A. Constantin

Targeting monocytes/macrophages in the treatment of rheumatoid arthritis

Biotherapies have revolutionized the treatment of RA. However, much work is needed to understand all the mechanisms of these biotherapies, and alternatives are needed to circumvent adverse effects and the high cost of these long-lasting treatments. In this article we outline some of the approaches we have used to target monocytes/macrophages as major components of inflammation and bone homeostasis. We also discuss how anti-TNF-α antibodies target monocytes/macrophages in the complex mechanisms contributing to inhibition of inflammation.

Non–TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial

Importance One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. Objective To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. Design, Setting, and Participants A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR]  ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. Interventions Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. Main Outcomes and Measures The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. Results Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). Conclusions and Relevance Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. Trial Registration clinicaltrials.gov Identifier: NCT01000441.

Rituximab in the spondyloarthropathies: data of eight patients followed up in the French Autoimmunity and Rituximab (AIR) registry

No data are available regarding the safety and efficacy of B-cell depletion in the spondyloarthropathies (SpA), except for two case reports. One patient with ankylosing spondylitis (AS) was prescribed rituximab (RTX) for lymphoma without any improvement of the AS.1 One patient with psoriatic arthritis responded to RTX.2 The French Autoimmunity and Rituximab (AIR) registry, prospectively collects data on patients treated with RTX on- and off-label for refractory arthritides by their clinicians.3 On 23 February 2009, 1383 patients with rheumatoid arthritis, 93 with systemic lupus erythematosus, 43 with primary Sjogren’s syndrome, 55 with vasculitis, 30 with myositis and 112 with other autoimmune or inflammatory diseases, had been included in AIR registry. Among the last group …

New insights into the genetics of immune responses in rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease with a strong genetic component. Numerous aberrant immune responses have been described during the evolution of the disease. In later years, the appearance of anti-citrullinated protein antibodies (ACPAs) has become a hallmark for the diagnosis and prognosis of RA. The post-translational transformation of arginine residues of proteins and peptides into citrulline (citrullination) is a natural process in the body, but for unknown reasons autoreactivity towards citrullinated residues may develop in disposed individuals. ACPAs are often found years before clinical manifestations. ACPAs are present in about 70% of RA patients and constitute an important disease marker, distinguishing patient groups with different prognoses and different responses to various treatments. Inside the human leukocyte antigen (HLA) region, some HLA-DRB1 alleles are strongly associated with their production. Genome-wide association studies in large patient cohorts have defined a great number of single nucleotide polymorphisms (SNPs) outside of the HLA region that are associated with ACPA positive (ACPA+) RA. The SNPs are generally located close to or within genes involved in the immune response or signal transduction in immune cells. Some environmental factors such as tobacco smoking are also positively correlated with ACPA production. In this review, we will describe the genes and loci associated with ACPA+ RA or ACPA- RA and attempt to clarify their potential role in the development of the disease.

Oral health-related quality of life among outpatients with rheumatoid arthritis

OBJECTIVES The aims of the Oral Status And Rheumatoid Arthritis (OSARA) cross-sectional study were to study the oral health-related quality of life and to assess the associated factors in a population of outpatients with rheumatoid arthritis in France. METHODS The data were collected by five trained and standardised dentists who asked each subject the questions of a socio-demographic, behavioural and medical questionnaire, which was completed with the medical records, and performed the dental examination. Each subject filled out two self-assessment questionnaires: the Health Assessment Questionnaire and the General Oral Health Assessment Index. RESULTS Seventy-three subjects were included. The mean age of the participants was 60.2 ± 11.9 years and 75.3% were women. For 58.3% of the subjects, their self-perceived oral health-related quality of life was described as poor. The logistic regression analysis found that a small number of teeth and marked difficulties in dressing and grooming were associated with bad oral health-related quality of life [ORa = 10.5 (1.96-56.19) and ORa = 4.3 (1.15-15.77), respectively]. CONCLUSIONS More care should be given to the prevention of dental diseases in order to improve the oral health-related quality of life of patients with rheumatoid arthritis and their self-esteem, which will already be heavily affected.

