In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at

/pdf/eular-recommendations-for-the-management-of-rheumatoid-4fujp4paik.pdf

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.

/pdf/the-pathogenesis-of-rheumatoid-arthritis-5ec7s76zig.pdf

The pathogenesis of rheumatoid arthritis.

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.11223

Objective
Autoantibodies have been demonstrated in single serum samples from healthy subjects up to 10 years before they developed rheumatoid arthritis (RA). However, the time course for the development of antibodies before onset of clinical RA is unknown, nor is it known which antibody, or combinations of antibodies, might be most sensitive or specific for predicting future development of the disease. The present study was undertaken to investigate this.

Methods
Patients with RA who had been blood donors before the onset of disease symptoms were enrolled. Frozen serum samples from each donor were retrieved, together with 2 serum samples from controls matched for age, sex, and date of donation. All samples were tested for IgM rheumatoid factor (IgM-RF) and anti–cyclic citrullinated peptide (anti-CCP) antibodies.

Results
Seventy-nine patients with RA (62% female; mean age at onset of symptoms 51 years) were included. A median of 13 samples (range 1–51) per patient were available; the earliest samples had been collected a median of 7.5 years (range 0.1–14.5) before the onset of symptoms. Thirty-nine patients (49%) were positive for IgM-RF and/or anti-CCP on at least one occasion before the development of RA symptoms, a median of 4.5 years (range 0.1–13.8) before symptom onset. Of the 2,138 control samples, 1.1% were positive for IgM-RF, and 0.6% were positive for anti-CCP.

Conclusion
Approximately half of patients with RA have specific serologic abnormalities several years before the onset of symptoms. A finding of an elevated serum level of IgM-RF or anti-CCP in a healthy individual implies a high risk for the development of RA. We conclude that IgM-RF and anti-CCP testing with appropriately high specificity may assist in the early detection of RA in high-risk populations.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.20018

Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors

Objective
Since modern treatment of rheumatoid arthritis (RA) is shifting toward aggressive antirheumatic therapy in an early phase of the disease, diagnostic tests with high specificity are desirable. A new serologic test (anti–cyclic citrullinated peptide [anti-CCP] enzyme-linked immunosorbent assay [ELISA]) was developed to determine the presence of antibodies directed toward citrullinated peptides, using a synthetic peptide designed for this purpose.

Methods
A cyclic peptide variant that contains deiminated arginine (citrulline) was designed and used as antigenic substrate in ELISA. Test parameters and diagnostic characteristics of the test were studied in patients with and without RA, in patients with various infectious diseases, and in a group of patients from an early arthritis clinic (EAC).

Results
Using prevalent RA and non-RA sera, the anti-CCP ELISA proved to be extremely specific (98%), with a reasonable sensitivity (68%). Also, in the EAC study group, the anti-CCP ELISA appeared to be highly specific for RA (96%). In comparison with the IgM rheumatoid factor (IgM-RF) ELISA, the anti-CCP ELISA had a significantly higher specificity (96% for CCP versus 91% for IgM-RF; P = 0.016) at optimal cut-off values. The sensitivity of both tests for RA was moderate: 48% and 54% for the anti-CCP ELISA and the IgM-RF ELISA, respectively (P = 0.36). Combination of the anti-CCP and the IgM-RF ELISAs resulted in a significantly higher positive predictive value of 91% (P = 0.013) and a slightly lower negative predictive value of 78% (P = 0.35) as compared with the use of the IgM-RF ELISA alone. The ability of the 2 tests performed at the first visit to predict erosive disease at 2 years of followup in RA patients was comparable (positive predictive value 91%).

Conclusion
The anti-CCP ELISA might be very useful for diagnostic and therapeutic strategies in RA of recent onset.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28200001%2943%3A1%3C155%3A%3AAID-ANR20%3E3.0.CO%3B2-3

The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.

Objective
To develop a clinical model for the prediction, at the first visit, of 3 forms of arthritis outcome: self-limiting, persistent nonerosive, and persistent erosive arthritis.

Methods
A standardized diagnostic evaluation was performed on 524 consecutive, newly referred patients with early arthritis. Potentially diagnostic determinants obtained at the first visit from the patient's history, physical examination, and blood and imaging testing were entered in a logistic regression analysis. Arthritis outcome was recorded at 2 years' followup. The discriminative ability of the model was expressed as a receiver operating characteristic (ROC) area under the curve (AUC).

