Delphine Lebrun

Stéphanie Mestrallet

Monique Dehoux

Jean Louis Golmard

Benjamin Granger

Sophie Georgin-Lavialle

Laurent Arnaud

Gilles Grateau

Jacques Pouchot

Bruno Fautrel
email: bruno.fautrel@aphp.fr

S Haial

S Georgin- Lavialle

Pr B Fautrel

Validation of the Fautrel Classification Criteria for Adult-Onset Still's Disease

Keywords: adult onset Still's disease, classification, diagnosis, ferritin, infection

Introduction

First described in 1971 by Bywaters [START_REF] Bywaters | Still's disease in the adult[END_REF], adult-onset Still's disease (AOSD) is considered a multigenic auto-inflammatory disorder [START_REF] Gerfaud-Valentin | Adult-onset Still's disease[END_REF][START_REF]Pathophysiology, subtypes, and treatments of adult-onset Still's disease: An update[END_REF]. Its incidence has been estimated at 0.16 per 100,000 in France (4), and 0.22 and 0.34 per 100,000 for men and women in Japan. Its prevalence was calculated at 0.73 and 1.74 for men and women in Japan [START_REF] Wakai | Estimated Prevalence and Incidence of Adult Still's Disease: Findings by a Nationwide Epidemiological Survey in Japan[END_REF]. Its main clinical features are a high spiking fever, maculopapular rash usually concomitant with the fever, polyarthralgia, sore throat, lymphadenopathy, and hepatosplenomegaly. Other features reported are myalgia, serositis, weight loss, abdominal pain, and more anecdotally, neurological manifestations, renal impairment and ophthalmologic involvement. Its biological abnormalities include leukocytosis, elevated polymorphonuclear neutrophil counts, elevated erythrocyte sedimentation rate and C-reactive protein level, and abnormal liver function results [START_REF] Bywaters | Still's disease in the adult[END_REF][START_REF] Gerfaud-Valentin | Adult-onset Still's disease[END_REF][START_REF] Fautrel | Adult-onset Still disease[END_REF][START_REF] Reginato | Adult onset still's disease: experience in 23 patients and literature review with emphasis on organ failure[END_REF][START_REF] Ohta | Adult Still's disease: review of 228 cases from the literature[END_REF][START_REF] Cush | Adult-onset Still's disease. Clinical course and outcome[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Castañeda | Adult-onset Still's disease: Advances in the treatment[END_REF]. For the last 20 years, the diagnostic value of serum ferritin and percentage of glycosylated ferritin has been suggested. Indeed, the synthesis of ferritin is increased under inflammatory conditions [START_REF] Moore | Causes and significance of markedly elevated serum ferritin levels in an academic medical center[END_REF][START_REF] Fautrel | Ferritin levels in adult Still's disease: any sugar?[END_REF]. Its level is increased in AOSD and is correlated with disease activity [START_REF] Schwarz-Eywill | Evaluation of serum ferritin as a marker for adult Still's disease activity[END_REF][START_REF] Fautrel | Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease[END_REF][START_REF] Van Reeth | Serum ferritin and isoferritins are tools for diagnosis of active adult Still's disease[END_REF]. A marked decrease in glycosylated ferritin level was reported to be highly suggestive of AOSD [START_REF] Fautrel | Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease[END_REF]. In 2001, Fautrel et al. demonstrated a specificity of 92.9% for AOSD diagnosis with the combination of glycosylated ferritin percentage < 20% and serum ferritin level greater than 5-fold the normal-value [START_REF] Fautrel | Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease[END_REF]. Decreased glycosylated ferritin percentage persists several weeks or even months after AOSD flares and is less associated with variations in disease activity [START_REF] Vignes | Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Still's disease[END_REF]. Other authors have demonstrated an association of glycosylated ferritin level with more rapid diagnosis [START_REF] Gerfaud-Valentin | Adultonset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients[END_REF]. However, low glycosylated ferritin fraction is not completely specific of AOSD and has also been reported in hemophagocytic lympho-histiocytosis (HLH) [START_REF] Fardet | Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome[END_REF].

Because of the clinical heterogeneity and low prevalence of AOSD, its diagnosis is difficult.

It often remains an exclusion diagnosis. Several differential diagnoses, namely infectious, neoplastic, autoimmune and systemic diseases, should be ruled out. Several clinical cases of misdiagnosis and inadequate therapeutic prescriptions have been reported [START_REF] Neishi | Adult Still's disease as a paraneoplastic manifestation of breast cancer[END_REF][START_REF] Kianzowa | Paraneoplastic adult Still's disease[END_REF][START_REF] Okamoto | A case of paraneoplastic syndrome mimicking adult Still's disease caused by rectal cancer[END_REF][START_REF] Liozon | Adult-onset Still's disease as a manifestation of malignancy: report of a patient with melanoma and literature review[END_REF][START_REF] Yoshioka | A case of chronic active Epstein-Barr virus infection mimicking adult-onset Still's disease[END_REF][START_REF] Dua | Mycoplasma pneumoniae infection associated with urticarial vasculitis mimicking adult-onset Still's disease[END_REF][START_REF] Hoenderkamp | Pyrexia and a rash[END_REF][START_REF] Zaidan | Whipple disease mimicking adultonset Still's disease and treated by anakinra: diagnosis using PCR[END_REF][START_REF] Shuo | Small intestine Crohn's disease presenting as fever mistaken for adult onset Still's disease[END_REF][START_REF] Kato | A case of cutaneous polyarteritis nodosa manifested by spiking high fever, arthralgia and macular eruption like adultonset Still's disease[END_REF].

Misdiagnosis could have important adverse consequences, because AOSD treatments, such as corticosteroids or immunosuppressive agents, can worsen the course of these differential diagnoses, especially infectious or neoplastic diseases.

Several classification criteria have been published. Although they were not intended for AOSD diagnosis but rather to identify homogeneous groups of patients in clinical research, they can be helpful for clinicians at the time of diagnosis [START_REF] Reginato | Adult onset still's disease: experience in 23 patients and literature review with emphasis on organ failure[END_REF][START_REF] Goldman | Acute febrile juvenile rheumatoid arthritis in adults: cause of polyarthritis and fever[END_REF][START_REF] Calabro | Adult onset Still's disease[END_REF][START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF][START_REF] Crispín | Adult-onset Still disease as the cause of fever of unknown origin[END_REF][START_REF] Vanderschueren | Adult-onset Still's disease: still a diagnosis of exclusion. A nested case-control study in patients with fever of unknown origin[END_REF][START_REF] Masson | Comparative study of 6 types of criteria in adult Still's disease[END_REF][START_REF] Kahn | Maladie de Still de l'adulte[END_REF] (Supplemental table 1).

All were developed with retrospective data. Most of these classifications included exclusion criteria [START_REF] Reginato | Adult onset still's disease: experience in 23 patients and literature review with emphasis on organ failure[END_REF][START_REF] Goldman | Acute febrile juvenile rheumatoid arthritis in adults: cause of polyarthritis and fever[END_REF][START_REF] Calabro | Adult onset Still's disease[END_REF][START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF][START_REF] Kahn | Maladie de Still de l'adulte[END_REF] and were developed without any control group [START_REF] Reginato | Adult onset still's disease: experience in 23 patients and literature review with emphasis on organ failure[END_REF][START_REF] Cush | Adult-onset Still's disease. Clinical course and outcome[END_REF][START_REF] Goldman | Acute febrile juvenile rheumatoid arthritis in adults: cause of polyarthritis and fever[END_REF][START_REF] Calabro | Adult onset Still's disease[END_REF][START_REF] Kahn | Maladie de Still de l'adulte[END_REF]. One study analyzed the sensitivity of several sets of criteria with a observational cohort of AOSD patients and showed the Yamaguchi criteria with the highest sensitivity [START_REF] Masson | Comparative study of 6 types of criteria in adult Still's disease[END_REF]. Another study demonstrated the highest sensitivity (96.2%) and good specificity (92.1%) for the Yamaguchi criteria [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF].

