Applied causal inference methods for sequential mediators

Background: Mediation analysis aims at estimating to what extent the effect of an exposure on an outcome is explained by a set of mediators on the causal pathway between the exposure and the outcome. The total effect of the exposure on the outcome can be decomposed into an indirect effect, i.e. the effect explained by the mediators jointly, and a direct effect, i.e. the effect unexplained by the mediators. However finer decompositions are possible in presence of independent or sequential mediators. Methods: We review four statistical methods to analyse multiple sequential mediators , the inverse odds ratio weighting approach, the inverse probability weighting approach, the imputation approach and the extended imputation approach. These approaches are compared and implemented using a case-study with the aim to investigate the role of adverse reproductive outcomes and infant respiratory infections on infant wheezing in the Ninfea birth cohort. Results: Using the inverse odds ratio weighting approach, the direct effect of maternal depression or anxiety in pregnancy is equal to a 59% (95% CI: 27%-94%) increased prevalence of infant wheezing and the mediated effect through adverse reproductive outcomes is equal to a 3% (95% CI:-6%-12%) increased prevalence of infant wheezing. When including infant lower respiratory infections in the mediation pathway, the direct effect decreases to 57% (95% CI: 25%-92%) and the indirect effect increases to 5% (95% CI:-5%,15%). The estimates of the effects obtained using the weighting and the imputation approaches are similar. The extended imputation approach suggests that the small joint indirect effect through adverse reproductive outcomes and lower respiratory infections is due entirely to the contribution of infant lower respiratory infections, independently from the increased prevalence of adverse reproductive outcomes. Conclusions: The use of these methods allows the study of multiple mechanisms underlying the association between an exposure and an outcome and provides a solution for the problem of intermediate confounding by considering the intermediate confounder as a sequential mediator. The choice of the method may depend on what is the effect of main interest, the nature of the variables involved in the analysis and the truthfulness of the underlying assumptions.

High spatial resolution analysis using indentation mapping differentiates biomechanical properties of normal vs. degenerated mouse articular cartilage

Characterizing the biomechanical properties of articular cartilage is crucial to understanding processes of tissue homeostasis vs. degeneration. In mouse models, however, limitations are imposed by their small joint size and thin cartilage surfaces. Here we present a 3D automated surface mapping system and methodology that allows for mechanical characterization of mouse cartilage with high spatial resolution. We performed repeated indentation mappings, followed by cartilage thickness measurement via needle probing, at 31 predefined positions distributed over the medial and lateral femoral condyles of healthy mice. High-resolution 3D x-ray microscopy (XRM) imaging was used to validate tissue thickness measurements. The automated indentation mapping was reproducible, and needle probing yielded cartilage thicknesses comparable to XRM imaging. When comparing healthy vs. degenerated cartilage, topographical variations in biomechanics were identified, with altered thickness and stiffness (instantaneous modulus) across condyles and within anteroposterior sub-regions. This quantitative technique comprehensively characterized cartilage function in mice femoral condyle cartilage. Hence, it has the potential to improve our understanding of tissue structure-function interplay in mouse models of repair and disease.

Modelling rheumatoid arthritis: A hybrid modelling framework to describe pannus formation in a small joint

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes pain, swelling and stiffness in the joints, and negatively impacts the life of affected patients. The disease does not have a cure yet, as there are still many aspects of this complex disorder that are not fully understood. While mathematical models can shed light on some of these aspects, to date there are not many such models that can be used to better understand the disease. As a first step in the mechanistic understanding of RA, in this study we introduce a new hybrid mathematical modelling framework that describes pannus formation in a small proximal interphalangeal (PIP) joint. We perform numerical simulations with this new model, to investigate the impact of different levels of immune cells (macrophages and fibroblasts) on the degradation of bone and cartilage. Since many model parameters are unknown and cannot be estimated due to a lack of experiments, we also perform a sensitivity analysis of model outputs to various model parameters (single parameters or combinations of parameters). Finally, we connect our numerical results with current treatments for RA, by discussing our numerical simulations in the context of various drug therapies using, for example, methotrexate, TNF-inhibitors or tocilizumab, which can impact different model parameters.

