Kazuki Yoshida

Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine.

Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health.

Biologic discontinuation studies: a systematic review of methods

Objectives We conducted a systematic review to assess the design and ‘failure definition’ in studies of biologic discontinuation in rheumatoid arthritis (RA). Methods We found 403 studies on PubMed, and included nine published papers and five abstracts from scientific meetings. We used a structured extraction form to collect information regarding study design and outcome (failure) definition. Results Three types of studies were found: randomised controlled trials, long-term extension studies of clinical trials and prospective discontinuation studies. The largest study had 196 subjects in the discontinuation arm. Most studies allowed concomitant use of non-biologic drugs at biologic discontinuation. Heterogeneity was also found in the failure definition. Although all studies used measures of disease activity, the threshold for failure and the time point of assessment differed among studies. Few studies incorporated changing use of non-biologic drugs or glucocorticoids into the failure definition. Conclusions Although many studies have examined the outcome of biologic discontinuation, they have all been relatively small. Typical practice studies from registries may add important information but will likely need to rely on a broader failure definition.

Multimorbidity and rheumatic conditions—enhancing the concept of comorbidity

The concept of multimorbidity is still poorly understood and not well integrated into medical care and research. For clinicians involved in rheumatology care for an ageing patient population who have multiple diseases, multimorbidity is the rule not the exception. The interaction of different diseases and the impact they have on important clinical outcomes, such as physical function, quality of life and mortality, should all be considered by the rheumatologist. Treatment decisions must be adapted for the patient with multimorbidity to best serve the individual and society. This Perspectives article describes the concept of multimorbidity, how it differs from comorbidity, and outlines why an increased understanding of multimorbiditiy will enhance our overall clinical practice and research focus.

Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction

BACKGROUND There is need for risk stratification of adverse events in patients with heart failure with HFpEF as the number of patients is increasing and prognosis of this population is poor. This study was performed to determine whether endothelial dysfunction measured by peripheral artery tonometry (PAT) can predict prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS We included 159 patients with HFpEF, and log-transformed reactive hyperemia index (L_RHI) was measured. Patients were followed-up for HF-related events, which including HF-related death and re-hospitalization due to congestive heart failure for 300 days. RESULTS A total of 32 HF-related events occurred during follow-up, including 4 deaths due to HF and 28 cases of re-hospitalization due to acute decompensated HF. Cox regression analysis indicated that L_RHI (HR 0.56, 95% CI: 0.39-0.80 for an increase of 0.1) was an independent predictor of HF-related events. Receiver operating characteristic analysis was performed for L_RHI, and the area under the curve was 0.73 (95% CI: 0.62-0.83). Moreover, a value of 0.49 was suggested as the optimal cut-off value for prediction of adverse events in this population. CONCLUSION L_RHI measured by non-invasive PAT is a predictor of poor prognosis in patients with HFpEF.

Discontinuation of tumour necrosis factor inhibitors in patients with rheumatoid arthritis in low-disease activity: persistent benefits. Data from the Corrona registry

BACKGROUND There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit. METHODS We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan-Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit. RESULTS We identified 717 eligible patients with RA from 35,656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit. CONCLUSIONS Discontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.

Clinical Effectiveness of Tolvaptan in Patients With Acute Heart Failure and Renal Dysfunction

BACKGROUND More efficacious and/or safer decongestive therapy is clearly needed in acute heart failure (AHF) patients complicated by renal dysfunction. We tested the hypothesis that adding tolvaptan, an oral vasopressin-2 receptor antagonist, to conventional therapy with loop diuretics would be more effective treatment in this population. METHODS AND RESULTS A multicenter, open-label, randomized control trial was performed, and 217 AHF patients with renal dysfunction (estimated glomerular filtration rate 15-60 mL • min(-1) • 1.73 m(-2)) were randomized 1:1 to treatment with tolvaptan (n=108) or conventional treatment (n=109). The primary end point was 48-hour urine volume. The tolvaptan group showed more diuresis than the conventional treatment group (6464.4 vs 4999.2 mL; P <.001) despite significantly lower amounts of loop diuretic use (80 mg vs 120 mg; P <.001). Dyspnea relief was achieved significantly more frequently in the tolvaptan group at all time points within 48 hours except 6 hours after enrollment. The rate of worsening of renal function (≥0.3 mg/dL increase from baseline) was similar between the tolvaptan and conventional treatment groups (24.1% vs 27.8%, respectively; P =.642). CONCLUSIONS Adding tolvaptan to conventional treatment achieved more diuresis and relieved dyspnea symptoms in AHF patients with renal dysfunction. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index/htm/ Unique identifier: UMIN000007109.

Clinical Characteristics of Patients with Remitting Seronegative Symmetrical Synovitis with Pitting Edema Compared to Patients with Pure Polymyalgia Rheumatica