In 2002, Fautrel et al. [START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF] proposed a new classification criteria set for AOSD, including the previously-mentioned biological parameters but with the advantage of not including exclusion criteria. The selected variables were classified into minor (maculopapular rash, leukocytes > 10,000/mm 3 ) and major criteria (spiking fever > 39°C, arthralgia, transient erythema, pharyngitis, polymorphonuclear neutrophil percentage > 80%, glycosylated ferritin percentage < 20%). AOSD was diagnosed with the presence of 4 major criteria or 3 major and 2 minor criteria. The sensitivity was 80.6% and specificity 98.5%, the latter being higher than that obtained with other sets [START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF]. This classification set includes the value of glycosylated ferritin indicating the pathognomony of this disease.

This study objective was to validate the Fautrel classification criteria with a different cohort and to compare its discriminative performance to that of the Yamaguchi criteria.

Patients and Methods

Study design

A retrospective, monocentric, observational, case control study was conducted.

Study population

We included all adult patients under management at the Pitié-Salpêtrière University Hospital in Paris who had ferritin and glycosylated ferritin assay testing at the biochemistry laboratory of Bichat Hospital from January 2000 to April 2013.

We excluded patients who were less than 18 years old, had incomplete medical charts, and were included in the previous study.

Collected data

Data were extracted from medical charts by one investigator (DL) who used a standardized form. The index date was the date of the glycosylated ferritin assay. All clinical, biological, and imaging features available at the time of or before the index date were collected as discrete variables (present or absent for clinical parameters, normal or abnormal for biological parameters according to predefined thresholds). Information suggestive of an alternative diagnosis was carefully searched, especially that corresponding to other immune-mediated inflammatory diseases [IMIDs, i.e., corresponding to criteria contained in other IMID classification sets, such as for Behcet's disease [START_REF] Dejaco | 13th International Conference on Behçet's Disease, May 24-27, 2008[END_REF][START_REF] Davatchi | Diagnosis/Classification Criteria for Behcet's Disease[END_REF], giant cell arteritis [START_REF] Hunder | The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis[END_REF], inflammatory myopathies [START_REF] Troyanov | Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients[END_REF], systemic lupus erythematosus (42), Sjogren's syndrome [START_REF] Vitali | Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group[END_REF], familial Mediterranean fever [START_REF] Pras | Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene[END_REF], rheumatoid arthritis [START_REF] Aletaha | Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF], spondyloarthritis [START_REF] Rudwaleit | The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection[END_REF][START_REF] Rudwaleit | The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general[END_REF], and HLH [START_REF] Henter | HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis[END_REF]].

In addition, diagnostic investigations to exclude an active infection or a neoplastic disease were noted. The diagnosis by the referring physician at the last follow-up was also noted (case report form in Supplemental table 2 and criteria for other IMIDs in Supplemental table 3).

Diagnostic certification of cases and controls

Patients were classified as AOSD patients or controls, based on clinical and laboratory information extracted from medical charts at the time of ferritin dosage or later. Inclusion in the AOSD group required: 1) a diagnosis of AOSD retained by the referring physician at last follow-up, 2) a diagnosis of AOSD retained by the investigator (DL), and 3) meeting none of the classification criteria sets for IMID described previously. Controls included patients without the AOSD definition and those with HLH, neoplasia, other IMIDs, hepatic diseases, infections, or other conditions. For patients with a discrepancy between the final diagnosis and classification criteria and/or featuring several classification criteria, group adjudication was performed by a multidisciplinary expert group (BF, GG, JP, LA, SGL) after revision of the case. During the multidisciplinary adjudication, patient data were presented in terms of a report summarizing disease history, clinical, laboratory and imaging findings and satisfaction of IMID classification criteria sets, except for the Yamaguchi and Fautrel classification sets which were not presented. In case of residual uncertainty despite the expert adjudication, cases were excluded.

Satisfying of AOSD classification criteria

Algorithms corresponding to the Fautrel and Yamaguchi classification criteria were applied to each patient. The classification criteria items that were missing in the medical chartmissing datawere considered absent.

Exclusion criteria were managed in two ways. The first was Yamaguchi classification in which these criteria were defined as absent according to the referring physician (indicated in the chart) and present if the final diagnosis was an infection, neoplasia or IMID. This method is designated hereafter as the "standard Yamaguchi classification". Second, exclusion criteria were defined as absence of exclusion criteria according to the referring physician and performance of diagnostic investigations including at least blood cultures, Epstein-Barr virus serology or PCR, and dosage of rheumatoid factor and anti-nuclear antibodies. The choice of these complementary exams was based on the Yamaguchi et al. study [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF]. This method is designated hereafter as the "strict Yamaguchi classification".

In addition, three composite classifications were applied to each patient. The first corresponded to the standard Yamaguchi classification, with the addition of ferritin level as a major criterion (considered present with ferritin level higher than normal), and is called "Yamaguchi +F>N" hereafter. The second corresponded to the standard Yamaguchi classification with the addition of glycosylated ferritin percentage (considered present with glycosylated ferritin fraction < 20%), and was called "Yamaguchi +FG < 20%". The three corresponded to the standard Yamaguchi classification with the addition of ferritin level 5 fold upper limit of the normal (considered present with ferritin level >5N), and was called "Yamaguchi +FG>5N".

Statistical analysis

Quantitative data are described with mean ± SD and categorical data as number (percentage).

The two groups were compared by Student t tests for quantitative variables and chi-square test or exact Fisher test for categorical variables. For each diagnostic method, sensitivity, specificity, positive and negative predictive values were estimated with their 95% confidence intervals by the bootstrap procedure with 1000 replicates. Sensitivity and specificity of the two classification criteria sets were compared by McNemar test. All computations involved use of SAS v9.3 (SAS Institute, Cary, NC, USA). P<0.05 was considered statistically significant.

Results

Population characteristics

During the study period, 1093 ferritin and glycosylated ferritin assays were performed by the biochemistry laboratory of Bichat Hospital. These assays involved 761 patients, of whom 426 had available and complete medical records. Overall, 81 of these cases were assessed by the multidisciplinary expert group. Finally, we identified 54 patients with AOSD and 278 were controls. We excluded 94 patients: 68 because they were younger than 18 years old or data from the medical record were incomplete and 26 because AOSD could not be definitely excluded or diagnosed (Figure 1).

The distribution of diseases for controls are in Table 1. The category "other" included especially drug eruption, urticaria, cristal arthropathies, and psychosomatic disorders.

Clinical and biological characteristics

Table 2 shows the main clinical and laboratory characteristics of AOSD patients and controls.

The mean age of AOSD patients was 38.9+15.6 years and 37.0% were male. AOSD patients were younger than controls. The cardinal symptoms of AOSD-fever, arthralgia, rash, leukocytosis and elevated polymorphonuclear neutrophils-were more frequent in AOSD patients than controls. Serum ferritin level > normal values (N) was higher for AOSD patients than controls (41/54 [75.9%] vs 155/278 [55.8%]), corresponding to a specificity of 44.2%. Ferritin level >5-fold higher than N was higher for AOSD patients than controls ( [11.5%], corresponding to an interesting specificity of 88.5% but a low sensitivity of 25.9%. AOSD patients and controls showed significant differences in the frequency of most variables except for gender, pericarditis, renal failure and anti-neutrophil cytoplasmic antibodies (ANCA).

Additional tests performed to rule out active infection

Discriminative performance of Fautrel criteria

The Fautrel criteria had sensitivity 87.0%, specificity 97.8%, and positive and negative predictive value 88.7% and 97.5%. Six patients were falsely classified as AOSD by this set, and seven AOSD diagnoses were missed. The false-positive cases were finally diagnosed as Castleman disease, endocarditis, pneumonitis, anti-NMDA (N-methyl-D-aspartate) receptor encephalitis, connective and granulomatosis (n=1 each). Among the seven missed AOSD patients, two had a monocyclic systemic form, three a polycyclic systemic form, and two a chronic articular forms. Two of these seven patients were discussed during the multidisciplinary consultation. These false-negative cases were classified as AOSD by the standard Yamaguchi set, which had sensitivity 96.3%, specificity 98.9%, and positive and negative predictive value 94.5% and 99.3%. Using the standard Yamaguchi criteria set, three controls were falsely classified as AOSD, and two AOSD diagnoses were missed. The three controls falsely classified as AOSD had an inflammatory myopathy, anti-NMDA receptor encephalitis and an unclassified inflammatory disease. The two AOSD missed cases had a polycyclic systemic form and were correctly classified with the Fautrel set. One of these cases was assessed during the multidisciplinary consultation. If we applied a stricter definition of exclusion criteria, the sensitivity of the Yamaguchi set decreased to 31.5% (p < 0.0001). In addition, 37 AOSD diagnoses were missed, although one alone was falsely classified as AOSD.

