Capturing Patient Value in an Economic Evaluation.

OBJECTIVE: Economic evaluations predominantly use generic outcomes, such as the Euro Quality of Life-5 Dimension (EQ-5D), to assess health status. However, because of the generic nature, they are less suitable to capture the quality of life of patients with specific conditions. Given the transition to patient-centered (remote) care delivery, this study aims to evaluate the possibility of using disease-specific measures in a cost-effectiveness analysis. METHODS: A real-life cohort from Maasstad Hospital (2020-2021) in the Netherlands, with 772 patients with rheumatoid arthritis (RA), was used to assess the cost-effectiveness of electronic consultations (e-consultations) compared with face-to-face consultations. The Incremental Cost-Effectiveness Ratio (ICER), based on the generic EQ-5D, was compared with ICER's based on RA-specific measures: the Rheumatoid Arthritis Impact of Disease (RAID) and Health Assessment Questionnaire-Disability Index (HAQ-DI). To compare the cost-effectiveness of these different measures, HAQ-DI and RAID were expressed in quality-adjusted life-years (QALYs) via estimated conversion equations. RESULTS: Disease-specific patient-reported outcome measures (PROMs) offer a promising alternative for traditional measures in economic evaluations, capturing patient-relevant domains more comprehensively. Because PROMs are increasingly applied in clinical practice, the next step entails modeling of an RA patient-wide conversion equation to implement PROMs in economic evaluations. CONCLUSION: The conventional ICER (eg, EQ-5D) indicates that e-consultations are cost-effective with cost savings of -€161,000 per QALY gained for a prevalent RA cohort treated in a secondary trainee hospital. RA-specific measures show similar results, with ICERs of -€163,000 per HAQ-DI (QALY) and -€223,000 per RAID (QALY) gained. RA-specific measures capture patient-relevant domains and offer the opportunity to improve the assessment and treatment of the disease impact.

Increase in axial spondyloarthritis diagnoses after the introduction of the ASAS criteria: a systematic review.

To explore the proportion of axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) diagnoses within all newly referred patients visiting rheumatology outpatient clinics. And more specifically, to analyze whether there is an effect of the introduction of the ASAS and CASPAR classification criteria for axSpA and PsA. We systematically searched Embase, Medline Ovid, Cochrane Central and Web of Science from database inception to November 2022. Articles that investigated new onsets of axSpA and PsA in adults from rheumatology clinics were included. In total, 170 out of 7139 studies were found eligible for full-text review, after which 33 unique studies were included. Seventeen studies reported new onsets of axSpA, and 20 studies of PsA. The pooled proportion of axSpA within all newly referred patients was 19% (95% CI 15-23%) and 18% (95% CI 14-22%) for PsA. The proportion of axSpA before 2009 was 3% (95% CI 0-6%) and increased up to 21% (95% CI 14-28%) after 2009. For PsA, limited data were available in order to analyze the proportions of PsA before 2006. Overall, heterogeneity was high (I2 > 95%, p < 0.001) that was most likely caused by geographical area, study design, setting and use of different referral strategies. The pooled proportion of axSpA and PsA among patients referred to the rheumatology outpatient clinic was 19 and 18%, respectively. Although the proportion of diagnosed axSpA patients seemed to increase after the introduction of the ASAS criteria, due to the large heterogeneity our findings should be interpreted with caution.

Meta-Analyses on the Effects of Disease-Modifying Antirheumatic Drugs on the Most Relevant Patient-Reported Outcome Domains in Rheumatoid Arthritis.

