Can clinical trials in rheumatology be improved?

With our growing dependence on clinical trials to assess the adequacy of available treatments for arthritic patients, attention is increasingly being focused on the tools we use in the design, analysis, and reporting of these studies and the ways in which we can improve them. This review outlines some of the major problems in terms of patient compliance, trial size, inadequate endpoints, and insufficient reporting, and highlights some of the work being done to overcome these difficulties. The greatest emphasis is placed on two issues. Firstly, there is a need for greater stringency in interpreting the results. Thus, more consideration needs to be devoted to the limitations of the measurements used and greater emphasis needs to be placed on analysis on the basis of "intention to treat". Secondly, there is a need to standardize common aspects of the trials, such as the detailed reporting of baseline data, a minimal set of outcome measures, comparable response thresholds, and the inclusion of statistics such as confidence intervals. Implementing these changes will increase comparability and yield a stronger possibility of significant results.     

Proteinuric renal disease in type 2 diabetes—Is remission of proteinuria associated with improved mortality and morbidity?

Aims

Patients with type 2 diabetes and macroalbuminuria are at high risk for end stage renal disease (ESRD), cardiovascular disease and death, but remission of proteinuria may improve prognosis. We examine the effectiveness of currently recommended treatments on inducing remission of proteinuria, and on morbidity and mortality.

Methods

Observational study of 78 patients with type 2 diabetes (46 male) with mean age (SD) of 61.5 (11) years, with a urinary albumin/creatinine ratio (ACR) ≥ 50 mg/mmol. All were treated with agents blocking the renin–angiotensin system. Follow-up was from recognition of ACR ≥ 50 mg/mmol until death or March 2011 (median 6 years). Remission of proteinuria was defined as ≥70% reduction from peak ACR, sustained for ≥1 year.

Results

Only 22 of 78 patients (28%) achieved remission of proteinuria. Thirty-six (46%) had at least one major event (death, dialysis or cardiovascular). Remission of proteinuria was associated with lower incidence of ESRD/death (9% vs 36%; p = 0.02) but cardiovascular events were not reduced (32% vs 30%). A third of patients had no retinopathy when albuminuria was first recognised, suggesting that non-diabetic renal pathologies were prominent. There was a significant interaction between the severity of diabetic retinopathy and remission of proteinuria on the risk of ESRD/death (p = 0.0003).

Conclusions

Remission of proteinuria was achieved in only a third of patients despite efforts to achieve blood pressure targets <130/80 mmHg. Failure to attain remission of proteinuria was associated with increased risk of ESRD or death, a risk compounded by the presence of severe diabetic retinopathy.     

Why is left ventricular hypertrophy so predictive of morbidity and mortality?

The prevalence, prognosis, and predictors of left ventricular hypertrophy (LVH) are reviewed, and theories of the pathogenesis of the relation between LVH and poor prognosis are summarized to highlight controversies in the field. In the Framingham Heart Study, which consists largely of white people, echocardiographic LVH has a prevalence of 14% in men and 18% in women. The prevalence of LVH is reported to be elevated in African Americans compared with whites, although the higher prevalence has been attributed to the increased prevalence of hypertension and obesity. Echocardiographic LVH is independently associated with a variety of cardiovascular endpoints, including coronary heart disease and stroke. Furthermore, after adjusting for other cardiovascular disease risk factors, LVH is associated with a doubling in mortality in both white and African American cohorts. Despite the intensive investigation of LVH, there remain many unanswered questions: To what extent do genetic or other factors account for the large portion of the variance in LVH that remains unexplained? What is the prognosis of LVH and left ventricular geometry in a population-based African American cohort? How does the development and progression of LVH relate to other risk factors and their treatment? What is the relation of LVH to poor prognosis? The proposed Jackson Heart Study will help address many important unanswered questions regarding LVH.     