The composite set, "Yamaguchi+F > N", had sensitivity 100.0%, specificity 97.1%, and positive and negative predictive value 87.1% and 100.0%. With this set, the number of falsenegative cases was reduced to 0. However, this combination wrongly classified eight controls as AOSD: five had a diagnosis of IgA nephropathy, pelvic fibrosis, sarcoidosis, unclassified autoimmune disease, unclassified autoinflammatory syndrome and the remaining three were previously misclassified with the standard Yamaguchi set.

The composite set, "Yamaguchi + F > 5N", displayed sensitivity 96.3%, specificity 98.6%, and positive and negative predictive value 92.9% and 99.3%. With this set, the number of false-negative cases was reduced to 0, and the number of false-positive cases was reduced to 4. The The latter included one patient with unclassified connectivite and three controls previously misclassified with the standard Yamaguchi set.

The composite set, "Yamaguchi+FG < 20%", had sensitivity 98.2%, specificity 98.6%, and positive and negative predictive value 93.0% and 99.6%. There was one false-negative case and four false-positive cases. The latter included one patient with chronic urticaria and three controls previously misclassified with the standard Yamaguchi set. The misclassified patients are described in Table 5.

These different sets showed excellent performance. However, the differences did not reach statistical significance, which did not allow us to compare these sets.

Discussion

This study validates the Fautrel classification criteria for AOSD with a different cohort than the original one. This criteria set shows good sensitivity and specificity, overcomes exclusion criteria and includes glycosylated ferritin fraction level. It also confirms the high discriminative power of the Yamaguchi criteria, which are highly affected by how exclusion criteria are interpreted. In addition, the two classification criteria sets featured no significantly significant differences.

The study design for validating classification criteria for AOSD is challenging. The first limitation of our study is its retrospective design. Although a prospective design is desirable to avoid any missing data, the low incidence of the disease, estimated at 0.16 per 100,000 in France (4), and the absence of a national cohort limit the feasibility of this design. Likewise, none of the other criteria sets were developed prospectively, which confirms this difficulty [START_REF] Reginato | Adult onset still's disease: experience in 23 patients and literature review with emphasis on organ failure[END_REF][START_REF] Cush | Adult-onset Still's disease. Clinical course and outcome[END_REF][START_REF] Goldman | Acute febrile juvenile rheumatoid arthritis in adults: cause of polyarthritis and fever[END_REF][START_REF] Calabro | Adult onset Still's disease[END_REF][START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF][START_REF] Crispín | Adult-onset Still disease as the cause of fever of unknown origin[END_REF][START_REF] Kahn | Maladie de Still de l'adulte[END_REF]. To minimize the bias in data recording, we ensured that patient records were comprehensive, and we used a standardized data collection form. However, the quality of medical charts was not consistent and several cases were excluded because of incomplete data. The second limitation concerns the selection of controls. The purpose of classification criteria is to separate AOSD patients and those with a disorder mimicking AOSD [START_REF] Fries | Criteria for rheumatic disease. different types and different functions[END_REF]. Only [START_REF] Vanderschueren | Adult-onset Still's disease: still a diagnosis of exclusion. A nested case-control study in patients with fever of unknown origin[END_REF] and our present study defined a control group. We selected the patients which both ferritin and glycosylated ferritin assay results. To our knowledge, combination of these 2 assays is prescribed only for patients with suspected AOSD or HLH [START_REF] Fardet | Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome[END_REF]. These data allowed us to identify cases and controls in the same population. Moreover, the identification of cases and controls was independent of serum ferritin and glycosylated ferritin levels to avoid any selection bias. Crispin et al. [START_REF] Crispín | Adult-onset Still disease as the cause of fever of unknown origin[END_REF] defined controls as patients with fever of unknown origin as defined by Petersdorf and Beeson, and separately defined AOSD patients. The patient selection in the study by Vanderschueren et al. [START_REF] Vanderschueren | Adult-onset Still's disease: still a diagnosis of exclusion. A nested case-control study in patients with fever of unknown origin[END_REF] was based on fever of unknown origin.

The size of the control group was also questionable. Because of our selection process, we did not calculate the number of needed controls, and five controls were included for one AOSD case. In comparison, three controls were included in the Yamaguchi et al. study [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF], five in the Crispin et al. study [START_REF] Crispín | Adult-onset Still disease as the cause of fever of unknown origin[END_REF], and two in the Fautrel et al. and Vanderschueren et al. studies [START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF][START_REF] Vanderschueren | Adult-onset Still's disease: still a diagnosis of exclusion. A nested case-control study in patients with fever of unknown origin[END_REF].

The classification procedure for AOSD patients was not based on Yamaguchi criteria set, unlike the Vanderschueren et al. validation study. However, physicians in charge of patients were fully aware of these classification criteria which might have influenced their final diagnosis. To limit this bias, we defined a procedure based on physician judgment at different steps to ascertain diagnosis and properly classify patients. The Yamaguchi et al. study was the only other one to use experts' judgment. This identification procedure of cases and controls is not perfect, but represents the most neutral approach to compare classification criteria sets.

Integrating the Yamaguchi exclusion criteria in data collection was complex. Indeed, these criteria include infections, malignancies, and rheumatic diseases. In current practice, what corresponds to these terms is unclear. Rheumatic diseases include rheumatoid arthritis and spondyloarthritis or IMID in a broader sense. We cannot determine whether additional investigations can reasonably eliminate all the confounding disorders. Previously cited studies [START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF][START_REF] Crispín | Adult-onset Still disease as the cause of fever of unknown origin[END_REF][START_REF] Vanderschueren | Adult-onset Still's disease: still a diagnosis of exclusion. A nested case-control study in patients with fever of unknown origin[END_REF] do not describe how these criteria were handled. In our study, exclusion criteria were first considered absent if the referring physician considered them as eliminated and present if the final diagnosis was infection, neoplasia or IMID, and second, considered absent if the referring physician had performed enough diagnostic investigations to rule them out, defined as at least blood culture, Epstein-Barr virus serology or PCR, dosage of rheumatoid factor and anti-nuclear antibodies. The choice of these additional tests was based on the Yamaguchi et al. study [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF].

In our study, the control group included patients with the main confounding disorders with AOSD. However, the spectrum of diagnoses slightly differed from that in other studies [START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF][START_REF] Crispín | Adult-onset Still disease as the cause of fever of unknown origin[END_REF][START_REF] Vanderschueren | Adult-onset Still's disease: still a diagnosis of exclusion. A nested case-control study in patients with fever of unknown origin[END_REF]. Our control group included some with liver diseases and no fever of unknown origin. Also, this is the only study including patients with HLH. Because of the similarity of clinical and biological signs of these two disorders, distinguishing them in common practice is difficult. The Fautrel classification criteria set demonstrated its ability to correctly classify these two distinct disorders.

The cardinal manifestations of AOSD-fever, arthralgia, rash, leukocytosis and increased polymorphonuclear neutrophils-were present in more than 70% patients with AOSD. The frequency of these manifestations in our study population was similar to that reported for other series [START_REF] Ohta | Adult Still's disease: review of 228 cases from the literature[END_REF][START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF][START_REF] Gerfaud-Valentin | Adultonset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients[END_REF][START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF]. Myalgia was observed in 35.2% of patients with AOSD. This symptom was found in comparable proportions in most studies [START_REF] Gerfaud-Valentin | Adultonset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients[END_REF][START_REF] Yamaguchi | Preliminary criteria for classification of adult Still's disease[END_REF][START_REF] Ohta | Adult Still's disease: a multicenter survey of Japanese patients[END_REF], except in the Pouchot et al. study [START_REF] Pouchot | Adult Still's disease: manifestations, disease course, and outcome in 62 patients[END_REF], in which 84% of patients had myalgia. Moreover, the present study confirms the diagnostic value of serum ferritin level > 5N and glycosylated ferritin level <20% [START_REF] Fautrel | Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease[END_REF][START_REF] Van Reeth | Serum ferritin and isoferritins are tools for diagnosis of active adult Still's disease[END_REF][START_REF] Fautrel | Proposal for a new set of classification criteria for adult-onset still disease[END_REF].

