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

The American College of Rheumatology (ACR) most recently published recommendations for use of disease modifying anti-rheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA) in 2008 (1). These recommendations covered indications for use, monitoring of side-effects, assessment of the clinical response to DMARDs and biologics, screening for tuberculosis (TB), and assessment of the roles of cost and patient preference in decision-making for biologic agents (1). Recognizing the rapidly evolving knowledge in RA management and the accumulation of new evidence regarding the safety and efficacy of existing and newer therapies, the ACR commissioned an update of the 2008 recommendations in select topic areas.

The 2012 revision updates the 2008 ACR recommendations in the following areas: (1) indications for DMARDs and biologics; (2) switching between DMARD and biologic therapies; (3) use of biologics in high-risk patients (those with hepatitis, congestive heart failure, and malignancy); (4) screening for TB in patients starting or currently receiving biologics; and (5) vaccination in patients starting or currently receiving DMARDs or biologics (Table 1).



Table 1

Overview Comparison of Topics and Medications Included in the 2008 and 2012 ACR RA Recommendations




METHODS
We utilized the same methodology as described in detail in the 2008 guidelines (1) to maintain consistency and to allow cumulative evidence to inform this 2012 recommendation update. These recommendations were developed by two expert panels: (1) a non-voting working group and Core Expert Panel (CEP) of clinicians and methodologists responsible for the selection of the relevant topic areas to be considered, the systematic literature review, and the evidence synthesis and creation of “clinical scenarios”; and (2) a Task Force Panel (TFP) of 11 internationally-recognized expert clinicians, patient representatives and methodologists with expertise in RA treatment, evidence-based medicine and patient preferences who were tasked with rating the scenarios created using an ordinal scale specified in the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness method (2–4). This method solicited formal input from a multi-disciplinary TFP panel to make recommendations informed by the evidence. The methods used to develop the updated ACR recommendations are described briefly below.

Systematic Literature Review – Sources, Databases and Domains
Literature searches for both DMARDs and biologics relied predominantly on PubMed searches) with medical subject headings (MeSH) and relevant keywords similar to those used for the 2008 ACR RA recommendations (see Appendices 1 and 2). We included randomized clinical trials (RCTs), controlled clinical trials (CCTs), quasi-experimental designs, cohort studies (prospective or retrospective), and case-control studies, with no restrictions on sample size. More details about inclusion criteria are listed below and in Appendix 3.

The 2008 recommendations were based on a literature search that ended on February 14, 2007. The literature search end date for the 2012 Update was February 26, 2010 for the efficacy and safety studies and September 22, 2010 for additional qualitative reviews related to TB screening, immunization and hepatitis (similar to the 2008 methodology). Studies published subsequent to that date were not included.

For biologics, we also reviewed the Cochrane systematic reviews and overviews (published and in press) in the Cochrane Database of Systematic Reviews to identify additional studies (5–8) and further supplemented by hand-checking the bibliographies of all included articles. Finally, the CEP and TFP confirmed that relevant literature was included for evidence synthesis. Unless they were identified by the literature search and met the article inclusion criteria (see Appendix 3), we did not review any unpublished data from product manufacturers, investigators, or the Food and Drug Administration (FDA) Adverse Event Reporting System.

We searched the literature for the eight DMARDs and nine biologics most commonly used for the treatment of RA. Literature was searched for eight DMARDS including azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. As in 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on infrequent use and lack of new data (Table 1). Literature was searched for nine biologics including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab; anakinra was not included in the recommendations due to infrequent use and lack of new data. Details of the bibliographic search strategy are listed in Appendix 1.