Association of IL-2RA and IL-2RB genes with erosive status in early rheumatoid arthritis patients (ESPOIR and RMP cohorts).

OBJECTIVES To assess the impact of single nucleotide polymorphisms (SNPs) in IL-2RA (rs2104286) and IL-2RB (rs743777 and rs3218253) genes on the risk of erosions in rheumatoid arthritis (RA) patients. METHODS This work is derived from 2 prospective cohorts of early RA: ESPOIR (n = 439) and RMP (n = 180). The proportions of patients with erosions at baseline and 1 year according to the genotypes of IL2RA (rs2104286) or the haplotypes constructed with the 2 SNPs of IL2RB were compared in the whole population and in ACPA positive patients. A meta-analysis assessing the risk of erosion depending on the haplotypes of the 2 SNPs of IL-2RB was performed using the Mantel-Haenszel method. A multivariate model was used to assess the independent effect of the haplotypes of IL-2RB on the risk of erosions. RESULTS The AC haplotype of IL-2RB carriage was significantly associated with the rate of erosions in ACPA positive patients in ESPOIR cohort (rate of erosions: AC/AC: 78% versus GC or GT/GC or GT: 44%, p = 0.001). A meta-analysis of ESPOIR and RMP cohorts confirmed that the carriage of AC haplotype was significantly associated with the rate of erosions at 1 year in the whole sample (OR[95%CI] = 1.92[1.14-3.22], p = 0.01) and in ACPA positive patients (OR[95%CI] = 3.34[1.68-6.67], p = 0.0006). A multivariate model in ESPOIR cohort demonstrated the independent effect of the carriage of the AC haplotype (6.03[1.94-18.69], p = 0.002) on the risk of erosions in ACPA+ patients. CONCLUSION A haplotype constructed with 2 SNPs located on IL-2RB gene was associated with erosive status in early RA.

Contribution of the 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography to the diagnosis of primary osseous Hodgkin lymphoma.

Hodgkin lymphoma typically presents as a nodal lesion and infrequently involves extra nodal sites. Although cases of primary extra-nodal Hodgkin lymphoma have been reported previously, the reality of the primitive nature of the disease was difficult to authenticate with traditional high resolution imaging techniques, such as computed tomography or magnetic resonance imaging, because they cannot evaluate the spread of the disease throughout the whole body. We report here a case of primary osseous Hodgkin lymphoma, regarded as stage I extranodal IE thanks to the important contribution of a new imaging technique, the 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography/ computed tomography (18F-FDG-PET/CT). PET enables systemic Hodgkin lymphoma with secondary bone invasion to be distinguished from primitive osseous Hodgkin lymphoma. This technique is highly specific in demonstrating the isolated osseous localisation of the tumour and should be recommended in all patients with putative osseous lymphoma.

1.60 Autoantibodies to human citrullinated fibrinogen (AhFibA) and their subfamilies directed to the fibrin peptides α36-50Cit38,42 and β60-7460,72,74 are prognostic markers of radiographic damage in the very early arthritides of the French ESPOIR cohort