We noted a great heterogeneity in both the number and type of the additional diagnostic tests performed. Some patients underwent no laboratory exams, whereas others had more than 20 tests. The lack of precise definition of the Yamaguchi exclusion criteria, in the form of a comprehensive list of diagnoses to exclude or exams to perform, explains this disparity. This situation attests to the complexity of Yamaguchi criteria used in clinical research.

The present study validates the Fautrel criteria for AOSD in a different cohort than the initial one, with sensitivity 87.0%, specificity 97.8% and accuracy 96.1%. This classification criteria set displayed higher sensitivity than the other sets except Yamaguchi's [START_REF] Masson | Comparative study of 6 types of criteria in adult Still's disease[END_REF]. Moreover, all evaluated sets achieved excellent performance. The differences among criteria did not reach statistical significance. A likely explanation for this result was the small size of the AOSD group. Finally, this study confirms the excellent performance of the Yamaguchi and Fautrel classification criteria in clinical research. The lower sensitivity of the Fautrel classification is offset by the absence of exclusion criteria. Moreover, this classification includes glycosylated ferritin level confirmed as specific in our study. In addition, the discriminative power of the Yamaguchi criteria is highly affected by how exclusion criteria are interpreted. In fact, by applying stricter exclusion criteria, the sensitivity significantly decreased to 31.5%. Although not perfect, the Fautrel classification seems more manageable than the Yamaguchi criteria in clinical research. Further validation studies should be carried out on other populations in other countries in order to confirm these data. A better understanding of the pathophysiology of AOSD could be the key to a more reliable diagnostic approach. Abbreviations: AOSD = adult-onset Still's disease; ns = not specified; PMN = polymorphonuclear neutrophil; LDH = lactate dehydrogenase; ANA = anti-nuclear antibodies; RF = rheumatoid factor; F = ferritin; GF = glycosylated ferritin; ANCA = antineutrophil cytoplasmic antibodies. *Normal serum ferritin levels were 200 µg/L for women, 300 µg/L for men. ">N" = serum ferritin level higher than the upper normal value, ">5N" = serum ferritin level greater than 5fold the upper normal value. ¤ Student test, § chi-square test, $ Fisher exact test

  the studies of Yamaguchi et al. (32), Fautrel et al. (33), Crispin et al. (34), Vanderschueren et al.

Figure 1 :

 1 Figure 1: Flow of patients in the study

Table 3

 3 summarizes the tests performed to exclude an active infection. The mean number of tests was 7.5+6.0 (median 6.0) for patients with AOSD. Blood cultures were more frequent

	for AOSD patients than controls (26/54 [48.2%] vs 89/278 [32.0%]). Epstein-Barr virus
	serology or PCR was more frequent for AOSD patients than controls (26/54 [48.2%] vs
	82/278 [29.5%]). Bacteriological analysis of body fluids (including cerebrospinal fluid,
	broncho-alveolar fluid, pericardial fluid, joint fluid, and sampling from abscesses) was more
	frequent for controls than AOSD patients (51/278 [18.4%] vs 3/54 [5.6%]). Six of the 54
	AOSD patients (11.1%) had additional tests during further disease flares.

Table 1 : Control group diagnoses

 1

	Specific Diagnosis

Table 2 : Main clinical and laboratory characteristics of patients with adult-onset Still's disease (AOSD) and controls

 2

	AOSD	Controls	p value
	(n=54)	(n=278)

Table 3 : Additional diagnostic tests performed to exclude infectious differential diagnosis in AOSD patients and controls

 3

	AOSD	Controls	p value
	(n=54)	(n=278)

Table 4 : Evaluation of AOSD classification criteria

 4

	Criteria sets	AOSD	Control	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)
		(n=54)	(n=278)	95% CI	95% CI	95% CI	95% CI	95% CI
	Fautrel	47	6	87.0 [77.1-95.7]	97.8 [96.0-99.3]	88.7 [73.3-96.2]	97.5 [95.5-99.3]	96.1 [94.0-98.0]
				°	°
	Yamaguchi
	Standard	52	3	96.3 [90.6-100.0]	98.9 [97.5-99.8]	94.5 [87.2-100.0]	99.3 [98.2-100.0]	98.5 [97.0-99.7]
	Strict	17	1	31.5 [19.1-43.6]	99.6 [98.9-100.0]	94.4 [81.3-100.0]	88.2 [84.8-91.5]	88.6 [85.2-91.9]
				****/°°°°	*/°
	Composite set
	Yamaguchi + F > N	54	8	100.0 [100.0-100.0]	97.1 [95.1-98.9]	87.1 [78.3-94.6]	100.0[100.0-100.0]	97.6 [96.1-99.1]
				**/°	*/°
	Yamaguchi + F > 5N	54	4	96.3 [89.7-100.0]	98.6 [97.1-99.6]	92.9 [85.5-98.3]	99.3 [97.9-100.0]	98.2 [96.7-99.4]
				*/NA	*/°
	Yamaguchi + FG < 20%	53	4	98.1 [93.8-100.0]	98.6 [97.1-99.7]	93.0 [86.0-98.3]	99.6 [98.9-100.0]	98.5 [97.0-99.7]
				*/°	*/°
	Abbreviations: PPV = positive predictive value; NPV = negative predictive value; F > N = means serum ferritin level higher than the upper
	normal value; FG = glycosylated ferritin; NA = not applicable
	Comparing the Fautrel set and this set according to the Mc Nemar test: *p >0.05, **p <0.05, ***p <0.01, ****p <0.001
	Comparing the standard Yamaguchi set and this set according to the Mc Nemar test: °p >0.05, °°p <0.05, °°°p <0.01, °°°°p <0.001
	CI95 were assessed by bootstrap procedure with 1000 replicates

Table 5 : Description of misclassified patients by the different studied classifications

 5

	Criteria sets	False positive		False negative
	Fautrel	Castleman's disease		2 monocyclic systemic forms
		Endocarditis		3 polycyclic systemic forms
		Pneumonitis		2 chronic articular forms
		Anti-NMDA receptor encephalitis
		Unclassified connectivite
		Unclassified granulomatosis
	Standard Yamaguchi	Inflammatory myopathy	2 polycyclic systemic forms
		Anti-NMDA receptor encephalitis
		Unclassified inflammatory diseases
	Strict Yamaguchi	Anti-NMDA receptor encephalitis	37 patients
	Yamaguchi+F > N	IgA nephropathy		None
		Pelvic fibrosis
		Sarcoidosis
		Unclassified autoimmune disease
		Unclassified	autoinflammatory
		syndrome
		Inflammatory myopathy
		Anti-NMDA receptor encephalitis
		Unclassified inflammatory diseases
	Yamaguchi+F > 5N	Anti-NMDA receptor encephalitis	None
		Unclassified inflammatory diseases
		Unclassified connectivite
		Inflammatory myopathy
	Yamaguchi+FG < 20%	Chronic urticaria		1 patient
		Inflammatory myopathy
		Anti-NMDA receptor encephalitis
		Unclassified inflammatory diseases
	Abbreviations: NMDA = N-Methyl-D-Aspartate; F >N = means serum ferritin level higher
	than the upper normal value; FG = glycosylated ferritin

Acknowledgments

We thank the clinicians from our institution who provided patient records: Pr Z. Amoura (Department of Internal Medicine), Pr O. Benveniste (Department of Internal Medicine), Pr E. Caumes (Department of Infectious Diseases), Pr M. Komajda (Department of Cardiology), Pr T. Similowski (Department of Pneumology), Pr M. Verny (Department of Geriatrics).

We thank L. Smales for its careful reading of the article, and JL. Golmard for its initial statistical analyzes.