/pdf/2012-update-of-the-2008-american-college-of-rheumatology-2zsrcxy352.pdf

2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.23721

American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Peptidylarginine deiminase (PAD, EC 3.5.3.15) enzymes catalyze the conversion of protein-bound arginine to citrulline. This post-translational modification may have a big impact on the structure and function of the target protein. In this review, we will discuss the effects of citrullination and its involvement in several human diseases, including rheumatoid arthritis and multiple sclerosis. So far, four isotypes of PAD have been described in mammals. We describe the existence of PAD in non-mammalian vertebrates and the existence of a fifth mammalian PAD. In addition, tissue-specific expression, genomic organization and evolutionary conservation of the different PAD isotypes will be discussed in detail. This article contains supplementary material which may be viewed at the BioEssays website at http://www.interscience.wiley.com/jpages/0265-9247/suppmat/2003/25/v25.1106.html.

PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease.

Introduction
Frequent assessments of rheumatoid arthritis (RA) disease activity allow timely adaptation of therapy, which is essential in preventing disease progression. However, values of acute phase reactants (APRs) are needed to calculate current composite activity indices, such as the Disease Activity Score (DAS)28, the DAS28-CRP (i.e. the DAS28 using C-reactive protein instead of erythrocyte sedimentation rate) and the Simplified Disease Activity Index (SDAI). We hypothesized that APRs make limited contribution to the SDAI, and that an SDAI-modification eliminating APRs – termed the Clinical Disease Activity Index (CDAI; i.e. the sum of tender and swollen joint counts [28 joints] and patient and physician global assessments [in cm]) – would have comparable validity in clinical cohorts.

/pdf/acute-phase-reactants-add-little-to-composite-disease-70jkm6lgps.pdf

Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score

Objective: To study the value of antibodies to citrullinated proteins/peptides for predicting joint outcomes in patients with recent onset rheumatoid arthritis (RA). 

Methods: 191 patients with RA onset within the past year were followed up prospectively for five years. Serum samples obtained from 145 patients at baseline before disease modifying antirheumatic drug treatment were examined using three anticitrullinated protein/peptide antibody assays: antiperinuclear factor (APF) by indirect immunofluorescence (IIF), antikeratin antibodies (AKA) by IIF, and anti-cyclic citrullinated peptide (CCP) antibodies by enzyme linked immunosorbent assay (ELISA). Radiographs of the hands and feet taken at baseline and after three and five years were evaluated using Sharp scores modified by van der Heijde. 

Results:Anti-CCP ELISA was positive in 58.9% of patients. APF/anti-CCP agreement was 77%. The likelihood of a total Sharp score increase after five years was significantly greater among patients with anti-CCP antibodies (67%; odds ratio (OR) 2.5; 95% confidence interval (95% CI) 1.2 to 5.0) or APF (57%; OR 2.4; 95% CI 1.2 to 4.9) but not rheumatoid factor (RF; OR 0.7; 95% CI 0.3 to 1.5). Mean values for radiographic damage, erosion, and joint narrowing scores at the three times were significantly higher in patients with anti-CCP or APF than in those without. AKA did not significantly predict radiographic damage. In separate analyses of patients with and without RF, anti-CCP or APF was better than RF for predicting total joint damage and joint damage progression after five years. 

Conclusion: Antibodies to citrullinated proteins/peptides determined early in the course of RA by APF IIF or anti-CCP ELISA are good predictors of radiographic joint damage. Further studies of clinical, laboratory, and genetic parameters are needed to improve RA outcome prediction in clinical practice.

https://ard.bmj.com/content/annrheumdis/62/2/120.full.pdf

Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage

Objective

To determine prognostic factors of radiologic damage and radiologic progression in early rheumatoid arthritis (RA).



Methods

A cohort of 191 patients with RA whose disease duration was shorter than 1 year were prospectively followed up for 3 years. Radiologic scores (as determined by Sharp's method, modified by van der Heijde) and radiologic progression were used as outcome measures. Numerous baseline clinical, laboratory, genetic, and radiographic data were obtained.



