Cardiovascular risk in patients with new gout diagnosis: is monosodium urate volume at ankles and feet on dual-energy computed tomography associated with previous cardiovascular events?

OBJECTIVES: Chronic inflammation associated with hyperuricaemia and urate deposition may contribute to an increased risk of developing cardiovascular (CV) events (CVE) in patients with gout. The aim of this study was to explore whether urate deposition on dual-energy CT (DECT) present at the diagnosis of gout is associated with a history of CVE. METHODS: Patients from a study on clinical value of DECT with mono or oligoarthritis who had gout according the 2015 EULAR/ACR classification criteria were included in this cross-sectional study. Urate volume on DECT was calculated. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors, scored with the Dutch risk prediction SCORE and the Framingham score. The data were analysed using logistic regression analyses. RESULTS: Sixty-eight patients were included. In the multivariable model, -next to significant associations of age (OR per year 1.1, 95% CI 1.04 to 1.02, p=0.02), HDLc per mmol/l (OR 0.04, 95% CI 0.002 to 0.8, p=0.03), and diabetes yes/no (OR 4, 95% CI 0.8 to 20.9, p=0.09)-, urate volumes at ankles/feet on DECT in the third and fourth quartile with first quartile as reference showed a trend of association (OR 4.8, 95% CI 0.6 to 42, p=0.1 and 6.4, 0.7 to 63, 0.1, respectively) with past CVE events (yes/ no). This association could be bidirectional. Almost two-third of newly classified gout patients had a high or very high CV risk. CONCLUSIONS: CVE history probably is associated with urate volumes already present at the time of diagnosis of gout. Our data corroborate the need of assessing and treating CV risk factors when diagnosing gout.

Cardiovascular risk in patients with new gout: should we reclassify the risk?

OBJECTIVES: Chronic inflammation, as seen in gout, may contribute to an increased risk of developing cardiovascular (CV) events (CVE). The aim of the study was to explore the effect of adding gout as a chronic inflammatory disease to the Dutch SCORE, a tool predicting 10-year CV mortality and morbidity. METHODS: This was a cross-sectional substudy including new patients with gout according the 2015 EULAR/ACR classification criteria who had participated in a trial on diagnostic accuracy of DECT with mono or oligoarthritis. Patients underwent a structured CV consultation, including assessment of CVE-history and of CV risk factors with the Dutch risk prediction SCORE. Chi-square test for trends was used to test for significance reclassification of the CV risk before and after adding gout to the Dutch SCORE. RESULTS: Seventy-six gout patients were included. SCORE was applied in 60 patients; 16 patients had experienced a prior CVE. The 10-year risk scores without gout as risk factor were high in 29 patients (48.3%), moderate in 6 (10%) and low in 25 (41.7%); with gout, the risk of 23/60 patients (38.3%) was reclassified from low to moderate in 6 patients (10%), from low to high in 11 (18.3%) and from moderate to high in 6 (10%), p<0.001 for trend. CONCLUSIONS: Adding gout to the risk prediction tools led to significant and clinically relevant reclassification of CV risk in new gout patients. Studies with large follow-up are warranted to validate these findings.

Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials.

OBJECTIVES: Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA. METHODS: Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders. RESULTS: DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: -0.62 (95% CI -1.14 to -0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies. CONCLUSIONS: In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs.

Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease-modifying antirheumatic drugs (TOPIRA): study protocol for a pragmatic trial.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. METHODS: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. DISCUSSION: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. TRIAL REGISTRATION: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.

RNA sequencing to predict response to TNF-α inhibitors reveals possible mechanism for nonresponse in smokers.

BACKGROUND: Several studies have employed microarray-based profiling to predict response to tumor necrosis factor-alpha inhibitors (TNFi) in rheumatoid arthritis (RA); yet efforts to validate these targets have failed to show predictive abilities acceptable for clinical practice. METHODS: The eighty most extreme responders and nonresponders to TNFi therapy were selected from the observational BiOCURA cohort. RNA sequencing was performed on mRNA from peripheral blood mononuclear cells (PBMCs) collected before initiation of treatment. The expression of pathways as well as individual gene transcripts between responders and nonresponders was investigated. Promising targets were technically replicated and validated in n = 40 new patients using qPCR assays. RESULTS: Before therapy initiation, nonresponders had lower expression of pathways related to interferon and cytokine signaling, while also showing higher levels of two genes, GPR15 and SEMA6B (p = 0.02). The two targets could be validated, however, additional analyses revealed that GPR15 and SEMA6B did not independently predict response, but were rather dose-dependent markers of smoking (p < 0.0001). CONCLUSIONS: The study did not identify new transcripts ready to use in clinical practice, yet GPR15 and SEMA6B were recognized as candidate explanatory markers for the reduced treatment success in RA smokers.