Supplemental table 1: Classification criteria sets for diagnosis of adult-onset Still's disease (AOSD)


Stéphane Hilliquin

Benjamin Hugues

Stéphane Mitrovic

Laure Gossec

Bruno Fautrel
email: bruno.fautrel@aphp.fr

Ability of disease-modifying antirheumatic drugs to prevent or delay rheumatoid arthritis onset: a systematic literature review and meta-analysis

Keywords: rheumatoid arthritis, very early arthritis, pre-RA, treatment, glucocorticoids, diseasemodifying antirheumatic drugs

Background: Recent advances in knowledge of the pathogenesis of rheumatoid arthritis (RA) has led to promoting very early intervention.

Objectives: To assess the efficacy of therapeutic interventions in preventing or delaying RA onset with a systematic literature review (SLR) and meta-analysis (MA).

Methods:

The SLR aimed to include all reports of randomized controlled trials of diseasemodifying antirheumatic drugs or glucocorticoids used in patients presenting genetic and/or environmental risk factors for RA and/or systemic autoimmunity associated with RA, and/or symptoms without clinical arthritis and/or unclassified arthritis and in RA patients. We searched PubMed, EMBASE and Cochrane databases for English articles published from 2006 to 2016 using the keywords "undifferentiated arthritis" or "very early rheumatoid arthritis" with "therapy" or "treatment". Main outcome was RA occurrence, defined as fulfillment of the 1987 ACR criteria.

The MA was performed with RevMan with the Mantel-Haenszel method.

49]. For people with undifferentiated arthritis, the MA of the 7 available studies revealed significant risk reduction with OR 0.73 [95% CI: 0.56 -0.97].

Conclusions:

This MA demonstrates that early therapeutic intervention may significantly reduce the risk of RA onset in this very first phase of the disease.

INTRODUCTION

During the last decades, substantial knowledge has accumulated on the very early stages of rheumatoid arthritis (RA), notably the very early immunological pathogenic mechanisms leading to RA [START_REF] Klareskog | What precedes development of rheumatoid arthritis?[END_REF][START_REF] Klareskog | Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis[END_REF][START_REF] Klareskog | Rheumatoid arthritis[END_REF][START_REF] Klareskog | Autoimmunity: lungs and citrullination[END_REF]. This knowledge has deeply altered the nosologic RA concept and its diagnosis.

For a long time, RA diagnosis required a quite complete and comprehensive clinical presentation, including bilateral symmetrical polyarthritis, involving the hands, eventually associated with serum rheumatoid factor (RF), nodules or radiographic joint erosions, as included in the 1987 American College of Rheumatology (ACR) classification criteria [START_REF] Arnett | The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis[END_REF]. This "full presentation" does not fit with RA early stages, and the 1987 ACR criteria were found to adequately classify patients as having RA only 2 years after disease onset [START_REF] Saraux | Ability of the American College of Rheumatology 1987 criteria to predict rheumatoid arthritis in patients with early arthritis and classification of these patients two years later[END_REF]. In 2010, the joint effort of the ACR and European League Against Rheumatism (EULAR) widened the spectrum of early RA by reducing the minimal synovitis number to 1 and including serum anticitrullinated peptide antibody (ACPA) positivity in addition to RF as immunologic biomarkers [START_REF] Aletaha | rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF]. The new classification showed higher sensitivity to detect patients with early RA [START_REF] Fautrel | Level of agreement of the 1987 ACR and 2010 ACR/EULAR rheumatoid arthritis classification criteria: an analysis based on ESPOIR cohort data[END_REF] and affected the diagnostic concept of unclassified arthritis (UA) as well as very early RA (VeRA) [START_REF] Krabben | Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis[END_REF][START_REF] Van Der Helm-Van Mil | The 2010 ACR/EULAR criteria for rheumatoid arthritis: do they affect the classification or diagnosis of rheumatoid arthritis?[END_REF].

The combination of advances in RA pathogenesis and progress in RA diagnosis has contributed to redefining the RA early stages as a continuum spreading over several years [START_REF] Klareskog | Autoimmunity: lungs and citrullination[END_REF]11] starting from [START_REF] Klareskog | What precedes development of rheumatoid arthritis?[END_REF] a first autoimmune phenomemon related to a host-environment interaction (e.g., interaction between smoking and the presence of the shared epitope leading to ACPA production); [START_REF] Klareskog | Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis[END_REF] preclinical RA (pre-RA), in which levels of autoimmunity biomarkers increase and mature, potentially associated with mild inflammatory features (e.g., arthralgia without arthritis/synovitis);

(3) UA with at least 1 synovitis present, without satisfaction of the 1987 ACR criteria (but potentially satisfying the 2010 ACR/EULAR criteria); and finally (4) defined RA, with "fullpicture" RA and satisfaction of 1987 ACR classification criteria [START_REF] Van Der Helm-Van Mil | The 2010 ACR/EULAR criteria for rheumatoid arthritis: do they affect the classification or diagnosis of rheumatoid arthritis?[END_REF]11]. These concepts have been retained in recent EULAR recommendations for research of individuals at risk of RA [START_REF] Gerlag | EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis[END_REF].

Besides diagnosis, the therapeutic issue is also important. Early therapeutic interventions, within the first months after RA onset, were clearly found associated with better RA outcomes [START_REF] Anderson | Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration[END_REF][START_REF] Lard | Early versus delayed treatment in patients with recentonset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies[END_REF][START_REF] Van Nies | Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts[END_REF], thereby validating the concept of a "window of opportunity". In addition, the PROMPT trial demonstrated the ability of early methotrexate initiation to prevent onset of RA in patients with unclassified arthritis [START_REF] Van Dongen | Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial[END_REF][START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF]. This situation raised the question of delaying or preventing RA if RA treatments are started at preclinical or in the very early clinical stages of the disease [11].

Although international clinical practice guildelines focus on methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in early RA [START_REF] Combe | update of the EULAR recommendations for the management of early arthritis[END_REF], numerous other therapeutic options are available, and several, including glucocorticoids or biologic DMARDs (bDMARDs), have been tested in individuals at risk of RA. A recent meta-analysis (MA) of studies of experimental animal models suggested that DMARDs are not equally efficacious in the prevention or treatment of the early arthritis animal model [START_REF] Dekkers | Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental animal models of arthritis: a systematic literature review and meta-analysis[END_REF].

Thus, we conducted a systematic literature review (SLR) and MA of randomized controlled trials (RCTs) of patients at risk of RA to assess the efficacy of glucocorticoids, csDMARDs or bDMARDs for preventing or delaying RA development and/or blocking structural damage. The notion of prevention of RA refers to the ability of a treatment to block the pathogenic process and prevent more established forms of RA. Thus, the target population for such an action is people at risk of RA (family history and presence of (high titer) autoantibodies, or with arthralgia and autoantibodies, or people with unclassified arthritis).

METHODS

Search strategy

We performed a systematic literature search of PubMed, Medline, EMBASE and the Cochrane Controlled Trials Register up to June 2017 for articles published from 2006 to 2016 and EULAR and ACR scientific meeting abstracts from the last 2 years (2015 and 2016). We used the following key words: "Arthritis, Rheumatoid"[MeSH] AND "very early" AND "treatments"[all fields] OR "therapy"[all field], or "undifferentiated arthritis"[All Fields] AND "therapy"[all fields] or "treatments"[all fields]. We limited our search to English-language reports of RCTs of adults ≥ 18 years old. In addition, we hand-searched reference lists of papers initially detected to identify additional relevant reports. The reports of clinical trials were initially selected on the basis of the title and abstract, then the full text. Duplicate references were removed.

Study selection criteria

To be selected, reports had to satisfy the following:

(1) The study design should be an RCT.

(2) The enrolled patient diagnosis should be one of (A) patients presenting genetic and/or environmental risk factors for RA and/or systemic autoimmunity associated with RA, and/or symptoms without clinical arthritis and/or unclassified arthritis [START_REF] Aletaha | rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF][START_REF] Gerlag | EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis[END_REF][START_REF] Hua | Diagnosis, prognosis and classification of early arthritis: results of a systematic review informing the 2016 update of the EULAR recommendations for the management of early arthritis[END_REF]; (B) patients with clinical arthritis evolving for < 16 weeks and fulfilling the 2010 ACR/EULAR criteria but not the 1987 ACR criteria.