Results

The change in the total radiologic score for the patients followed up over 3 years was a mean ± SD increase of 6.1 ± 6.2. Radiologic progression was observed in 71 of the 172 patients for whom there were data at the end of the study. By univariate analysis with Fisher's exact test, radiologic scores and progression at followup were closely correlated with the baseline values of the erythrocyte sedimentation rate (ESR), C-reactive protein level, IgM and IgA rheumatoid factor positivity, antiperinuclear antibody positivity, radiologic scores, duration of morning stiffness, and RA-associated HLA–DRB1∗04 genes. No correlation was demonstrated with sex, age, Disease Activity Score, swollen or tender joint counts, extraarticular manifestations, Health Assessment Questionnaire score, Ritchie Articular Index, patient's assessment of pain, positivity for anti–heat-shock protein 90-kd antibodies, anticalpastatin antibodies, anti-RA33 antibodies, antinuclear antibodies, YKL-40, or antikeratin antibodies, and HLA–DRB1∗01 genes. The logistic regression analysis revealed that the only baseline values that were predictive of the 3-year radiologic scores were IgM rheumatoid factor positivity, DRB1∗04 genes, pain score, and total radiologic score. Progression of joint damage was predicted by the ESR, IgM rheumatoid factor positivity, DRB1∗04 genes, and erosions score at baseline.



Conclusion

Prognostic factors for radiographic damage in early RA were identified. A combination of these baseline values allowed us to draw up a predictive arithmetic score that could be used to predict radiologic damage at 3 years and radiologic progression in individual patients.

Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study.

BACKGROUND
The best management after ileocolonic resection is still unknown in Crohn's disease (CD). We compared step-up and top-down approaches to prevent short and long-term postoperative recurrences in CD patients.


METHODS
From a comprehensive database, consecutive CD patients who underwent intestinal resection (2014-2021) were included. Top-down (biologics started within the first month after surgery) or step-up strategies (no biologic between surgery and colonoscopy at 6 months) were performed with systematic colonoscopy at 6 months and therapeutic escalation if Rutgeerts index was ≥i2a (endoscopic postoperative recurrence). Propensity score analysis was applied for each comparison.


RESULTS
Among 115 CD patients, top-down was the most effective strategy to prevent endoscopic postoperative recurrence (46.8% vs 65.9%, P = .042) and to achieve complete endoscopic remission (Rutgeerts index = i0; 45.3% vs 19.3%; P = .004) at 6 months. We did not observe any significant difference between the 2 groups regarding clinical postoperative recurrence (hazard ratio [HR], .86 [0.44-1.66], P = .66) and progression of bowel damage (HR, 0.81 [0.63-1.06], P = .12). Endoscopic postoperative recurrence at 6 months was associated with increased risk of clinical postoperative recurrence (HR, 1.97 [1.07-3.64], P 0.029) and progression of bowel damage (HR, 3.33 [1.23-9.02], P = .018). Among the subgroup without endoscopic postoperative recurrence at 6 months, the risks of clinical postoperative recurrence and progression of bowel damage were significantly improved in the top-down group (HR, 0.59 [0.37-0.94], P = .025; and HR, 0.73 [0.63-0.83], P < .001, respectively).


CONCLUSIONS
Top-down strategy should be the preferred management to prevent short and long-term postoperative recurrence in CD.

Top-down Versus Step-up Strategies to Prevent Postoperative Recurrence in Crohn's Disease.

Impact Of The Ileal Microbiota On Surgical Site Infections In Crohn's Disease: A Nationwide Prospective Cohort.

Robotic right hemicolectomy is gaining in popularity due to the recognized technical benefits associated with the robotic platform. However, there is a lack of standardization regarding the optimal anastomotic technique in this cohort of patients, namely stapled or handsewn intra‐ or extra‐corporeal anastomosis. The ergonomic benefit associated with the robotic platform lends itself to intracorporeal anastomosis (ICA). The aim of this study was to compare the short‐term clinical outcomes of stapled versus handsewn ICA.

A Dubois

Papers

Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage

Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study.

Top-down Versus Step-up Strategies to Prevent Postoperative Recurrence in Crohn's Disease.

Impact Of The Ileal Microbiota On Surgical Site Infections In Crohn's Disease: A Nationwide Prospective Cohort.

A multicentre, prospective cohort study of handsewn versus stapled intracorporeal anastomosis for robotic hemicolectomy