OBJECTIVE: Whereas in the treatment of rheumatoid arthritis much evidence exists on the effects of current pharmacologic treatment on clinical outcomes, little is known about the effects on patient-reported outcomes. This systematic review aims to evaluate the effects of disease-modifying antirheumatic drugs (DMARDs) on the patient-relevant domains of pain, fatigue, activity limitation, overall emotional and physical health impact, and work/school/housework ability and productivity. METHODS: A literature search was conducted to identify randomized controlled trials wherein registered DMARDs were compared with placebo or methotrexate and reported the effects on patient-reported outcomes included in the International Consortium of Health Outcomes Measurement standard set for inflammatory arthritis. Random effects meta-analyses using the standardized mean differences of change scores as the effect measure were performed for the domains of pain, fatigue, and activity limitation, comparing DMARDs with placebo and methotrexate. The other 2 domains were presented narratively. RESULTS: Across the 5 domains, 69 records belonging to 52 studies were identified. All meta-analyses showed a decrease of burden when DMARDs were compared with placebo (standardized mean differences [95% confidence interval] in pain -0.80 [-0.99, -0.61], fatigue -0.48 [-0.64, -0.32], and activity limitation -0.56 [- 0.63, -0.49]) and when compared with methotrexate (-0.55 [-0.70, -0.41), -0.44 [-0.55, -0.33], and - 0.37 [-0.44, -0.30], respectively). CONCLUSION: DMARDs decrease the burden in all the domains that are relevant to patients. Effect sizes may be influenced by DMARD type. Therefore, in the decision for rheumatoid arthritis treatment, patient-reported outcomes should be taken into account.

Defining the care delivery value chain and mapping the patient journey in rheumatoid arthritis.

Rheumatoid Arthritis (RA) is a chronic disease that impacts patients' quality of life. Sophisticated organization of care delivery drives quality improvement. Therefore, the study objective was establishing a validated process map of the care cycle for RA patients. Hence, increasing transparency and optimizing care delivery and identifying areas of improvement. To map the RA care cycle, the care delivery value chain (CDVC) approach was used as framework to document activities and resources systematically. A mixed method study was conducted where quantitative data on activities were collected from health records and unstructured interviews with medical staff were held. Consequently, the process map was separately validated in a consensus meeting with a delegation of the medical staff and patient advisory board. At the start of the care cycle, the focus is predominantly on defining the treat-to-target strategy and examining disease activity. Towards the monitoring phase, tapering medication and managing the disease through patient-reported outcome measures are becoming increasingly important. Although patient's functioning, quality of care and patient's evaluation of received care are monitored, reflection of CDVC and engaging patients in the evaluation process resulted in improvement actions on outcome and process level. Mapping the RA care cycle following a systematic approach, provides insight and transparency in delivered activities, involved resources and the engagement of patients and caregivers at multiple levels, contributing to a system facilitating value-based care delivery. The CDVC framework and applied methodology is recommended in other conditions. Future research will focus at assigning outcomes and costs to activities and evaluating interventions to explore patient value.

Barriers and facilitators for implementation of a digital referral algorithm for inflammatory arthritis - a qualitative assessment in patients and caregivers.

PURPOSE: Difficulty to recognize inflammatory rheumatic diseases (IRD) in a primary care setting leads to late referral to secondary care. An evidence-based digital referral algorithm can support early referral, yet implementation in daily practice only succeeds with support of end users. We aim to understand the context of implementing a digital referral algorithm and explore the potential barriers and facilitators to implementation. METHODS: This qualitative study comprised focus groups and an online survey. Focus groups were performed with patients from outpatient rheumatology clinics. Surveys were sent out to general practitioners and rheumatologists distributed over The Netherlands. The presented digital referral algorithm originates from the JOINT referral study. Thematic analysis was used with inductive and deductive approaches. RESULTS: In total 26 patients participated distributed over three focus groups, and 215 caregivers (104 rheumatologists, 111 general practitioners) filled out the survey. Both patients and caregivers endorse the need for early referral, and recognize the perceived benefit of the digital algorithm. Potential barriers include the complexity of currently included questions, and the outcome lacking information on what to do with no risk of IRD. In order for implementation to be successful, the inclusivity, accessibility, content and outcome of the algorithm are considered important themes. CONCLUSION: Successful implementation of a digital referral algorithm needs a systematic multi-facetted approach, considering the barriers and facilitators for implementation as discussed. Since the majority of identified barriers and facilitators was overlapping between all stakeholders, findings from this study can reliably inform further decision strategies for successful implementation.

A systematic review on time trend incidence of rheumatoid arthritis in outpatient rheumatology clinics.