Symptoms in first-degree relatives of patients with rheumatoid arthritis: evaluation of cross-sectional data from the symptoms in persons at risk of rheumatoid arthritis (SPARRA) questionnaire in the PRe-clinical EValuation of Novel Targets in RA (PREVeNT-RA) Cohort

Background First-degree relatives (FDRs) of people with rheumatoid arthritis (RA) have a fourfold increased risk of developing RA. The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire was developed to document symptoms in persons at risk of RA. The aims of this study were (1) to describe symptoms in a cohort of FDRs of patients with RA overall and stratified by seropositivity and elevated CRP and (2) to determine if patient characteristics were associated with symptoms suggestive of RA. Methods A cross-sectional study of FDRs of patients with RA, in the PREVeNT-RA study, who completed a study questionnaire, provided a blood sample measured for rheumatoid factor, anti-CCP and CRP and completed the SPARRA questionnaire. Moderate/severe symptoms and symmetrical, small and large joint pain were identified and described. Symptoms associated with both seropositivity and elevated CRP were considered suggestive of RA. Logistic regression was used to determine if symptoms suggestive of RA were associated with patient characteristics. Results Eight hundred seventy participants provided all data, 43 (5%) were seropositive and 122 (14%) had elevated CRP. The most frequently reported symptoms were sleep disturbances (20.3%) and joint pain (17.9%). Symmetrical and small joint pain were 11.3% and 12.8% higher, respectively, in those who were seropositive and 11.5% and 10.7% higher in those with elevated CRP. In the logistic regression model, seropositivity, older age and feeling depressed were associated with increased odds of small and symmetrical joint pain. Conclusions This is the first time the SPARRA questionnaire has been applied in FDRs of patients with RA and has demonstrated that the presence of symmetrical and small joint pain in this group may be useful in identifying people at higher risk of developing RA.

Small joint polyarthritis – An unusual presentation of scrub typhus in a child

Scrub typhus is a common Rickettsial infection which is endemic in tropical regions. It is characterised by fever, eschar, thrombocytopenia, lymphadenopathy and organomegaly. Scrub typhus has significant morbidity and mortality owing to its multisystemic involvement. Non-inflammatory polyarthritis of small joints is an uncommon presentation in paediatric scrub typhus. We discuss a five-year-old boy who presented with fever, small joint polyarthritis, hepatosplenomegaly and pathognomonic eschar with positive scrub IgM ELISA. Arthritis resolved completely with doxycycline therapy without any deformity.

POS0574 RELATIONSHIP BETWEEN INVOLVED JOINT FOR REGION AND MODIFIED HEALTH ASSESSMENT QUESTIONNAIRE SCORE IN JAPANESE PATIENT WITH RHEUMATOID ARTHRITIS

Objectives:Rheumatoid arthritis (RA) is a chronic inflammatory disease that involves various joints in whole body. For evaluation of daily life activities (ADL), modified Health Assessment Questionnaire (mHAQ) is usually used. This index configures eight ADL functions these are separated by predominant extremities. This study aimed to evaluate how involved joint affect ADL predominantly in real world setting.Methods:A total of 24,450 times of consultation with RA patient were visited in the institute. Here, patient with RA was interviewed every another visit, and involved joint in whole body, pain score with visual analog scale (PS-VAS), and mHAQ were recorded. Involved joints were divided by four regions in accordance with joint size and part; small joint in upper extremities (US), large joint in upper extremities (UL), small joint in lower extremities (LS), and large joint in lower extremities (LL). mHAQ was also separately evaluated in accordance with predominant regions; upper extremities predominant mHAQ (mHAQ_UE), and lower extremities predominant mHAQ (mHAQ_LE). Adding to these parameters, as an index for disease activity monitoring, components of the simplified disease activity index score (SDAI) was also recorded. Relationship between mHAQ for each predominant extremities, and these parameters and sex, age, disease duration of RA, anti-cyclic citrullinated polypeptide antibodies (ACPA), rheumatoid factor (RF), and Sharp/van der Heijde score (SHS), were statistically evaluated using linear regression analysis.Results:mHAQ_UE significantly correlated with age, ACPA and RF titre, SHS, tenderness joint count (TJC), patient’s global assessment (PGA), evaluator’s global assessment (EGA), C-reactive protein (CRP), US, UL, LL, and PS-vas, whereas mHAQ-LE significantly correlated with all parameters that demonstrated significant correlation with mHAQ-UE and disease duration. mHAQ also correlated with all parameters those that demonstrated significant correlation with mHAQ-LE. Interestingly, all of mHAQ-UE, mHAQ-LE, and mHAQ did not correlated significantly with swollen joint count (SJC) and LS.Conclusion:mHAQ is influenced by various factors, however, SJC and involvement of small joint in lower extremities did not affect mHAQ.Disclosure of Interests:None declared