Data extraction

Two independent readers (SH, BH) extracted the following data by using a standardized form: patient characteristics at baseline (i.e., demographics and disease characteristics, including classification criteria fulfilment); therapeutic intervention; occurrence of RA at week 52 or closest time point, defined as fulfillment of the 1987 ACR classification criteria [START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF][START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF][START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF][START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF] or ACR EULAR 2010 or according to the rheumatologist's opinion [START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Gerlag | A Single Infusion of Rituximab Delays the Onset of Arthritis in Subjects at High Risk of Developing RA[END_REF]; clinical remission rates at week 52, defined by validated composite criteria (i.e., Disease Activity Score in 28 joints [DAS28] [START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF][START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF][START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF][START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF][START_REF] Emery | Combination etanercept and methotrexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study[END_REF], Simple DAI [SDAI], Clinical DAI [CDAI] or boolean [START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF], with adequate threshold); structural damage progression seen on X-rays at week 52 (Table 2) based on the van der Heijde-modified Sharp score or any other validated score [START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF][START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF][START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF][START_REF] Emery | Combination etanercept and methotrexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study[END_REF]; and safety based on a descriptive analysis.

To define specific phases of RA, patients were classified into groups according to the EULAR recommendations for terminology [START_REF] Gerlag | EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis[END_REF] Study quality was assessed by the Jadad scale [START_REF] Jadad | Assessing the quality of reports of randomized clinical trials: is blinding necessary?[END_REF] with 2 questions (answer Yes/No) for randomization, 2 for masking, and 1 (answer Yes/No) evaluating the reporting of withdrawals and dropouts. A total of 5 points could be awarded, with higher scores indicating higher quality.

Statistical analysis and MA

The MA was performed accordingly to the Cochrane Collaboration guidelines [START_REF]Cochrane Handbook for Systematic Reviews of Interventions[END_REF] for RA occurrence, defined as a definite RA, which is mostly according to the 1987 ACR classification criteria in the literature (or ACR EULAR 2010) at week 52 or closest time point, radiographic progression and clinical remission. Concerning RA occurrence, data at week 52 and beyond this time were pooled to strengthen the results. A sensitivity analysis was conducted to isolate the impact of TNF-blocker treatment. Statistical heterogeneity was tested by the chi-square Q test, [START_REF] Higgins | Quantifying heterogeneity in a meta-analysis[END_REF]; with significant heterogeneity, a random-effects model was used. The MA was performed with RevMan v5.3 (The Nordic Cochrane Centre, Copenhagen, 2014) with the Mantel-Haenszel method, estimating odds ratios (ORs) and 95% confidence intervals (CIs). A descriptive analysis was performed for other measures such as the DAS28, Health Assessment Questionnaire (HAQ), and side effects (infectious, intolerance).

RESULTS

Selected studies

The search identified 595 abstracts, with reports of 10 RCTs selected (including 2 congress abstracts) and 10 exploited for analysis (Figure 1). The main reasons for exclusion were disease duration at baseline (many studies included patients with RA evolving for more than 16 weeks); study design (i.e., non-RCTs); study endpoints different from the outcomes of interest; and incomplete results (i.e., missing data for means and/or SD). The mean Jadad score was 5, which indicates high methodological quality of studies.

Seven were related to (e) criteria, two to (d) and one to (f) [START_REF] Gerlag | EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis[END_REF]. The therapeutic strategies tested were methylprednisolone at a single dose of 80 mg [START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF] or 120 mg [START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF], intramuscularly in 2 studies; dexamethasone at the dose of 100 mg IM at week 0 and week 6 [START_REF] Bos | Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial[END_REF] oral methotrexate up to 30 mg/week for X weeks or months in 1 study [START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF]; TNF blockersinfliximab (3 mg/kg at weeks 0-2-4-6-14 +/-22) [START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Durez | Infliximab Versus Placebo in Adult Patients with ACPA Positive Undifferentiated Arthritis[END_REF] or etanercept (50 mg/kg/wk) [START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF][START_REF] Emery | Combination etanercept and methotrexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study[END_REF] at labelled dosesin 4 studies, used alone or with methotrexate (up to 30 mg/wk); intravenous abatacept (100 mg/kg every 2 weeks for 1 month, then monthly) [START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF] at a labelled dose in 1 study; and finally intravenous rituximab at 1 g once only in 1 study (Table 1).

The SLR and MA included 1,239 patients (mean percentage of females 66.0 %with weighted mean age 45.8 ± 15.2 years and mean symptom duration 16.2 ± 12.6 weeks.

Data synthesis

Preventing or delaying RA occurrence

RA occurrence, defined as satisfaction of the 1987 ACR classification criteria, was found in 9 of 10 papers assessing methylprednisolone (80 to 120 mg intramuscularly), dexamethasone, methotrexate, TNF blocker (infliximab in the Saleem and Durez trial; etanercept in EMPIRE), abatacept or rituximab.

2 studies are related to arthralgia without arthritis (d) [START_REF] Gerlag | A Single Infusion of Rituximab Delays the Onset of Arthritis in Subjects at High Risk of Developing RA[END_REF][START_REF] Bos | Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial[END_REF] evaluating dexamethasone and rituximab. 7 are related to unclassified arthritis (e) [START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF][START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF][START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF][START_REF] Durez | Infliximab Versus Placebo in Adult Patients with ACPA Positive Undifferentiated Arthritis[END_REF][START_REF] Van Der Helm-Van Mil | A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions[END_REF].

In the group arthralgia without arthritis (d), the MA of the 2 available studies did not show significant reduction in RA occurrence at week 52 or more (pooled OR 0.74, 95% CI [0.37; 1,49] (figure 2a).

For people with undifferentiated arthritis (e), the MA of the 7 available studies revealed significant risk reduction with OR 0.73 [95% CI: 0.56 -0.97]. All drugs tended to reduce the risk of RA occurrence, except TNF blockers (Figure 2a).

As a sensitivity analysis, the MA was performed without the 2 TNF-blocker studies, which resulted in a more significant pooled OR: 0.68, 95% CI [0.50; 0.92] (Figure 2b).

Clinical remission

Clinical remission at week 52, according to the DAS28, SDAI, CDAI or boolean definitions, was available for 5 studies of glucocorticoids and TNF blockers (etanercept or infliximab) or abatacept.

The Saleem and Durez study used another criteria (no swollen joint and C-reactive protein level < 10 mg/L). Only the COMET trial [START_REF] Emery | Combination etanercept and methotrexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study[END_REF] demonstrated a significant effect of etanercept on remission.

The MA revealed that early intervention increased the odds of achieving remission (pooled OR 1,84, 95% CI [1.08; 3.16]) (Figure 3).

Radiographic progression

Data on radiographic progression were available for 5 studies, evaluating methylprednisone, methotrexate, or a TNF blocker (etanercept and infliximab). The outcomes were the Sharp score (modified or not) and Larsen score. No significant risk reduction was revealed for radiographic progression (Figure 4). The MA yielded a pooled OR of 1.36 (95% CI [0.82; 2.27]). We found no difference between treatments for radiographic progression. The analysis without TNF blockers did not alter the results.

Other outcomes and side effects

With the descriptive analysis, similar side effects were observed between placebo and methylprednisone without notable difference [START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF]. The observed side effects were the expected ones: hypertension, lower-limb oedema [START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF], anaphylactic reaction and mood swings [START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF]. The PROMPT study found no signficant safety difference for methotrexate versus placebo (26/55 with methotrexate and 18/55 with placebo, p = 0.17). Side effects described were benign gastrointestinal events, elevated serum liver enzyme levels and dermal/mucosal events with methotrexate. bDMARDs were associated with respiratory and urinary tract infecions, with 2 severe cases [START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF].

No malignancy was identified. There were 10 safety events with abatacept versus 11 with placebo [START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF]. The most frequently reported events were nasopharyngitis, urinary-tract infection and gastroenteritis. The abstract for the PRAIRI study (rituximab) did not specify side effects [START_REF] Gerlag | A Single Infusion of Rituximab Delays the Onset of Arthritis in Subjects at High Risk of Developing RA[END_REF].