Objectives: To classify patients with rheumatoid arthritis (RA) in an earlier stage of the disease, the ACR/EULAR classification criteria were updated in 2010. These criteria might have led to an increased incidence of RA in the rheumatology clinic. Since a higher incidence increases the socio-economic burden of RA, it is worthwhile to evaluate whether there is a time effect. Materials and methods: A systematic review was conducted using Embase, Medline Ovid, Cochrane Central, and Web of Science from database inception to February 2021. Included were only articles that addressed incidence rates of rheumatoid arthritis from rheumatology outpatient clinics. Results: Of the 6,289 publications only 243 publications on RA were found eligible for full-text review. Nine studies were included reporting incidence. The pooled incidence for RA was 11% (95% CI 6-16%) per year. Over time the incidence increased after the introduction of the 2010 ACR/EULAR classification criteria. Overall there was a high intragroup heterogeneity (I 2 = 97.93%, p < 0.001), caused by geographical area, study design and differences in case definitions. Conclusion: Although the incidence seems to increase after the introduction of the 2010 ACR/EULAR criteria, no conclusions can be drawn on this time effect due to heterogeneity.

The IMPACT study: A clustered randomized controlled trial to assess the effect of a referral algorithm for axial spondyloarthritis.

BACKGROUND: A substantial number of patients with chronic low back pain (CLBP) have axial spondyloarthritis (axSpA), but early recognition of these patients is difficult for general practitioners (GPs). The Case Finding Axial Spondyloarthritis (CaFaSpA) referral strategy has shown to be able to identify patients with CLBP at risk for axSpA, but its impact on clinical daily practice is yet unknown. OBJECTIVE: To assess the effect of the CaFaSpA referral strategy on pain caused by disability in primary care patients with CLBP. METHODS: Within this clustered randomized controlled trial 93 general practices were randomized to either the CaFaSpA referral model (intervention) or usual primary care (control). In each group primary care patients between 18 and 45 years with CLBP were included. The primary outcome was disability caused by CLBP, measured with the Roland Morris Disability Questionnaire (RMDQ) at baseline and four months. Secondary outcome was the frequency of new axSpA diagnosis. Descriptive analyses were performed, and a linear mixed-effects model was used. RESULTS: In total 679 CLBP patients were included of which 333 patients were allocated to the intervention group and 346 to the control group. Sixty-four percent were female and mean age was 36.2 years. The mean RMDQ score at baseline was 8.39 in the intervention group and 8.61 in the control group. At four months mean RMDQ score was 7.65 in the intervention group and 8.15 in the control group. This difference was not statistically significant (p = 0.50). Six (8%) out of the 75 finally referred patients, were diagnosed with axSpA by their rheumatologist. CONCLUSIONS: The CaFaSpA referral strategy for axSpA did not have an effect on disability after four months caused by CLBP. However, the strategy is able to detect the axSpA patient within the large CLBP population sufficiently. Trial registration number: NCT01944163, Clinicaltrials.gov.

Can Free Water Transport Be Used as a Clinical Parameter for Peritoneal Fibrosis in Long-Term PD Patients?

Sodium sieving in peritoneal dialysis (PD) occurs in a situation with high osmotically-driven ultrafiltration rates. This dilutional phenomenon is caused by free water transport through the water channel aquaporin-1. It has recently been described that encapsulating peritoneal fibrosis is associated with impaired free water transport, despite normal expression of aquaporin-1. In this review, it will be argued that free water transport can be used for assessment of fibrotic peritoneal alterations, due to the water-binding capacity of collagen. Finally, the consequences for clinical practice will be discussed.

Encapsulating peritoneal sclerosis is associated with T-cell activation.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an excessive fibrotic response of the peritoneum that may occur after long-term peritoneal dialysis (PD). The underlying pathophysiology is poorly understood, but involvement of peritoneal inflammatory T helper 1 cells may be pivotal. METHODS: Soluble interleukin-2 receptor alpha (sCD25) concentration was measured as a marker for T-cell activation in serum and ascites from EPS patients and various control patient groups. Peritoneal biopsies were stained for the presence of T cells, and T cells isolated from ascites of EPS patients were characterized in detail for differentiation status and cytokine expression. RESULTS: Serum sCD25 concentrations are significantly and specifically increased in EPS patients compared with haemodialysis, PD and predialysis patients. Peritoneal effluent of stable PD patients contains very low levels of sCD25, while sCD25 levels in ascites of EPS patients are high and indicative of local production. In the years preceding the diagnosis of EPS, the serum sCD25 concentrations increased while remaining at stable levels in control PD patients. The peritoneum and ascites of EPS patients showed a significant influx of T cells with relatively increased numbers of CD4(+) T cells. These T cells were fully differentiated and displayed a T helper 1 cell type with a pro-inflammatory cytokine profile. CONCLUSIONS: Increased serum sCD25 concentrations and peritoneal lymphocytosis in EPS patients indicate the involvement of activated T cells in the pathophysiology of excessive fibrosis.