Clinical evolution, and morbidity and mortality of primary Sjögren's syndrome

OBJECTIVES: To study the clinical and laboratory profile evolution, as well as morbidity and mortality impact, of primary Sj?gren's syndrome (pSS), in a large cohort of patients followed-up longitudinally. METHODS: We studied the evolution of the clinical picture and laboratory profile of pSS, the incidence and predictors for systemic sequelae, and the impact of pSS on overall survival in a prospective cohort study of 261 patients with pSS. Analyses included calculation of incidence rates, Cox proportional hazards predictive models, and estimation of standardized mortality ratios (SMRs) compared with the general Greek population, adjusting for age and sex. RESULTS: Glandular manifestations of the syndrome were typically present at the time of diagnosis. Systemic manifestations such as arthritis, Raynaud's phenomenon, purpura, interstitial nephritis, and liver involvement, as well as the serological profile, also did not change substantially during subsequent follow-up. Incidence rates for peripheral neuropathy, glomerulonephritis, and lymphoproliferative disorders were 3.3, 6.6, and 12.2 per 1,000 person-years, respectively. Glomerulonephritis and lymphoma tended to co-exist in the same patients (relative risk, 34.0; P < .0001). The development of lymphoproliferative disorders was associated with low levels of C4 complement (relative risk, 7.5; P = .0016), the presence of mixed monoclonal cryoglobulins (relative risk, 7.9; P = .0012), and purpura (relative risk, 3.9; P = .037). Low levels of C4 was the strongest predictor for mortality after adjusting for age (relative risk, 6.5; P =.0041). Patients with pSS had an SMR of 2.07 (95% CI, 1.03 to 3.71). However, when patients with adverse predictors were excluded, the mortality rate was identical to that of the general population (SMR 1.02). CONCLUSIONS: The initial presentation of pSS determines subsequent outcome. Purpura, decreased C4 complement levels, and mixed monoclonal cryoglobulinemia are adverse prognostic factors. The overall mortality of patients with pSS compared with the general population is increased only in patients with adverse predictors.     

Can age and aging be measured?

Are age and aging measurable? Yes, of course they are, if all types of quantification are included. Nevertheless, a lot of questions have to be discussed with regard to different concepts of age, e.g., chronological age, biological age, subjective age, mean age, life expectancy, etc. Even the question when someone should be labeled old cannot be answered without reference to a priori hypotheses and demographic development. Beyond that, aging is not a standardized process. Aging is dependent on multiple individual and environmental conditions and there is a large interindividual variability which is often underestimated. Research on these aging processes is itself dependent on the instruments used, e.g., the methods of a longitudinal or cross-sectional study. Aging is a multifaceted and quite individual process.     

Can eradication rate of gastric Helicobacter pylori be improved by killing oral Helicobacter pylori?

AIM:To evaluate the influence of oral Helicobacter pylori(H.pylori)on the success of eradication therapy against gastric H.pylori.METHODS:A total of 391 patients with dyspepsia were examined for H.pylori using the saliva H.pylori antigen test(HPS),13C-urea breath test(UBT),gastroscopy,and gastric mucosal histopathological detection.Another 40 volunteers without discomfort were subjected to HPS and13C-UBT,and served as the control group.The 233 patients who were13C-UBT+were enrolled in this study and divided into 4 groups.Patients who were HPS-and13C-UBT+(n=53)received triple therapy alone.Those who were both HPS+and13CUBT+(n=180)were randomly divided into 3 groups:(1)the O+G+t group which received triple therapy alone(n=53);(2)the O+G+tm group which received both triple therapy and mouthrinse treatment(n=65);and(3)the O+G+tmp group which received triple therapy,mouthrinse,and periodontal treatment(n=62).The HPS and13C-UBT were continued for 4 wk after completion of treatment,and the eradication rate of gastric H.pylori and the prevalence of oral H.pylori in the 4 groups were then compared.RESULTS:The eradication rates of gastric H.pylori in the O-G+t group,the O+G+tm group,and the O+G+tmp group were 93.3%,90.0%,and 94.7%respectively;all of these rates were higher than that of the O+G+t group(78.4%)[O-G+t group vs O+G+t group(P=0.039);O+G+tm group vs O+G+t group(P=0.092);O+G+tmp group vs O+G+t group(P=0.012);O+G+tm group vs O-G+t group(P=0.546);O+G+tmp group vs O-G+t group(P=0.765);O+G+tm group vs O+G+tmp group(P=0.924)].The eradication of gastric H.pylori was significantly improved using the combination of triple therapy,mouthrinse,and periodontal treatment.The eradication rates of gastric H.pylori in the peptic ulcer group,chronic atrophic gastritis group and control group were higher than in the duodenitis group and the superficial gastritis group.The prevalence rates of oral H.pylori in the O-G+t group,O+G+t group,O+G+tm group and O+G+tmp group following treatment were 0%,76.5%,53.3%,and 50.9%,respectively[O-     