DISCUSSION

The present SLR and MA provides information that a very early therapeutic intervention may significantly reduce the risk of RA onset with patients at risk of RA and significantly increase the rate of clinical remission. Although the notion of a window of opportunity is well accepted in people with already diagnosed RA [START_REF] Van Nies | Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts[END_REF][START_REF] Quinn | Window of opportunity in early rheumatoid arthritis: possibility of altering the disease process with early intervention[END_REF], our work reveals that an even earlier therapeutic intervention could prevent RA or delayed its onset. This conclusion seems to be available in patients with arthritis. In symptomatic patients without arthritis, no significant reduction was observed, potentially partly due to a lack of power with the only 2 available studies. This work also suggests that the beneficial effect of very early treatment in RA could differ between csDMARDs or bDMARDs. Although a reduced risk of RA occurrence was observed with glucocorticoids, methotrexate, abatacept or rituximab, the trend seemed not confirmed for TNF blockers [START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF]. This finding is likely to be a class effect rather than a single molecule effect because it was observed with 2 different agents, one soluble receptor (etanercept) and one monoclonal antibody (infliximab). They may be not as important in the very early steps of the disease in which autoimmune phenomenon are present but not joint or systemic inflammation [START_REF] Deane | Editorial: Prevention of Rheumatoid Arthritis: Now Is the Time, but How to Proceed?[END_REF].

TNF blockers have been mainly tested, and are currently recommended, in established active RA and eventually in early RA with pejorative prognostic factors such as high swollen joint count, increased acute-phase reactant levels or joint erosions; this is in line with the association between TNF and detectable inflammation [START_REF] Smolen | EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update[END_REF][START_REF] Singh | Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying antirheumatic drugs: a systematic review and network meta-analysis[END_REF][START_REF]Biologic or Tofacitinib Monotherapy for Rheumatoid Arthritis in People With Traditional Disease-Modifying Anti-Rheumatic Drug (DMARD) Failure: A Cochrane Systematic Review and Network Meta-Analysis (NMA)[END_REF][START_REF] Singh | Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis[END_REF][START_REF] Vanier | An improved matrix to predict rapid radiographic progression of early rheumatoid arthritis patients: pooled analyses from several databases[END_REF]. Pharmacologic agents such as glucocorticoids, methotrexate, rituximab or abatacept may have a broader effect and act higher in the pathogenic cascade, including antigen presentation and early steps of the autoimmune reaction; they could thus prevent the immune system activation, whereas TNF blockers could only reduce already existing inflammation. We have no data available for interleukin 6 (IL-6) blocking agents, although IL-6 seems to be involved in the very early steps of RA pathogenesis [START_REF] Gottenberg | Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort[END_REF].

Several strengths of the study must be underlined. The study applied the methodological standards recommended by the Cochrane collaboration for an SLR and MA, including double data extraction and entry [START_REF]Cochrane Handbook for Systematic Reviews of Interventions[END_REF]. Although people in very early phases of the disease constitute a challenging population for clinical research, 9 reports of RCTs were identified and the data could be integrated in the MA. These trials cover almost all possible modes of action for RA, except IL-6 blockers and JAK inhibitors.

However, our work has some limitations. Although data about about RA diagnosis according to 1987 ACR classification criteria were available in most of the studies (7 of 9), only a few reported data on clinical remission (5 of 9). Structural damage information was assessable in 5 studies ; however, the progression was small in RA, and we could not identify any significant benefit of early therapeutic intervention for this outcome. In addition, we found substantial heterogeneity in the outcome measures used in the selected trials: DAS28, SDAI, CDAI or Boolean definitions for remission and Larsen or van der Heijde-modified Sharp score for radiographic progression. For feasibility reasons, we pooled the remission rates or percentages for patients without structural damage progression, regardless of the tool used. This move could have biased our results in part.

An important concern comes with the distinction of the very early steps of RA [START_REF] Gerlag | EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis[END_REF][START_REF] Deane | Editorial: Prevention of Rheumatoid Arthritis: Now Is the Time, but How to Proceed?[END_REF]. We chose the cutoff of 4 months of disease duration to select the studies for our MA, which was based on data from a few studies [START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF][START_REF] Emery | Combination etanercept and methotrexate provides better disease control in very early (<=4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study[END_REF] using the cutoff of 3 to 4 months to define the very early RA phase. This choice is of course partly arbitrary and reveals the complexity to define the initial RA phases, which constitute a continuum [START_REF] Klareskog | What precedes development of rheumatoid arthritis?[END_REF] rather than a succession of clearly different health states [START_REF] Deane | Editorial: Prevention of Rheumatoid Arthritis: Now Is the Time, but How to Proceed?[END_REF][START_REF] Raza | Timing the therapeutic window of opportunity in early rheumatoid arthritis: proposal for definitions of disease duration in clinical trials[END_REF]. The 2010 ACR/EULAR criteria [START_REF] Aletaha | rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF] allowed for identifying RA patients at an earlier stage than did the 1987 criteria [START_REF] Fautrel | Level of agreement of the 1987 ACR and 2010 ACR/EULAR rheumatoid arthritis classification criteria: an analysis based on ESPOIR cohort data[END_REF]. However, the criteria are operational only for patients with significant RA symptoms and do not cover the whole spectrum of people with less specific symptoms such as those with arthralgia or limited arthritis, with or without family history of RA, and/or with or without serum ACPA positivity. The development of clinical practice guidelines for people at risk of RA was an important step forward [START_REF] Gerlag | EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis[END_REF] but did not completely fix the overlap of the existing definitions of the RA early phases [START_REF] Deane | Editorial: Prevention of Rheumatoid Arthritis: Now Is the Time, but How to Proceed?[END_REF][START_REF] Raza | Timing the therapeutic window of opportunity in early rheumatoid arthritis: proposal for definitions of disease duration in clinical trials[END_REF]. Despite these difficulties, our results reinforce the view of "the sooner the better" in terms of therapeutic decision making within the pathogenic RA continuum. This paradigm raises an important additional question related to the duration of such a very early therapeutic intervention aiming to prevent RA onset or completely abate the disease. Whatever the RA stage, the risk of relapse seems substantial when treatments are not maintained [START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF][START_REF] Verstappen | Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial[END_REF][START_REF] Machold | The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis[END_REF][START_REF] Saleem | Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?[END_REF][START_REF] Emery | Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)[END_REF][START_REF] Nam | A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial[END_REF][START_REF] Gerlag | A Single Infusion of Rituximab Delays the Onset of Arthritis in Subjects at High Risk of Developing RA[END_REF]. However, there is potential for "immunologic remission" in some RA patients [i.e., resolution of any sign of joint or systemic inflammation with disappearance of serum autoantibodies (RF or ACPA)] [START_REF] Schett | Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions[END_REF]. Early or very early intervention may favor such immunologic remission and could correspond to some kind of resetting of the immune system with complete resolution of any autoimmune phenomenon. The optimal strategy for such patients could then be an induction therapeutic sequence to prevent RA or achieve immunologic remission, then a drug tapering or discontinuation sequence to reach sustained and stable drug-and disease-free states [START_REF] Boer | Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study)[END_REF][START_REF] Heimans | A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study[END_REF][START_REF] Espinoza | Remission-induction therapies for early rheumatoid arthritis: evidence to date and clinical implications[END_REF][START_REF] Nagy | Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now?[END_REF]. This move would probably require as an intermediary step a better assessment and quantification of the risk of developing RA for a given patient to facilitate the implementation of more personalized therapeutic schemes. A risk stratification score, based on family history as well as patient clinical and biologic features, has been proposed in the context of the Leiden Early Arthritis Clinic [START_REF] Nagy | Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now?[END_REF]. Finally, this notion of prevention in patients at risk of developing RA needs to be handled with caution for 2 reasons.