Peritoneal effluent MMP-2 and PAI-1 in encapsulating peritoneal sclerosis.

BACKGROUND: Recently, the use of effluent matrix metalloproteinase 2 (MMP-2) and plasminogen activator inhibitor 1 (PAI-1) as potential biomarkers of peritoneal fibrosis has been demonstrated during longitudinal follow-up of incident peritoneal dialysis (PD) patients. This study focuses on effluent MMP-2 and PAI-1 as early diagnostic markers in the preceding years of patients who develop encapsulating peritoneal sclerosis (EPS). STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: PD patients who developed EPS were compared with controls using a 1:3 case-control design with a minimum PD duration of 57 months. INDEX TESTS: Dialysate appearance rates of MMP-2 and PAI-1. REFERENCE TEST: EPS cases identified by 2 experienced nephrologists and a radiologist based on predefined criteria. RESULTS: 11 patients developed EPS within our center. The time course of MMP-2 appearance rates, studied by means of a linear repeated-measures model 4 years prior to the diagnosis of EPS, showed no difference between long-term controls and patients with EPS. In contrast, higher PAI-1 appearance rates were found in patients with EPS compared with controls (P=0.01). At a lag time of 1 year prior to EPS diagnosis, time-specific receiver operating characteristic curve analyses indicated a discriminative ability for PAI-1 appearance rate of 0.77 (95% CI, 0.63-0.91). A discriminative capacity was absent for those of MMP-2. LIMITATIONS: Low event rate of EPS prevented independent validation in this single-center study. CONCLUSIONS: Elevated levels of PAI-1 appearance rates are present in patients who develop EPS, pointing to progressive peritoneal fibrosis and sclerosis. The PAI-1 appearance rate has fair discriminative capacity from 3 years prior to EPS diagnosis. Therefore, effluent PAI-1 may aid in monitoring peritoneal fibrosis and serve as a biomarker for EPS.

Is the systemic microvascular endothelial glycocalyx in peritoneal dialysis patients related to peritoneal transport?

BACKGROUND/AIMS: The capillary wall coated by the endothelial glycocalyx is the main transport barrier during peritoneal dialysis (PD). Here, we investigated the relationships between measurements of the systemic endothelial glycocalyx and peritoneal transport in PD patients. METHODS: We performed sidestream darkfield (SDF) imaging of the sublingual microvasculature in 15 patients, measured the perfused boundary region (PBR), which includes the permeable part of the glycocalyx, and calculated the estimated blood vessel density (EBVD). All patients underwent a peritoneal permeability analysis. RESULTS: No relationships were present between the imaging and peritoneal transport parameters, neither in the group as a whole nor in fast transporters. In patients with nonfast peritoneal transport status, PBR had a negative relationship with EBVD and small solute transport, and a positive one with net ultrafiltration (NUF). The EBVD showed a positive correlation with glucose absorption and a negative one with NUF. We found no relationships with the peritoneal transport of albumin. CONCLUSIONS: No relationships are present between the systemic endothelial glycocalyx, which was assessed by SDF, and peritoneal transport. In nonfast transporters, a reduction in blood vessel density caused by endothelial glycocalyx alterations or a thicker permeable phase of the glycocalyx delaying the access of small solutes to the small pores may be important. .

Current status and practical use of effluent biomarkers in peritoneal dialysis patients.

Long-term peritoneal dialysis therapy can lead to alterations in the function and morphology of the peritoneal membrane. Assessment of the peritoneal dialysis membrane usually is done by investigating the transport of small solutes and fluid. Assessment of morphologic alterations and their development would require repetitive peritoneal biopsies that usually are not feasible. Peritoneal tissues are bathed in dialysis solutions during peritoneal dialysis and may secrete or shed substances that can be recovered in peritoneal effluent. These molecular effluent biomarkers may give insight into morphologic changes. In this review, established and emerging candidate biomarkers in peritoneal dialysis are discussed. Additionally, requirements, challenges, and clinical applications of effluent biomarkers in peritoneal dialysis are addressed.