AB0172 ELDERLY ONSET RHEUMATOID ARTHRITIS (EORA): WHAT TO EXPECT IN REAL LIFE

Background:The term elderly onset of rheumatoid arthritis (EORA) refers to patients with rheumatoid arthritis (RA) onset after the age of 60. Data published in the literature suggest a special clinical pattern and different prognostic factors in this class of patients.Objectives:To analyze prospectively a cohort of patients diagnosed with EORA, their disease particularities, comorbidities and treatment.Methods:This cohort included consecutive EORA patients, diagnosed and treated in “Sfanta Maria” Clinical Hospital, Bucharest, Romania. The study was conducted for 2 years. Demographic, clinical and laboratory data was obtained. Disease activity was assessed using Disease Activity Score of 28 joints with erythrocyte sedimentation rate (DAS28-ESR). The patients were monitored using disease activity, treatment schedule modifications and possible adverse reactions.Results:The cohort included 110 patients (88 females, 22 males). Their mean age at the beginning of disease manifestations was 70.14 years and the mean age at the diagnosis was 70.85 years. There was no statistical difference regarding the patient’s residential area (urban/rural) and the period between the appearance of clinical signs and the moment of diagnosis confirmation. A great proportion of patients (77 patients, 70%) had seropositive RA, ACPA being found in 84% of the patients with seropositive RA. The mean DAS28-ESR at the diagnosis was 4.44(±1.54). A proportion of 40% of the patients had moderate disease activity, 35 patients (32.73%) - high disease activity, 11 patients (10%) - low disease activity and unexpectedly there were 19 patients (17.27%) in remission at the moment of RA diagnosis. Joint distribution was analyzed: 61.82% patients had large joint involvement, 91.82% - small joint involvement and 53.64 % had mixed joint pattern involvement. A negative significant correlation was found between the small joint involvement pattern and the body mass index (BMI) (p=0.028, R=-0.21). The mean BMI at the diagnosis was 25.81±5.358. Ninety five patients (86,36%) had at least one cardiovascular comorbidity. Hypertension was found in 70% of the patients. Only 4.55% of the patients had rheumatoid nodules and a similar proportion (4.55) had Sjogren syndrome associated. Pulmonary fibrosis was found in only 2 patients. At the moment of diagnosis 50% of patients had anemia, 36.36% had osteoporosis, 25.46% of the patients - hepatic disease, 11.82% - chronic kidney failure and 6.36% were found with a neoplasia. The main conventional synthetic disease modifying drug (csDMARD) that was recommended was methotrexate (81.8%). The second most used csDMARD was hydroxichroloquine (42 patients, 38,18%). The proportion of patients with monotherapy (50%) was similar to that with csDMARD combination (49.09%). During the follow up period only 8 patients (7.27%) had biologic therapy (4 patients - an anti TNF drug). Non steroid anti-inflammatory drugs were used in 46.63%. Cortisone therapy was used for more than 3 months in 80% of the patients. In patients with biologic therapy chronic glucocorticoids were stopped. At least one infection was documented in 20.91% of patients: 2 patients out of 6 patients (33.33%) with biologic DMARD, 14.81% of the patients with csDMARD combination and 21.81% of the patients with csDMARD monotherapy. csDMARD therapy was well tolerated with only 23.63% adverse reactions.Conclusion:Compared to the data published in the literature, in our cohort the rate female:male was higher (4:1). A distinct feature was the high proportion of patients with seropositive RA. The joint pattern seems to be influenced by BMI: small joint pattern is less found in patients with higher BMI. As expected, the patients with EORA had multiple cardiovascular comorbidities. Arterial hypertension was the most frequent. Caution is needed in choosing treatment regarding comorbidities and the risk of infection in these patients.References:[1]Villa-Blanco JI, Calvo-Alén J. Elderly onset rheumatoid arthritis: differential diagnosis and choice of first-line and subsequent therapy. Drugs Aging. 2009;26(9):739-50.Disclosure of Interests:None declared