Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease

Specific human monoclonal antibodies antagonize cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4 mAbs), a negative regulator of the immune system, inducing unrestrained T-cell activation. In patients with advanced or metastatic melanoma, one of these agents, ipilimumab, produced considerable disease control rates and, for the first time, a clear improvement in overall survival outcomes. However, accumulating clinical experience with anti-CTLA-4 mAbs identified a novel syndrome of autoimmune and autoinflammatory side effects, designated as "immune-related adverse events," including mainly rash, colitis, and hepatitis. Autoimmune hypophysitis has emerged as a distinctive side effect induced by anti-CTLA-4 mAbs. This condition may be life threatening because of adrenal insufficiency if not promptly recognized, but it may easily be diagnosed and treated if clinically suspected. Hypopituitarism caused by these agents is rarely reversible and prolonged or life-long substitutive hormonal treatment is often required. The precise mechanism of injury to the pituitary triggered by anti-CTLA-4 mAbs is yet to be fully elucidated.     

Understanding why rheumatoid arthritis patient treatment preferences differ by race

Objective

Rheumatoid arthritis (RA) patient preferences may account for some of the variability in treatment between racial groups. How and why treatment preferences differ by race is not well understood. We sought to determine whether African American and white RA patients differ in how they evaluate the specific risks and benefits related to medications.

Methods

A total of 136 RA patients completed a conjoint analysis interactive computer survey to determine how they valued the specific risks and benefits related to treatment characteristics. The importance that respondents assigned to each characteristic and the ratio of the importance that patients attached to overall benefit versus overall risk were calculated. Subjects having a risk ratio <1 were classified as being risk averse.

Results

The mean age of the study sample was 55 years (range 22–84). Forty‐nine percent were African American and 51% were white. African American subjects assigned the greatest importance to the theoretical risk of cancer, whereas white subjects were most concerned with the likelihood of remission and halting radiographic progression. Fifty‐two percent of African American subjects were found to be risk averse compared with 12% of the white subjects (P < 0.0001). Race remained strongly associated with risk aversion (adjusted odds ratio [95% confidence interval] 8.4 [3.1, ?23.1]) after adjusting for relevant covariates.

Conclusion

African American patients attach greater importance to the risks of toxicity and less importance to the likelihood of benefit than their white counterparts. Effective risk communication and improved understanding of expected benefits may help decrease unwanted variability in health care.

     

Effect of hyaluronic acid in symptomatic hip osteoarthritis: A multicenter,randomized, placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA).

Methods

A multicenter, randomized, parallel‐group, placebo‐controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment.

Results

Eighty‐five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent‐to‐treat analysis (mean ± SD decrease 7.8 ± 24.9 mm with HA versus 9.1 ± 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events.

Conclusion

Our findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.

     

Characteristics of Pathological Gamblers with a Problem Gambling Parent

This analysis compares the characteristics of adult pathological gamblers with and without a problem gambling parent. A sample of 517 individuals with current DSM‐TV pathological gambling was categorized based on presence of a parental problem gambler. Groups were compared on clinical characteristics, gambling severity, gambling‐related problems, and psychiatric comorbidity. Although the groups were similar on most measures, pathological gamblers with at least one problem gambling parent were more likely to have a father with an alcohol abuse/dependence problem; have financial and legal problems; and report daily nicotine use. Females with a problem gambling parent had significantly earlier onset of gambling behavior, were significantly more likely to have a father with an alcohol use disorder, and were significantly more likely to have financial problems secondary to gambling than females without a problem gambling parent. Males with a problem gambling parent were significantly more likely to have a father with an alcohol use disorder and have legal problems secondary to gambling compared to males without a problem gambling parent. Treatment approaches may need to be tailored for specific problems secondary to gambling and gender issues based on the history of having a problem gambling parent.     

Improving survival with deferiprone treatment in patients with thalassemia major: A prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone–deferoxamine (DFP–DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP–DFO, or combined DFP–DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males.No deaths occurred with the DFP-alone or the combined DFP–DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP–DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment.The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value < 0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value < 0.013).In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.     

Long-term sequential deferiprone–deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial

A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone–deferoxamine (DFO–DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8–12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP–DFO patients compared with DFP-alone patients ( P  = 0·005). Kaplan–Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P  = 0·3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP–DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs. This trial was registered at http://www.clinicaltrials.gov as # NCT00733811.     

3D mapping of mini-mental state examination performance in clinical and preclinical Alzheimer disease

The Mini-mental State Examination (MMSE) is a brief cognitive screening instrument frequently used to track Alzheimer disease (AD) progression. We investigated the structural neuroimaging correlates of MMSE performance in patients with clinical and preclinical AD. We analyzed structural magnetic resonance imaging data from 29 probable AD and 5 MCI patients who later converted to probable AD using an advanced 3D cortical mapping technique. MMSE scores were entered as covariates in a general linear model that predicted the gray matter density at each cortical surface point. The results were corrected for multiple comparisons by permutation testing. The global permutation-corrected significance for the maps linking gray matter loss and cognitive decline was P=0.005 for the left and P=0.012 for the right hemisphere. Strongest correlations between MMSE score and gray matter integrity were seen in the entorhinal, parahippocampal, precuneus, superior parietal, and subgenual cingulate/orbitofrontal cortices. Significant correlations were also seen bilaterally in the temporal, the middle frontal and the left angular and supramarginal gyri. As a global cognitive measure, MMSE depends on the integrity of widely distributed cortical areas in both brain hemispheres with left-sided predominance.     

Early diagnostics and therapeutics for Alzheimer's disease--how early can we get there?

Alzheimer's disease (AD) is a major threat for the rapidly aging world population. AD is the leading cause of dementia and a major cause of death in developed countries. The disease puts a tremendous practical, emotional and financial burden on individuals and governments. Clinicians and researchers in the AD field face great challenges: the pathophysiological processes that cause AD are not well understood, definite diagnosis of AD requires autopsy, and therapeutic options are limited to treating the symptoms rather than the cause of the disease. Nevertheless, new insights into the earliest events that lead to development of AD increase hope that reliable diagnostics and efficacious therapies may emerge.     

Ceftobiprole- and Ceftaroline-Resistant Methicillin-Resistant Staphylococcus aureus

The role of mecA mutations in conferring resistance to ceftobiprole and ceftaroline, cephalosporins with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity, was determined with MRSA strains COL and SF8300. The SF8300 ceftaroline-passaged mutant carried a single mecA mutation, E447K (E-to-K change at position 447), and expressed low-level resistance. This mutation in COL conferred high-level resistance to ceftobiprole but only low-level resistance to ceftaroline. The COL ceftaroline-passaged mutant, which expressed high-level resistance to ceftobiprole and ceftaroline, had mutations in pbp2, pbp4, and gdpP but not mecA.