Should we screen for hemochromatosis? An examination of evidence of downstream effects on morbidity and mortality

BACKGROUND: Population-based hemochromatosis screening has been suggested with the rationale that identification and treatment of subclinical disease would decrease morbidity and mortality due to hemochromatosis. OBJECTIVE: To examine the prevalence of elevated serum transferrin saturation levels and the burden of illness of hemochromatosis in terms of ambulatory visits, hospitalizations, and death in the United States. PARTICIPANTS AND METHODS: Four nationally representative data sets were used for the analysis of the prevalence of hemochromatosis as well as ambulatory care, hospitalizations, and deaths related to hemochromatosis. Participants included men and nonpregnant women aged 18 years and older in the Third National Health and Nutrition Examination Survey (1988-1994) and the 1996, 1997, and 1998 National Ambulatory Care Survey, National Hospital Discharge Survey, and Underlying Cause-of-Death Mortality Files. The data sets were based on single measurements of serum transferrin saturation levels, serum ferritin levels, and healthcare provider-recorded diagnoses according to the International Classification of Diseases, Ninth Revision, Clinical Modification, code for hemochromatosis. RESULTS: The prevalence of elevated serum transferrin saturation levels ranged from 1% to 6%. When an elevated serum transferrin saturation level of 55% is combined with an elevated serum ferritin level, the prevalence decreases from 1.9% to 0.65%. The proportion of diagnosed hemochromatosis utilization out of total ambulatory visits, hospitalizations, and deaths is stable across the measures and the 3 years of data ranging from 0.01% to 0.03%. When white men were examined separately, the relationships remained the same as those among the general population of adults. CONCLUSIONS: Although a substantial proportion of adults whose condition is not currently diagnosed would be identified in a population-based screening program for subclinical hemochromatosis, diagnosed morbidity or mortality owing to hemochromatosis is considerably lower than would be expected. Recommendations for screening programs may need to be revisited.     

How can the assessment of fistula-in-ano be improved?

PURPOSE. Fistula-in-ano anatomy and its relationship with anal sphincters are important factors influencing the results of surgical management. Preoperative definition of fistulous track(s) and the internal opening play a primary role in minimizing iatrogenic damage to the sphincters and recurrence of the fistula. METHODS. Physical examination and endoanal ultrasound (performed with a 10 MHz endoprobe), either conventionally or with an injection of hydrogen peroxide, were performed in 26 consecutive patients. Results were matched with surgical features to establish their accuracy in preoperative fistula-in-ano assessment. RESULTS. Accuracy rates of clinical examination endoanal ultrasound, and hydrogen peroxide-enhanced ultrasound were 65.4, 50, and 76.9 percent for primary tracks, 73.1, 65.4, and 88.5 percent for secondary tracks, and 80.8, 80.8, and 92.3 percent for horseshoe extensions, respectively. Compared with physical examination and endoanal ultrasound, accuracy of hydrogen peroxide-enhanced ultrasound was higher for transsphincteric and intersphincteric primary tracks and horseshoe extensions. Both endoanal ultrasound and hydrogen peroxide-enhanced ultrasound displayed a significantly higher accuracy in detecting the internal openings (53.8 and 53.8 percent, respectively) compared with clinical evaluation (23.1 percent;P=0.027). CONCLUSIONS. Our data suggest that hydrogen peroxide-enhanced ultrasound can be very reliable and useful in the definition of fistula anatomy, its relationship with anal sphincters, and, hence, surgical strategy. It also improves identification of secondary extensions, particularly horseshoe tracks. This method, besides being safe, economic and reputable, both preoperatively and postoperatively, could be helpful in checking operative results and recurrence.Presented at The American Society of Colon and Rectal Surgeons' 100^th Anniversary and Tripartite Meeting, Washington, D.C., May 1 to 6, 1999.