RA – the British experience

Antimalarial drugs are effective disease modifying agents in RA with a low incidence of serious toxic effects. Recently, combinations of second-line agents have been used in RA in attempts to treat patients with no response to a number of single agents, or suboptimal response to a single agent. Combinations of drugs have been selected for maximum efficacy and minimum toxicity, but clinical trials are difficult to design and interpret. In particular, ensuring adequate power to detect small differences in response poses a major problem. Antimalarials are an attractive choice for combination therapy due to their efficacy, mechanisms of action and toxicity profile. In this review, the evidence for the use of antimalarials in combination in RA is examined. No advantage has been shown in combining antimalarials with gold, penicillamine or sulphasalazine compared with monotherapeutic regimens. There is some evidence to suggest a beneficial combination of antimalarials with methotrexate, but this is as yet inconclusive. Open non-randomised uncontrolled studies have shown that antimalarials combined with cytotoxic agents are effective but highly toxic. The authors conclude that there is little good evidence to support the introduction of combination second-line drug therapy for RA into widespread therapeutic use.

Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis

SummaryBackground A favourable benefit/risk ratio for treatment of rheumatoid arthritis (RA) with second-line drugs has been established only in short-term studies. The present investigation addresses the question of whether RA patients with a good response to long-term treatment with second-line drugs benefit from continuation of such treatment.Methods A 52-week randomised double-blind placebo-controlled multicentre study was conducted to assess the effect of stopping second-line therapy in 285 RA patients with a good long-term therapeutic response. The patients either continued the second-line drug (n=142) or received a placebo (n=143). The endpoint was a flare, defined as recurrence of synovitis.Findings At entry into the study median duration of second-line drug therapy was 5 years (range 2-33). At 52 weeks the cumulative incidence of a flare was 38% for the placebo group and 22% for the continued therapy group (p=0·002). The risk of a flare was 2·0 times higher for patients receiving placebo than for those continuing the second-line drug (95% Cl 1·27 to 3·17). The same trend was found for each second-line drug separately, with the exception of d-penicillamine. Side-effects that necessitated dose reduction or discontinuation occurred in 2 patients in each group.Interpretation Second-line drugs continue to be effective in RA patients who have responded well to initial treatment.