A survey of Australian rheumatologists' perspectives of nutrition needs in systemic sclerosis.

Aim: Systemic sclerosis (scleroderma) is an incurable inflammatory condition synonymous with unique nutrition needs. As rheumatologists are frequently responsible for managing the various organ manifestations, this study aimed to understand the service needs and nutritional concerns of rheumatologists involved in the care of adults with systemic sclerosis. Methods: A 13-item online qualitative and quantitative survey was distributed via REDCap® from January to March 2022 to rheumatologists who are members of the Australian Scleroderma Interest Group and consult patients with systemic sclerosis. Data were collected on rheumatologists' demographics, and their views on symptoms observed, nutrition concerns and priorities, and preferred dietetic service provision for their patients. Data are reported as number (%). Results: Of 27 eligible rheumatologists, 17 (63%) completed the survey. All rheumatologists reported gastrointestinal symptoms in their patients (n = 17, 100%); predominantly reflux (n = 17, 100%) and dysphagia (n = 17, 100%). Weight loss was observed by the majority of rheumatologists (n = 15, 88%). Rheumatologists reported patients used food avoidance/special diets to manage symptoms (n = 12, 71%). Dietetic consultation was reported as potentially beneficial by all rheumatologists, with the preferred time being when symptoms increase or change (n = 15, 88%), and the preferred approaches being written resources (n = 15, 88%), face-to-face (n = 14, 82%) and telephone consultation (n = 14, 82%). Advice on gaining weight (n = 14, 82%) and systemic sclerosis symptom management (n = 13, 77%) were the most desired education topics reported. Conclusion: Rheumatologists commonly observe gastrointestinal symptoms in patients with systemic sclerosis and report dietetics services would be advantageous in supporting their patients to gain weight and better manage their symptoms.

Using the derived 28-joint disease activity score patient-reported components (DAS28-P) index as a discriminatory measure of response to disease-modifying anti-rheumatic drug therapy in early rheumatoid arthritis.

BACKGROUND: The 28-joint disease activity score (DAS28) is a widely used measure to assess disease activity in rheumatoid arthritis (RA). The DAS28-P index, a derived proportion of the patient-reported components (joint tenderness and patient global assessment) within the DAS28, has been utilized as a discriminatory measure of non-inflammatory pain mechanisms in RA. This study aimed to evaluate the use of the DAS28-P index as a predictor of treatment response in early RA. METHODS: Patients with early RA enrolled in a supplemental fish oil clinical trial received a combination of disease-modifying anti-rheumatic drugs (DMARDs) according to a 'treat-to-target' protocol. First, consecutive measures of the DAS28-P index, derived from the DAS28-erythrocyte sedimentation rate (DAS28-ESR), at each visit over a 1-year period were estimated for each patient. Then, distinct subgroups of treatment responders based on the trajectories of the DAS28-P indices were identified using bivariate k-means cluster analysis. Data on baseline predictors as well as longitudinal outcomes of disease impact and DMARD use over a 1-year period and radiographic progression over a 3-year period were collected and analyzed using a random intercept, population-averaged generalized estimating equation model. RESULTS: 121 patients were included (74% female; mean age of 57; median of 16 weeks of active disease) and a 3-cluster model was identified-the 'Responders' group (n = 58; 48%), the 'Partial Responders' group (n = 32; 26%), and the 'Non-Responders' group (n = 31; 26%). The 'Partial Responders' group had consistently higher proportions of the DAS28-P index throughout the study period and had minimal radiographic progression over time, with the lowest joint erosion score of 0.9 [95% confidence interval (CI) 0.2, 1.6], observed at the 3-year follow-up. At 52 weeks, the methotrexate dose was higher for both 'Partial Responders' and 'Non-Responders' groups (18.5 mg [95% CI 15.5, 21.5] and 18.6 mg [95% CI 15.3, 21.8] respectively), when compared with the 'Responders' group (12.8 mg [95% CI 14.7, 20.9]). CONCLUSIONS: Persistently high DAS28-P index scores are useful to distinguish poor patient global assessment and excessive treatment escalation in early RA, suggestive of underlying non-inflammatory pain contributing to higher disease activity score. Early identification of patients with discordant subjective and objective components of composite disease activity measures may allow better tailoring of treatment in RA.

Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. METHODS: Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. RESULTS: A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (ß = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (ß = 0.56. P = 0.01) and did not carry the shared epitope (ß = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. CONCLUSION: Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.

Repeat serological testing for anti-citrullinated peptide antibody after commencement of therapy is not helpful in patients with seronegative rheumatoid arthritis.

AIM: To Investigate the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy. BACKGROUND: Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) define 'seropositive' rheumatoid arthritis (RA). Both predict unfavourable disease course, development of extra-articular features and treatment outcomes. We investigated the prevalence of seroconversion to ACPA after commencement of triple disease-modifying anti-rheumatic drug (DMARD) treat-to-target therapy. METHODS: DMARD-naïve patients with RA according to the 1987 American College of Rheumatology criteria and disease duration of <96 weeks were enrolled. RF and ACPA levels were recorded at baseline and sequentially during triple DMARD therapy. RESULTS: A total of 368 patients were followed for a median of 272 weeks. Of 154 patients seronegative for ACPA at recruitment, 10 (6.5%) seroconverted at some point. Nine of these were positive for RF at baseline and baseline RF titre was predictive of seroconversion. Four (2.6%) patients remained seropositive. No patients seroconverted from negative to positive for both RF and ACPA. Median time to seroconversion for ACPA was 29 months. CONCLUSION: Persistent seroconversion of ACPA from negative to positive after diagnosis in patients with RA is uncommon. ACPA and RF double negative patients are highly unlikely to ever develop ACPA positivity with a risk <1%. It is therefore unlikely to be helpful or cost effective to perform serial ACPA measurements in patients with seronegative RA after commencement of a treat-to-target strategy.

Scleroderma in Cairns: an epidemiological study.

BACKGROUND: Systemic sclerosis (SSc) refers to an autoimmune fibrosing disorder with high disease burden and mortality. The prevalence of 23/100 000 in South Australia (SA) is among the highest documented, but anecdotally it is higher still in Cairns. AIMS: To ascertain the prevalence of SSc in Cairns and surrounding regions, and to compare the demographic and clinical characteristics of patients with SSc in Cairns with those in SA. METHODS: Patients with SSc in Cairns were ascertained through hospital records and by referrals from specialist physicians in the region. These patients were interviewed and completed a structured questionnaire. Their physical findings and autoantibodies were recorded. These patients were compared with the SA patients enrolled in the Australian Scleroderma Cohort Study. RESULTS: A total of 81 patients was identified in Cairns, giving an estimated cross-sectional prevalence of 33.7/100 000. Among 65 patients interviewed in Cairns, 23 were born in Cairns, 16 had migrated to Cairns to ameliorate their Raynaud phenomenon and 26 for other reasons. The clinical features in both cohorts were similar, although Cairns had a lower prevalence of digital ulcers (30.8% vs 46.6%; odds ratio (OR) = 0.5035, 95% confidence interval (CI): 0.2839-0.8929, P = 0.0271) and higher prevalence of calcinosis (29.2% vs 17.0%; OR = 2.005, 95% CI: 1.055-3.382). CONCLUSIONS: The higher prevalence of SSc in Cairns is partly, but not completely, due to migration. Differences in clinical features are not entirely explained by the warmer climate. There is a need for greater rheumatologic services in the Cairns region.

The neutrophil-lymphocyte ratio in early rheumatoid arthritis and its ability to predict subsequent failure of triple therapy.

OBJECTIVES: To assess whether the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) can predict those who subsequently require escalation of disease modifying therapy because of continued disease activity in rheumatoid arthritis (RA). METHODS: Patients with newly diagnosed RA were recruited from the Early Arthritis Clinic at the Royal Adelaide Hospital. All patients commenced "triple-therapy" with a standardised protocol of methotrexate, sulfasalazine and hydroxychloroquine, and were reviewed every three to six weeks. DMARD therapy was adjusted according to a pre-defined algorithm if not in low disease activity. The NLR, PLR and other markers of disease activity including ESR, CRP and DAS28 were collected, as well as current therapy. The primary outcome measure was failure of triple-therapy to maintain low-disease activity (DAS28<3.2) at 12 months. RESULTS: Two-hundred and twenty-two patients met inclusion criteria. The mean age was 54.2 ±â€¯15.4 years, with a mean disease duration of 22.3 ±â€¯25.0 weeks. Forty-five (20%) patients had failed triple therapy by one year. The mean baseline NLR was significantly higher in those who failed triple therapy compared with those who did not (3.7 ±â€¯2.8 vs. 2.9 ±â€¯1.5; p = 0.02), however, the PLR was not significantly different. A baseline NLR>2.7 was an independent predictor of treatment failure (OR 2.65, CI 1.23-5.72, p = 0.01) whilst the PLR, ESR, CRP and DAS-28ESR were not. CONCLUSION: The NLR is significantly increased in those who subsequently fail triple-therapy for RA, and it outperformed conventional markers of disease activity. The NLR may offer an inexpensive, objective and reproducible prognostic marker in RA. Further studies are justified to confirm its potential role in guiding the management of RA.