Firstly, in all the trial, the treatment of patients with arthralgia and autoantibodies or with unclassifed arthritis have mainly shown their capacity to delay or postpone RA onset, but only a minority of them will durably remain asymptomatic if the tested DMARD is discontinued [START_REF] Van Dongen | Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial[END_REF][START_REF] Van Aken | Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)[END_REF][START_REF] Gerlag | A Single Infusion of Rituximab Delays the Onset of Arthritis in Subjects at High Risk of Developing RA[END_REF]. Secondly, it must be kept in mind that these patients may correspond to patients achieving spontaneous remission with no or only little role for the DMARD. In a recent work conducted in the ESPOIR and the Leiden early arthritis cohorts, such an evolutioni.e., DMARDfree sustained remissioncould be observed in 5.4% (29/533 in ESPOIR) to 11.5% (85/738 in LEAC) [START_REF] Van Nies | Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden early arthritis clinic and ESPOIR cohorts[END_REF]. It is important to note that delay is not prevention. It remains to date unknown whether a minority will remain asymptomatic after DMARD is discontinued.

This question deserves to be further studied, why not by creating a two arms study with early intervention in case of arthralgia and auto-immunity comparing intervention only when clinical arthritis develops.

In conclusion, this SLR and MA clearly demonstrates the potential benefits of very early therapeutic intervention for people who start RA and specifically its ability to prevent established RA. Our results fit perfectly with the 2017 EULAR campaign on early actions in rheumatic disorders:

"Don't delay, Connect today"

(https://www.eular.org/what_we_do_dont_delay_connect_today.cfm).

( 3 )

 3 Study treatment should be glucocorticoids or any other DMARD, either a csDMARD (methotrexate) or bDMARD (tumor necrosis factor [TNF] blocker or other mode of action).

( 4 )

 4 Study outcomes should be measured at week 52 or closest time point.

  as follows : (a) : genetic risk factors for RA ; (b) environmental risk factors for RA ; (c) : systemic auto-immunity associated with RA ; (d) : symptoms without clinical arthritis ; (e) unclassified arthritis ; (f) RA.

Figure 1 :Figure 2 a.

 12 Figure 1: Flow of studies in the review

Figure 3 :Figure 4 :

 34 Figure 3: Clinical remission at week 52

Table 1 :

 1 Study characteristics : unclassified arthritis (i.e., patients presenting arthritis and ultrasound-detected synovitis, without ACPA or RF positivity); VeRA (i.e., patients with clinical arthritis evolving for < 16 weeks and fulfilling the 2010 ACR/EULAR criteria but not the 1987 ACR criteria). ACPA: anticitrullinated protein antibody. RF: rheumatoid factor. DAS: disease activity score. HAQ: health assessment questionnaire. RA occurrence : according to ACR 1987 for all studies except for PRAIRI and STIVEA which correspond to the rheumatologist's opinion.

	Trial name (reference)	Inclusion	Terminolog y (REF)	N	Intervention	Outcome	Evaluation Time of Outome
	Bos 2009 (31)	Arthralgia	(d)	83	Dexamethasone 100mg IM,	-RA occurrence	-W52 and more (mean duration of
		without			W0 and W6		follow up: 52,5 months)
		synovitis
	Gerlag 2016	Arthralgia	(d)	81	RTX 1000 mg J0	-RA occurrence	-29 months
	(PRAIRI) (26)	without
		synovitis
	Verstappen2009	UA	(e)	224 80 mg MP	-DAS	-Baseline, W24, 52
	(STIVEA) (21)	ACPA/RF+ naive of			W0-1-2	-HAQ -Radiographic score	-Baseline, W52 -W52
		treatment				-RA occurrence*	-W52
	Machold 2009	UA	(e)	303 120 mg MP J0	-DAS	-Baseline, W12, W52
	(SAVE) (22)	ACPA/RF +				-RA occurrence	-12 months
		Naive
	Van Dongen	UA	(e)	55	MTX until 30 mg/wk	-DAS	-Baseline, W12, W52
	2007 (PROMPT)	ACPA/RF + GC allowed				-Radiographic score -RA occurrence	-Baseline, M18 -30 months, 60 months
	(17)
	Saleem 2008	UA	(e)	17	INF 3 mg/kg	-DAS	-Baseline, W12, 24
	(23)	ACPA/RF + GC allowed			W0-2-4-6-14	-HAQ -Radiographic score	-Baseline, W12, 24, -W52
						-RA occurrence	-W52
	Durez 2011	UA ACPA +	(e)	30	INF	-RA occurrence	-12 months
	(48)				3 mg/kg W0, 2, 6, 14, 22	-DAS28 -ACR 20 -50-70	-W52 -W14
	Nam 2013	UA	(e)	82	ETN50 mg/wk + MTX	-DAS	-Baseline, W12, W52, M18
	(EMPIRE) (25)	ACPA/RF + GC allowed				-HAQ -Radiographic score	-Baseline, W52, M18 -Baseline, W52, M18
						-RA occurrence	-12 Months
	Emery 2009	UA	(e) or (f)	11	ABA 100 mg/kg	-DAS	-Baseline, W24, 52
	(ADJUST) (24)	ACPA/RF + or VERA			Day: 1-15-29-57-85-113-141-169	-Radiographic score -HAQ	-Baseline, W52 -Baseline
		GC allowed				-RA occurrence	-6 Months
		(<10mg/day)
	Emery 2011	VERA	(f)	112 MTX vs. MTX + ETN 50	-DAS28	-W52
	(COMET) post-				mg/wk	-Radiographic score	-Baseline, W52
	hoc [48]

UA

Table 2 :

 2 Main outcome results * DAS28<2.6 ; *** No SJ and ≤ 2 tender joint (TJ) + 2/3 of following: normal CRP level, visual analog scale score for pain or activity <10/100 + no past or current treatment with disease-modifying antirheumatic drugs (DMARDs) or glucocorticoids except study drug; ****Simple DAI ≤3.3 DXM : Dexamethasone. GC: glucocorticoids. MP: methylprednisolone. Pcb: Placebo. MTX: methotrexate. INF: infliximab. ABA: abatacept. ETN: etanercept. RTX: rituximab. n.a.: not available

	Trial name (reference)	Group		RA occurrence W52 or more		% Clinical remission W52	% No radiographic progression W52 or more
	Bos 2009 (31)	Pcb DXM IM	22,5 16,7	9/40 7/42	n.a.	n.a.	n.a.	n.a.
	Gerlag 2016	RTX+CS	34	14/41	n.a.	n.a.	n.a.	n.a.
	(PRAIRI)(26) ‡	Pcb	40	16/40
	Verstappen 2009	MP IM	48.6	54/111	20.7	23/111	12.7	9/71
	(STIVEA) (21) ‡	Pcb	60.4	67/111	11.7	13/111	14.8	9/61
	Machold 2009 (SAVE)	MP	47.6	69/145	16.2	32/198 ***	n.a.	n.a.
	(22)	Pcb	52.4	76/145	17.8	33/185
	Van Dongen 2007	MTX	40	22/55	n.a.	n.a.	88	48/55
	(PROMPT) (17)	Pcb	53	29/55			73	40/55
	Saleem 2008 (23)	IFN	100	10/10	20	2/10	80.0	8/10
		Pcb	71.4	5/7	14.3	1/7	71.4	5/7
	Durez 2011 (48)	Pcb INF	66.7 73.3	10/15 11/15	21.4 50.0	3,2/15 7,5/15 **	n.a.	n.a.
	Nam 2013 (EMPIRE) (25)	MTX+ETN MTX+Pcb	61,5 63,5	33/52 35/53	68.8 47.5 62.5	38/55 ** 26/55 **** 34/55 **	93.1 (87.1=M18) 95.5	51,2/55 52,5/55
					37.0	20/55 ****	(80.0=M18)
	Emery 2009 (ADJUST)	ABA	46.2	12/26	47.4	9/19 **	n.a.	n.a.
	(24)	Pcb	66.7	16/24	38.5	5/13
	Emery 2011 (COMET) post-hoc [48]	ETN+MTX MTX	n.a.	n.a.	69.8 24.1 34.7	44/63 ** 15,2/63**** 17/49 **	80.6 73.9	50,8/63 36,2/49
					13.6	6,7/49 ****
	‡diagnosis of RA relied on the rheumatologist's opinion.

*

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