Objective. To compare clinical features of patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and patients with polymyalgia rheumatica (PMR) and to explore the purported association between RS3PE and malignancy. Methods. We did a retrospective chart review of patients with RS3PE and PMR treated in a community-based hospital between January 2000 and December 2009. Outcomes assessed were clinical course of disease and associated malignancies. Results. We identified 28 patients with RS3PE and 123 with pure PMR. All patients with RS3PE fulfilled PMR criteria as well. Age, comorbidity, erythrocyte sedimentation rate, duration and progression of symptoms, treatment response to initial low-dose steroids, and steroid complication rates were similar in both groups. Patients with RS3PE were more likely to be male (79% vs 41%; p = 0.001) and to have a history of smoking (39% vs 15%; p = 0.008) and a higher rate of depression (11% vs 2%; p = 0.044) at diagnosis. Among those with RS3PE, hip pain was less common (39% vs 74%; p = 0.001) than in the PMR group. No patients with RS3PE and 6 patients with pure PMR (4.9%) developed another rheumatological disease during followup. Seven of 9 patients (78%) with concurrent cancer presented slightly more frequently with systemic symptoms compared to patients without cancer (48%; p = 0.098), especially with fatigue (56% vs 22%; p = 0.037) and anorexia (33% vs 9.0%; p = 0.047). Despite rigorous cancer screening in patients with RS3PE, however, the rate of associated malignancy was not statistically different from that of patients with pure PMR [2 (7%) vs 7 (6%), respectively; p = 0.673]. Conclusion. Despite evidence that RS3PE is clinically distinct from PMR, we observed characteristics, treatment response, and outcomes like those expected in pure PMR. Compared to patients with pure PMR, patients with RS3PE are more likely to be male, to be depressed, and to smoke. Contrary to earlier studies, no clear association of RS3PE with malignancy was found despite rigorous cancer screening, although clinicians should be aware that patients with concurrent cancer may manifest more systemic signs and symptoms, as well as steroid resistance.

Carperitide Is Associated With Increased In-Hospital Mortality in Acute Heart Failure: A Propensity Score-Matched Analysis.

BACKGROUND Carperitide (α-human A-type natriuretic peptide) has been used for more than one-half of all acute heart failure (AHF) patients in Japan. However, its clinical effectiveness is not well documented. METHODS We retrospectively identified AHF patients presenting with acute onset or worsening of symptoms and admitted to 1 of the 3 participating hospitals. Propensity score-matched analysis was performed. The primary end point was in-hospital mortality. RESULTS Of all of the AHF patients included in this study, 402 (38.7%) were treated with carperitide, and in-hospital mortality rate for the total cohort was 7.6%. We matched 367 pairs of patients treated with and without carperitide according to propensity score. In this matched cohort, treatment with carperitide was associated with in-hospital mortality (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.17-3.85; P = .013). Potentially more harmful effects were observed in elderly patients (OR 2.93, 95% CI 1.54-5.91). CONCLUSIONS Carperitide was significantly associated with increased in-hospital mortality rate in AHF patients. Our results strongly suggest the necessity for well designed randomized clinical trials of carperitide to determine its clinical safety and effectiveness.

Development of a multimorbidity index: Impact on quality of life using a rheumatoid arthritis cohort.

OBJECTIVE To develop a multimorbidity index (MMI) based on health-related quality of life (HRQol). METHODS The index was developed in an observational RA cohort. In all, 40 morbidities recommended as core were identified using ICD-9 codes. MMIs of two types were calculated: one by enumerating morbidities (MMI.count) and the other by weighting morbidities based on their association with HRQol as assessed by EQ-5D in multiple linear regression analysis (using β-coefficients; MMI.weight). MMIs were compared to the Charlson comorbidity index (CCI) and externally validated in an international RA cohort (COMORA Study). RESULTS In all, 544 out of 876 patients were multimorbid. MMI.count was in the range 1-16 (median = 2) and MMI.weight in the range 0-38 (median = 1). Both indices were more strongly associated with EQ-5D than CCI (Spearman: MMI.count = -0.20, MMI.weight = -0.26, and CCI = -0.10; p < 0.01). R(2) obtained by linear regression using EQ-5D as a dependent variable and various indices as independent variables, adjusted for age and gender, was the highest for MMI (R(2): MMI.count = 0.05, MMI.weight = 0.11, and CCI = 0.02). When accounting for clinical disease activity index (CDAI) R(2) increased: MMI.count = 0.18, MMI.weight = 0.22, and CCI = 0.17, still showing higher values of MMI compared with CCI. External validation in different RA cohorts (COMORA, n = 3864) showed good performance of both indices (linear regression including age, gender, and disease activity R(2) = 0.30 for both MMIs). CONCLUSION In our cohort, MMI based on EQ-5D performed better than did CCI. Findings were reproducible in another large RA cohort. Not much improvement was gained by weighting; therefore a simple counted index could be useful to control for the effect of multimorbidity on patients overall well-being.

The impact of multimorbidity status on treatment response in rheumatoid arthritis patients initiating disease-modifying anti-rheumatic drugs

OBJECTIVE When treating RA patients, remission (REM) or at least low disease activity (LDA) is the ultimate therapeutic goal. The aim of this study was to assess the impact of multimorbidity on achieving REM or LDA. METHODS In a prospective RA cohort, we identified patients initiating any DMARD with follow-up data 1 year after. Treatment effects were measured using the clinical disease activity index (CDAI) and the modified health assessment questionnaire (MHAQ); multimorbidity status was assessed using a counted multimorbidity index (cMMI). The proportion of patients reaching REM or LDA 1 year after DMARD commencement with respect to the cMMI was evaluated. In regression models, we calculated the odds ratio of achieving REM or LDA, and predicted CDAI and MHAQ 1 year after DMARD commencement for various levels of cMMI, adjusting for age, sex, disease duration, serostatus, disease activity at DMARD commencement, number of previous DMARDs, and type of DMARD, steroid and NSAID use. RESULTS A total of 815 patients started DMARDs; 414 were on the same DMARD after 1 year. The proportion of these patients achieving REM or LDA after 1 year was significantly lower in the patients with higher cMMI, following a linear trend (P < 0.01). After accounting for covariates, the odds ratio for REM associated with each additional morbidity in the cMMI was 0.72 (95% CI 0.55, 0.97) and 0.81 (95% CI 0.70, 0.94) for LDA. One year after DMARD initiation, CDAI (+0.16 per additional morbidity) and MHAQ scores (+0.15 per additional morbidity) were significantly worse (both P < 0.05). CONCLUSION Increased multimorbidity negatively affects the therapeutic goal of REM and LDA.