Factors associated with medication adherence in a longitudinal study of rheumatoid arthritis patients.

BACKGROUND: Identification of key determinants of medication adherence may assist with designing interventions to improve this important parameter. The aim of the study was to determine the rate and predictors of self-reported medication adherence in patients with rheumatoid arthritis (RA) over one-year follow-up. METHODS: Socio-demographic, disease, therapy and patient-related factors were obtained from a longitudinal observational cohort of RA patients between May 2014 and June 2016. Medication adherence was measured using self-reported Compliance Questionnaire for Rheumatology (CQR) at baseline, 6 and 12 months. Mixed-effects modelling was used to investigate the relationship between adherence and potential predictors. RESULT: Of 185 patients invited, 110 were included in the study. The median level of adherence was 71%-74% during the study period. Around 27%-30% of patients achieved > 80% adherence, while roughly one-fifth reported a CQR score within the lower quartile (CQR < 63%). After adjustment for potential confounders, increased age (ß = 0.19, P = 0.010), higher self-efficacy (ß = 0.89, P = 0.039) and higher medication necessity belief (ß = 1.12, P < 0.0001) were associated with better self-reported adherence. CONCLUSION: We found a moderate level of self-reported adherence over time and significant association with age, self-efficacy and medication necessity belief. The modifiable predictors of adherence found in this study can be used as a potential target for adherence-improving interventions.

Disease activity trajectories in early rheumatoid arthritis following intensive DMARD therapy over 3 years: association with persistence to therapy.

OBJECTIVE: To identify the disease activity trajectories during intensive triple disease modifying anti-rheumatic drug (DMARD) therapy over 3 years in rheumatoid arthritis (RA) patients and to evaluate the association with treatment persistence. METHODS: Disease Activity Score in 28 joints, baseline risk factors and medication usage were obtained from a longitudinal observational cohort of early RA patients, most of whom were treated with combination DMARD therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine. Persistence of each DMARD was defined as the duration of time from initiation to cessation. A group-based trajectory modelling technique was used to identify disease activity trajectories. RESULT: Three disease activity trajectories (good [43.8%], moderate [39.7%] and poor [16.5%]) were identified in a cohort of 297 patients. Most baseline risk factors, medication usage, the rate of treatment persistence and the effect of persistence on disease activity differed among patients in each of the three trajectories. Although the rate of persistence was higher in the trajectory with a good outcome, the association with persistence was more pronounced among patients who were in the poor outcome trajectory. Persistence with at least two or all three baseline DMARDs was associated with a decrease in disease activity to a broadly similar degree in all trajectories. CONCLUSION: After correction for other baseline prognostic factors, persistence with initial DMARDs contributes to heterogeneity in disease activity trajectory and there was an association between persistence with initial DMARD therapy and lower long-term disease activity.

Adherence to combination DMARD therapy and treatment outcomes in rheumatoid arthritis: a longitudinal study of new and existing DMARD users.

