High risk of depression, anxiety, and an unfavorable complex comorbidity profile is associated with SLE: a nationwide patient-level study.

OBJECTIVES: The aim of this national population-based, retrospective database study is to compare the comorbidity profiles of systemic lupus erythematosus (SLE) patients and general population controls matched for age, gender, and region and assess the risk of depression or anxiety when controlled for age, gender and adjusted for the Charlson Comorbidity Index (CCI). METHODS: Claims data of 1051 patients diagnosed with SLE (full population between January 01, 2011, and December 31, 2014) from the Hungarian National Health Insurance Fund have been analyzed against matched controls (1:5 ratio) with a follow-up of 30 months. The first record of SLE diagnosis was considered the diagnosis date. The odds ratio (OR) and 99.9% confidence interval (CI) of having depression or anxiety among patients with SLE vs. controls have been assessed using logistic regression models. RESULTS: SLE patients report more comorbidities than the matched general population both in pre- and post-index periods (mean CCI 1.79 vs. 1.15 and 2.78 vs. 1.22 [both p<0.001], respectively). Both SLE patients and controls diagnosed with depression or anxiety had significantly higher CCI than those without comorbid depression or anxiety (p<0.001). However, SLE patients had a twofold higher risk of depression or anxiety than matched controls when controlled for age, gender, and adjusted for CCI. CONCLUSION: Our analysis indicates the enormity of comorbidity burden in SLE, especially that of anxiety and depression. The size and complexity of the comorbidity burden emphasizes the importance of early diagnosis and intervention with comprehensive modalities incorporating attention to comorbidities in SLE patients.

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis.

OBJECTIVE: To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). METHODS: An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. RESULTS: Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). CONCLUSIONS: These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.

Pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis.

OBJECTIVES: To summarise, by a systematic literature review (SLR), the evidence regarding pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis (D2T RA), informing the EULAR recommendations for the management of D2T RA. METHODS: PubMed, Embase and Cochrane databases were searched up to December 2019. Relevant papers were selected and appraised. RESULTS: Two hundred seven (207) papers studied therapeutic strategies. Limited evidence was found on effective and safe disease-modifying antirheumatic drugs (DMARDs) in patients with comorbidities and other contraindications that limit DMARD options (patients with obesity, hepatitis B and C, risk of venous thromboembolisms, pregnancy and lactation). In patients who previously failed biological (b-)DMARDs, all currently used b/targeted synthetic (ts-)DMARDs were found to be more effective than placebo. In patients who previously failed a tumour necrosis factor inhibitor (TNFi), there was a tendency of non-TNFi bDMARDs to be more effective than TNFis. Generally, effectiveness decreased in patients who previously failed a higher number of bDMARDs. Additionally, exercise, psychological, educational and self-management interventions were found to improve non-inflammatory complaints (mainly functional disability, pain, fatigue), education to improve goal setting, and self-management programmes, educational and psychological interventions to improve self-management.The identified evidence had several limitations: (1) no studies were found in patients with D2T RA specifically, (2) heterogeneous outcome criteria were used and (3) most studies had a moderate or high risk of bias. CONCLUSIONS: This SLR underscores the scarcity of high-quality evidence on the pharmacological and non-pharmacological treatment of patients with D2T RA. Effectiveness of b/tsDMARDs decreased in RA patients who had failed a higher number of bDMARDs and a subsequent b/tsDMARD of a previously not targeted mechanism of action was somewhat more effective. Additionally, a beneficial effect of non-pharmacological interventions was found for improvement of non-inflammatory complaints, goal setting and self-management.

Diagnostic issues in difficult-to-treat rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis.