Results
The developed prediction model consisted of 7 variables: symptom duration at first visit, morning stiffness for ≥1 hour, arthritis in ≥3 joints, bilateral compression pain in the metatarsophalangeal joints, rheumatoid factor positivity, anti–cyclic citrullinated peptide antibody positivity, and the presence of erosions (hands/feet). Application of the model to an individual patient resulted in 3 clinically relevant predictive values: one for self-limiting arthritis, one for persistent nonerosive arthritis, and one for persistent erosive arthritis. The ROC AUC of the model was 0.84 (SE 0.02) for discrimination between self-limiting and persistent arthritis, and 0.91 (SE 0.02) for discrimination between persistent nonerosive and persistent erosive arthritis, whereas the discriminative ability of the American College of Rheumatology 1987 classification criteria for rheumatoid arthritis was significantly lower, with ROC AUC values of 0.78 (SE 0.02) and 0.79 (SE 0.03), respectively.

Conclusion
A clinical prediction model was developed with an excellent ability to discriminate, at the first visit, between 3 forms of arthritis outcome. Validation in other early arthritis clinics is necessary.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.10117

How to diagnose rheumatoid arthritis early: A prediction model for persistent (erosive) arthritis

Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies

/pdf/anticitrullinated-protein-peptide-antibody-and-its-role-in-2n1pzvolw2.pdf

Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis.

SUMMARY Objective. Early arthritis patients referred to an Early Arthritis Clinic (EAC ) (n= 233) were compared to 241 patients from the routine out-patient clinic with respect to lag time between the onset of symptoms and the visit to the rheumatologist, clinical presentation and the consistency of the diagnosis after 1 yr. Results. The reduction in median lag time for the EAC patients was at least 3 months. An insidious onset of symptoms was found more often in the rheumatoid arthritis (RA) patients in the routine clinic. In 70% of all cases, a diagnosis could be made after 2 weeks and, if the clinical diagnosis was definite RA, this hardly changed during the following year. Early erosions were seen in 25% of RA patients and were associated with a positive rheumatoid factor (OR 2.08, 95% CI 0.95‐4.59). Conclusion. An early diagnosis of RA at the EAC is possible and reliable; the high frequency of erosions illustrates the need for early treatment. During the last decade, evidence has accumulated that area with 300 000 inhabitants. The GPs were motivated emphasizes how crucial the early phase of rheumatoid to refer patients if at least two of the following features arthritis (RA) is [1]. The number of swollen joints is were present: joint pain, joint swelling or reduction of maximal at this time of the disease and the rate of joint mobility. Any of these features had to have a appearance of erosions is at its greatest in the early history of <2 yr. years of RA [2, 3]. Moreover, it has become clear that All patients referred to the special EAC were seen RA should be considered as a severe disease, which is within 1 week. The patients were included if (1) the illustrated by the association with an at least moderate arthritis was confirmed by a rheumatologist, (2) the disability in 80% of patients and with an increased risk history of symptoms indeed lasted <2 yr and (3) the of mortality [4]. Early treatment with disease- patient had not been visiting a rheumatologist elsemodifying anti-rheumatic drugs (DMARDs) appears where for the same problem. Patients sent through to improve the outcome [4‐6 ]. In order to start early direct referral from the general practitioner treatment of RA early in the disease course, a special (GP-EAC ) were compared to patients seen in routine Early Arthritis Clinic ( EAC ) was started in Leiden. out-patient care (routine group) during the period One of the goals of this EAC was to establish an early 1993‐1996, provided that these also met the inclusion diagnosis of RA at a time when the ACR criteria criteria of the EAC. (which include a 6 weeks observation of the arthritis The onset of the arthritis was designated as ‘acute’ by a physician) are not fulfilled and to test reliability. in the case of onset of symptoms within 1 week, as The clinic was also meant to detect and promptly treat ‘insidious’ when the complaints were gradually increasinflammatory disorders other than RA. ing during several weeks or months, and ‘intermittent’ This paper reports on the occurrence, clinical pre- when the patient had been suVering from periods with sentation and lag time between the onset of symptoms arthritis during several weeks or months. and the visit to the rheumatologist of an early arthritis In every patient, routine diagnostic screening was cohort as seen in a special EAC. These patients were performed, including erythrocyte sedimentation rate compared to early arthritis patients who visited the ( ESR), C-reactive protein (CRP), haematological routine out-patient clinic in the same period. In addi- screening, liver enzymes, renal function, rheumatoid tion, the practicability of an early diagnosis and the factor ( RF ) and antinuclear antibodies (ANA). In all consistency of the diagnosis after 1 yr were evaluated. patients, serology on Chlamydia, Yersinia, parvovirus and Borrelia was performed at the first visit, and in

/pdf/diagnosis-and-course-of-early-onset-arthritis-results-of-a-2lggnhgx5d.pdf

Henk Visser

Papers

The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.

How to diagnose rheumatoid arthritis early: A prediction model for persistent (erosive) arthritis

Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies

Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis.

Diagnosis and course of early-onset arthritis: results of a special early arthritis clinic compared to routine patient care.