Medication adherence is believed to be a major contributor to treatment outcomes yet studies quantifying this relationship as rare in rheumatoid arthritis (RA). To determine the association of adherence to DMARD therapy with treatment outcomes among new and existing DMARD users over 2 years. Relevant clinical parameters were obtained from a longitudinal cohort of RA patients, most of who were treated with combination therapy. Patients were classified as adherent if the proportion of days covered for each DMARD was ≥80%. Outcome measures were the change in the disease activity score in 28 joints (DAS28), simplified disease activity index (SDAI), modified health assessment questionnaires (mHAQ) and proportion of patients who achieved response criteria. An inverse propensity-score weighting method was used to estimate the association of adherence with each outcome. Of 194 patients invited, a total of 111 patients (new = 45 and existing = 66 DMARD users) met study eligibility. DMARD-naive patients demonstrated relatively higher rates of adherence compared to existing users. After controlling for confounding variables, adherence was significantly associated with reduction in DAS28 (ß = -1.5, 95% CI of ß = - 2.17 to -0.83, p < 0.0001), SDAI (ß = -9.44, 95% CI of ß = -15.53 to -3.35, p = 0.002) and mHAQ (ß = -0.269, 95% CI of ß, -0.462 to -0.077, p = 0.017) over 2 years among new patients and adherent patients were more likely to achieve most response criteria compared to non-adherent patients. Such associations were not replicated among existing DMARD users. Adherence to combination DMARD therapy was associated with improvements in disease activity and functional outcomes in the first 2 years of therapy.

Determining the acceptable level of physician compliance with a treat-to-target strategy in early rheumatoid arthritis.

OBJECTIVE: To determine the minimum cut-points for rate of physician compliance with a treat-to-target (T2T) strategy needed to achieve optimal rates of remission or low disease activity (LDA). METHOD: In this analysis of longitudinal observational data from patients with early RA, physician compliance with a T2T treatment protocol was determined for each clinic visit over 3 years. Remission and LDA were measured by Disease Activity Score in 28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI). The minimum physician compliance rates for predicting these outcomes were calculated using receiver operating characteristic (ROC) curves. RESULT: Overall, 149 patients completed 3078 clinic visits over 3 years of follow-up. Treatment decisions complied with the T2T protocol in 2343 of these visits (76.1%). The minimum cut-points for physician compliance rates that predicted remission and LDA according to DAS28 were 81.1% and 70.7%, respectively, and to predict remission and LDA according to SDAI, the respective cut-points were 92.7% and 77.4%. Based on these cut-points, three categories of physician compliance with T2T were proposed: high (to maximize the likelihood of achieving remission, > 80% according to DAS28 or > 90% according to SDAI/CDAI); medium (the minimal physician compliance to achieve LDA, 70-79% according to DAS28 or 75-89% for SDAI/CDAI); and low (< 70% for DAS28 and < 75% for SDAI/CDAI), where remission and LDA are unlikely). When patients were stratified by baseline disease activity, the physician compliance rate cut-points were similar for most outcomes at year 3. CONCLUSION: Using real-life clinical data, we determined the thresholds for physician compliance with a T2T strategy that stratified patients according to their disease outcomes and proposed a system for classifying physician compliance as high, medium and low.

Effect of Adherence to Protocolized Targeted Intensifications of Disease-modifying Antirheumatic Drugs on Treatment Outcomes in Rheumatoid Arthritis: Results from an Australian Early Arthritis Cohort.

OBJECTIVE: To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). METHODS: Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. RESULTS: A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16-2.50; p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06-3.56; p = 0.033). After 3 years, adherence was also associated with improvement in physical function (ß=0.12, 95% CI 0.06-0.18; p < 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). CONCLUSION: Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence.

Reduced corticosteroid-binding globulin cleavage in active rheumatoid arthritis.

OBJECTIVE: Corticosteroid-binding globulin (CBG), the cortisol transport protein, is cleaved from high-affinity (haCBG) to low-affinity (laCBG) CBG at sites of inflammation releasing bioavailable, anti-inflammatory cortisol. Rheumatoid arthritis (RA) is a glucocorticoid-responsive disorder, with paradoxically normal cortisol levels despite elevated inflammatory mediators. Our objective was to determine whether CBG cleavage relates to RA disease activity. We hypothesized that impaired CBG cleavage may limit delivery of free cortisol to inflamed joints in RA. DESIGN: Prospective, cross-sectional observational study. SETTING AND PARTICIPANTS: Fifty-three patients with RA recruited from a Rheumatology outpatient clinic at a tertiary referral centre in Adelaide, Australia, and 73 healthy controls. MEASUREMENTS: Total CBG, haCBG and laCBG, total, free and salivary cortisol, inflammatory markers including interleukin-6 soluble receptor (IL-6sR) and macrophage migration inhibitory factor and clinical measures of disease activity. RESULTS: Among patients with RA, a wide range of disease activity scores was observed (DAS28: range 1·2-6·4). laCBG was lower in patients with RA (mean ± SEM); 153 ± 9, compared with healthy controls; 191 ± 8 nmol/l, P = 0·003. Levels of total and haCBG were higher in patients with more severe RA disease activity. Free and total cortisol, free cortisol:IL-6sR ratio and total cortisol:IL-6sR ratio correlated negatively with disease activity. CONCLUSIONS: These results suggest that patients with RA have reduced CBG cleavage compared to healthy controls and that cleavage is reduced further with higher RA disease activity. Hence, impaired CBG-mediated delivery of endogenous cortisol may perpetuate chronic inflammation in RA.