OBJECTIVES: To summarise the evidence on diagnostic issues in difficult-to-treat rheumatoid arthritis (D2T RA) informing the EULAR recommendations for the management of D2T RA. METHODS: A systematic literature review (SLR) was performed regarding the optimal confirmation of a diagnosis of rheumatoid arthritis (RA) and of mimicking diseases and the assessment of inflammatory disease activity. PubMed and Embase databases were searched up to December 2019. Relevant papers were selected and appraised. RESULTS: Eighty-two papers were selected for detailed assessment. The identified evidence had several limitations: (1) no studies were found including D2T RA patients specifically, and only the minority of studies included RA patients in whom there was explicit doubt about the diagnosis of RA or presence of inflammatory activity; (2) mostly only correlations were reported, not directly useful to evaluate the accuracy of detecting inflammatory activity in clinical practice; (3) heterogeneous, and often suboptimal, reference standards were used and (4) (thus) only very few studies had a low risk of bias.To ascertain a diagnosis of RA or relevant mimicking disease, no diagnostic test with sufficient validity and accuracy was identified. To ascertain inflammatory activity in patients with RA in general and in those with obesity and fibromyalgia, ultrasonography (US) was studied most extensively and was found to be the most promising diagnostic test. CONCLUSIONS: This SLR highlights the scarcity of high-quality studies regarding diagnostic issues in D2T RA. No diagnostic tests with sufficient validity and accuracy were found to confirm nor exclude the diagnosis of RA nor its mimicking diseases in D2T RA patients. Despite the lack of high-quality direct evidence, US may have an additional value to assess the presence of inflammatory activity in D2T RA patients, including those with concomitant obesity or fibromyalgia.

EULAR definition of difficult-to-treat rheumatoid arthritis.

BACKGROUND: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking. OBJECTIVE: The Task Force in charge of the "Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step. METHODS: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting). RESULTS: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. CONCLUSIONS: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research.

Large-scale mortality gap between SLE and control population is associated with increased infection-related mortality in lupus.

OBJECTIVE: The aim of the present study was to analyse the incidence, prevalence, mortality and cause of death data of adult SLE patients and matched controls in a full-populational, nationwide, retrospective study. METHODS: This non-interventional study was based on database research of the National Health Insurance Fund of Hungary. A total of 7888 patients were included in the analyses, within which two subgroups of incident patients were created: the 'All incident SLE patients' group consisted of all incident SLE patients (4503 patients), while the 'Treated SLE patients' group contained those who received relevant therapy in the first 6 months after diagnosis (2582 patients). RESULTS: The median age of the SLE population was found to be 46.5 years (women 85%). The incidence rate was 4.86 and 2.78 per 100 000 inhabitants in the 'All incident SLE patients' and 'Treated SLE patients' groups, respectively. The standardized mortality ratio was 1.63 and 2.09 in the 'All incident SLE patients' and 'Treated SLE patients' groups, respectively. Overall survival was significantly lower (P < 0.001) in both groups than in the general population, with hazard ratio = 2.17 in the 'All incident SLE patients' group and hazard ratio = 2.75 in the 'Treated SLE patients' group. There was no significant difference between SLE and control deaths regarding cerebrovascular conditions as the cause of death. Generally, cancer-related deaths were less common, while haematological cancer and infection-related deaths were more common in SLE patients. CONCLUSION: Infections, especially sepsis, had the largest positive effect on top of the extra mortality of SLE. This highlights that SLE patients are at increased risk of infection-related death.

Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents.

The five TNF inhibitors currently approved for the treatment of RA are characterised by differences in their molecular structures, half-lives, administration routes, dosing intervals, immunogenicity, and use in women who wish to become pregnant. TNF inhibitors still represent the first biologic after conventional synthetic DMARD (csDMARD) in the majority of patients according to registry data. This was possibly because they were historically the first biological agents available (biological DMARDS with a different mechanism of action or targeted synthetic DMARDs did not become available until 2006s), and so switching from one to another was frequent in the case of an inadequate response and/or side effects. TNF inhibitors are also efficacious for other inflammatory joint and spine diseases, and have been approved for inflammatory bowel disease, uveitis and psoriasis. In addition, national registries have provided long-term safety data and demonstrated their beneficial effect on cardiovascular morbidity and mortality. However, approximately 30-40% of patients discontinue anti-TNF treatment because of primary failure, secondary loss of response, or intolerance. The options for managing anti-TNF treatment failures include switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action (swapping). The aim of this review is to evaluate the pros and cons of whether it is more appropriate to choose a second anti-TNF biological agents after the failure of the first or swap treatment early.