Variability of effluent cancer antigen 125 and interleukin-6 determination in peritoneal dialysis patients.

BACKGROUND: Cancer antigen (CA) 125 is a glycoprotein that provides data on the state of the peritoneal membrane in peritoneal dialysis (PD). Interleukin-6 (IL-6) acts as a mediator in acute-phase responses. The study evaluated the usefulness of CA125 and IL-6 in random effluent samples, by assessing their variability in individual patients during clinical practice at the outpatient department. METHODS: This longitudinal prospective study was conducted from 2007 till 2009. Participants included 52 stable PD patients aged ≥ 18 years. Effluent samples were obtained during regular outpatient visits and appearance rates (ARs) were calculated. Inter- and intra-individual variability was determined by the coefficient of variation (CV). A linear mixed model was used to analyse time courses. Furthermore, release patterns of these effluent markers were studied. RESULTS: CA125-AR of short-term patients (≤ 24 months) ranged from 39.2 to 766.7 U/min and IL-6-AR from 15.5 to 220.0 pg/min. Long-term patients (≥ 25 months) had a CA125-AR of 7.3-1534.0 U/min and IL-6-AR of 6.9-956.4 pg/min. Overall, CV(intra) was 15% in effluent CA125-AR and 28% in IL-6-AR. Intermediate sampling during a 4-h dwell showed a linear increase of CA125 and IL-6 effluent concentrations. The trend of CA125-AR was different (P = 0.001) between short- and long-term patients. A negative relationship was found between CA125 (r = -0.44, P = 0.02) and PD duration. CONCLUSIONS: The clinical relevance of effluent CA125 determinations from an unstandardized dwell during every outpatient visit is reasonable, as judged from the CV(intra). The inferior CV(intra) values of ARs as compared to effluent values indicate that ARs should only be calculated under standardized conditions. A single IL-6 measurement, as a predictor of outcome, should be interpreted cautiously.

Induction of chronic kidney failure in a long-term peritoneal exposure model in the rat: effects on functional and structural peritoneal alterations.

BACKGROUND: A long-term peritoneal exposure model has been developed in Wistar rats. Chronic daily exposure to 3.86% glucose based, lactate buffered, conventional dialysis solutions is possible for up to 20 weeks and induces morphological abnormalities similar to those in long-term peritoneal dialysis (PD) patients. The possible effects of kidney failure in this model are unknown. The aim was to analyze the effects of chronic kidney failure on peritoneal function and morphology, alone and in combination with PD exposure, in a well-established, long term, peritoneal exposure model in the rat. ♢ METHODS: 40 male Wistar rats were randomly assigned into four experimental groups: no nephrectomy, no peritoneal exposure (sham; n = 8); nephrectomy, no peritoneal exposure (Nx; n = 12); no nephrectomy, with peritoneal exposure (PD; n = 8); and nephrectomy, with peritoneal exposure (NxPD; n = 12). The nephrectomy consisted of a one-step 70% nephrectomy. The peritoneal exposure groups were infused once daily for 16 weeks with a 3.86% glucose-based dialysis solution. Development of chronic kidney disease was monitored during the experiment. Peritoneal function and morphological assessment of the peritoneal membrane were performed at the end of the experiment. ♢ RESULTS: During follow-up the nephrectomized groups developed uremia with remarkable renal tubular dilatation and glomerular sclerosis in the renal morphology. Functionally, uremia (Nx) and PD exposure (PD) alone showed faster small solute transport and a decreased ultrafiltration capacity, which were most pronounced in the combination group (NxPD). The presence of uremia resulted in histological alterations but the most severe fibrous depositions and highest vessel counts were present in the PD exposure groups (PD and NxPD). Significant relationships were found between the number of vessels and functional parameters of the peritoneal vascular surface area. ♢ CONCLUSION: It is possible to induce chronic kidney failure in our existing long-term peritoneal infusion model in the rat. The degree of impairment of kidney function after 16 weeks is comparable to chronic kidney disease stage IV. Uremia per se induces both functional and morphological alterations of the peritoneal membrane. An additive effect of these alterations is present with the addition of chronic kidney failure to the model. The latter makes the present long-term model important in better understanding the pathophysiology of the peritoneal membrane in PD.