Characterising deviation from treat-to-target strategies for early rheumatoid arthritis: the first three years.

INTRODUCTION: Treat-to-target (T2T) strategies using a protocol of pre-defined adjustments of disease-modifying anti-rheumatic drugs (DMARDs) according to disease activity improve outcomes for patients with rheumatoid arthritis (RA). However, successful implementation may be limited by deviations from the protocol. The aim of this study was to determine the prevalence of protocol deviation, explore the reasons and identify subsets of patients in whom treatment protocols are more difficult to follow. METHODS: In this retrospective cohort study, treatment-naïve patients with RA of less than one year's duration, attending a dedicated early arthritis clinic between 2001 and 2013, were followed for three years from initiation of combination therapy with conventional DMARDs which was subsequently modified according to a T2T protocol. At each clinic visit, whether deviation from the protocol occurred, the type of deviation and the reasons for deviation were assessed. The relationship between protocol deviations and baseline variables was determined using linear regression analysis. RESULTS: In total, 198 patients contributed 3,654 clinic visits. The prevalence of protocol deviations was 24.5% and deviation in at least at one clinic visit was experienced by 90.4% of patients. The median time to first deviation was 30 weeks. Continuing existing treatment rather than intensifying therapy was the most common type of deviation (59.9%). Patient and physician related factors were the most common reasons for deviation, each accounting for 24.7% of deviations, followed by toxicities (23.3%) and comorbidities (20.0%). The prevalence of protocol deviations was lower among patients who achieved remission after three years (13.1%; 162 deviations out of 1,228 visits) compared with those who were not in remission (30.9%; 523/1692) (P<0.0001). On multivariate analysis, only body mass index (P=0.003) and helplessness score (P=0.04) were independent predictors of protocol deviations although the predictive power of the model was not strong (R2=0.17). CONCLUSIONS: Deviation from a T2T protocol occurred in one quarter of visits, indicating that applying the T2T approach is feasible in clinical practice. Failure to escalate dose when indicated was commonly encountered, and just under half of the observed deviations were related to either toxicities or comorbidities and were therefore justifiable on clinical grounds.

A biomarker of n-3 compliance in patients taking fish oil for rheumatoid arthritis.

Dietary fish oil supplements have been shown to have benefits in rheumatoid arthritis (RA), other inflammatory diseases, and in cardiovascular disease. As with any medical advice, variability will exist with regard to adherence and consequent biochemical or pharmacophysiologic effects. The aim was to explore the utility of plasma phospholipid EPA as a measure of n-3 PUFA intake and response to standardized therapeutic advice given in an outpatient or office practice setting, to increase dietary n-3 PUFA, including a fish oil supplement. Patients with early RA were given verbal and written advice to alter their dietary n-3 PUFA intake, including ingestion of 20 mL of bottled fish oil on juice daily. The advice included instructions to increase n-3 PUFA and to avoid foods rich in n-6 PUFA. Every 3 mon, blood samples were obtained for analysis of plasma phospholipid FA. Plasma phospholipid EPA was used as the primary index of n-3 PUFA intake. A diverse response was seen, with about one-third of patients achieving a substantial elevation of plasma phospholipid EPA over the 12-mon study period. A third had little change, with the remainder achieving intermediate levels. Data obtained longitudinally from individual patients indicated that substantial elevations of EPA (> 5% total plasma phospholipid FA) could be maintained for more than 3 yr. Plasma phospholipid EPA is a convenient measure of adherence to advice to take a dietary n-3 PUFA-rich fish oil supplement This measure may prove a useful adjunct to intention to treat analyses in determining the effect of dietary fish oil supplements on long-term outcomes in arthritis and other chronic inflammatory diseases. It may also provide a guide to the effectiveness of therapeutic and preventive messages designed to increase n-3 PUFA intake.