The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial.

BACKGROUND: The treatment of hypothyroidism with levothyroxine is effective and simple; however, recommendations for the starting dose vary considerably. To our knowledge, the levothyroxine starting dose has never been studied prospectively. METHODS: We conducted a prospective, randomized, double-blind trial that compared a full starting levothyroxine dose of 1.6 mug/kg with a low starting dose of 25 mug (increased every 4 weeks) in patients with newly diagnosed cardiac asymptomatic hypothyroidism. Safety was studied by documenting cardiac symptoms and events, and efficacy was studied by monitoring thyrotropin and free thyroxine levels and by assessing improvement of signs and symptoms and quality of life. RESULTS: Seventy-five consecutive patients were enrolled, of whom 50 underwent randomization. At baseline, the severity of hypothyroidism and age were comparable in the full-dose (n = 25) vs the low-dose group (n = 25): thyrotropin, 61 vs 48 mIU/L; free thyroxine, 0.56 vs 0.64 ng/dL (7.2 vs 8.2 pmol/L); and age, 47 vs 47 years. No cardiac complaints or events were documented during treatment or at bicycle ergometry at baseline, 12 weeks, or 24 weeks. Euthyroidism was reached in the full-dose vs the low-dose group in 13 vs 1 (4 weeks), 19 vs 3 (8 weeks), 19 vs 9 (12 weeks), 20 vs 14 (16 weeks), 20 vs 18 (20 weeks), and 21 vs 20 (24 weeks) patients (P = .005). However, signs and symptoms of hypothyroidism and quality of life improved at a comparable rate. CONCLUSION: A full starting dose of levothyroxine in cardiac asymptomatic patients with primary hypothyroidism is safe and may be more convenient and cost-effective than a low starting dose regimen.

Do radiographic joint damage and disease activity influence functional disability through different mechanisms? Direct and indirect effects of disease activity in established rheumatoid arthritis.

OBJECTIVE: To explore the relationship between rheumatoid arthritis (RA) disease activity and functional disability over time, considering indirect (predictive) and direct (concurrent) associations as well as the influence of radiographic joint damage and treatment strategy. METHODS: Functional disability [Health Assessment Questionnaire (HAQ)], disease activity [28-joint Disease Activity Score (DAS28)], and radiographic joint damage [Sharp/van der Heijde score (SHS)] were measured in 4 consecutive randomized controlled trials with increasingly intensive (tight control) treatment strategies. Average followup time for the 3 cohorts was 97, 53, and 50 months, respectively. Next to current DAS28, the previous DAS28 was used to study the predictive effect of a change in DAS28 on progression of functional disability (HAQ). Finally, it was investigated whether SHS mediated the predictive effect of DAS28. RESULTS: In patients treated with intensive treatment strategies, the progression of HAQ over time was statistically significantly less (p < 0.0001). The predictive influence of DAS28 on HAQ progression increased over the duration of the disease. SHS was not found to influence HAQ progression and did not mediate the predictive effect of DAS28. In the less intensively treated patients, the direct effect of disease activity decreased with disease duration, and contrarily, SHS did influence HAQ progression, but was not found to (fully) mediate the predictive effect of DAS28. CONCLUSION: In patients with RA treated with modern treatment strategies, there is less functional decline over time. Further, disease activity does predict functional decline but joint damage does not. This might indicate that factors associated with cumulative disease activity but not visible on radiographs can influence functional decline in patients with RA. This further underlines the importance of disease activity as a treatment target in early RA and in established RA.

[Merkel cell carcinoma during treatment with TNF-alpha inhibitors: coincidence or warning?]. / Merkelcel-carcinoom bij gebruik van TNF-α-blokkers. Toeval of waarschuwing?

BACKGROUND: Increasing numbers of patients are being treated with TNF-alpha inhibitors. Two patients in our outpatient clinic developed Merkel cell carcinoma during treatment with TNF alpha inhibitors. Since this is a very rare malignancy, this is a remarkable observation. CASE DESCRIPTION: A 70-year-old male with rheumatoid arthritis had been treated with etanercept for two years when he discovered a nodule on his elbow that started growing rapidly. It was diagnosed as Merkel cell carcinoma. Despite treatment, the patient died 2 years later. CONCLUSION: Merkel cell carcinoma is an aggressive malignancy with a clinically benign aspect. Patients treated with TNF-alpha inhibitors possibly have an increased risk of developing this malignancy.