Background and Objective In established RA, autoantibodies (AAB) to human citrullinated fibrinogen (AhFibA) were demonstrated to be mainly composed of two subfamilies of AAB directed to immunodominant epitopes borne by the fibrin peptides α36-50Cit38,42 and β60-74Cit60,72,74,respectively. Serum reactivity toward those peptides defines subgroups of patients. In the present study, we investigated whether AhFibA, anti-α36-50Cit38,42 and β60-74Cit60,72,74 AAB, have different predictive values for disease outcome in very early RA. We also analysed whether these AAB differentially associate with SE and tobacco exposure. Materials and Methods The French ESPOIR cohort is comprised of very early RA and of undifferentiated arthritides (UA) of less than 6-month duration. AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB were assayed by ELISA at baseline. After 3-year follow up, 701 patients were diagnosed RA according to the ACR/EULAR 2010 criteria. Relationships between SE HLA-DR alleles, tobacco exposure and the 3 AAB were analysed on those patients. Disease activity (DAS28, HAQ) and radiographic damage (SHS) were evaluated at baseline, and after 2- or 3-year follow up. Associations with clinical parameters and predictive value of each AAB were investigated. Results AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB were detected in 349/701 (50%), 203/701 (29%), and 257/701 (37%), RA sera, respectively. Their positive predictive values for RA (72%, 82%, and 79%, respectively) were not significantly different. The presence and titre of each AAB were associated with SE HLA-DR alleles without significant additional effect of tobacco exposure. When 2 vs 0 copies of SE alleles were present, the odds ratios for AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB presence reached 8.0, 6.1 and 9.5, respectively. Neither the presence nor the titres of AhFibA, α36-50Cit38,42 and β60-74Cit60,72,74 AAB were associated with DAS28 or HAQ at baseline and after 2 years. However, for the 3 AAB, patients whose sera contained one or several AAB had a progression of SHS during the first 3 years (medians from 6 to 8 depending on the subgroup), significantly higher than the AhFibA-negative patients (median = 4). Nevertheless, no significant correlation was observed between the titres of AAB and radiographic progression. Conclusion Not only AhFibA but also their anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB subfamilies, are prognostic markers for bone erosion in RA. Moreover, AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB are similarly associated to HLA-DR and to tobacco exposure.

AB0703 Impact of ANTI-TNF agents on patient-reported outcomes in spondyloarthritis: a systematic review of the literature and meta-analysis

Background Disability, alteration in quality of life and fatigue are frequently reported in spondyloarthritis (SpA). Anti-TNF demonstrated clinical efficacy in SpA. However efficacy on patient-reported outcomes (PROs) may differ from medical assessment. Objectives To assess the impact of anti-TNF on quality of life, disability and fatigue reported by SpA patients. Methods Design: systematic review and meta-analysis of the literature. Data sources: two authors (SL and YD) independently screened PubMed-Medline, Cochrane library and EMBASE databases until November 2016. Key words: (“Patient reported” OR “quality of life” OR fatigue OR FACIT) AND (spondyloarthritis OR “psoriatic arthritis” OR “ankylosing spondylitis”) AND (anti-TNF OR certolizumab OR etanercept OR adalimumab OR infliximab OR golimumab). Articles selection: randomized controlled trials (RCTs), published in English, assessing efficacy of anti-TNF on PROs, in ankylosing spondylitis (AS), psoriatic arthritis (PsA) or SpA according to the ASAS criteria. Data collected: fatigue assessed by FACIT score, quality of life assessed by Short Form 36 (SF36) mental and physical component or by Health AssessementQuestionnary Disability Index (HAQ). Data analysis: Article quality was evaluated by the JADAD scale. For SF36 and HAQ outcomes, pooled variations at 12 and 24 weeks were computed by meta-analysis. Heterogeneity was measured by I2 index. Results Of the 604 articles identified, 37 references were eligible for systematic review and 13 for meta-analysis. Our systematic review identified 10 RCTs concerning AS, 20 concerning PsA and 7 concerning axial SpA. However due to the heterogeneity in available statistical data, references eligible for meta-analysis were mainly related to PsA. HAQ assessment was available for a meta-analysis in 8 studies. HAQ was significantly improved at 12 and 24 weeks with anti-TNF. The impact on HAQ variation at week 24 was -0.29 points [95% CI: -0.37, -0.22]. Heterogeneity was important (I2 =57%; see figure). Ten studieswere eligible for a meta-analysis of anti-TNF effect on SF36 mental form. An improvement was observed at 12 and 24 weeks, although superior at 24 weeks. The effect at week 24 was 2.78 [95% CI: 1.87 - 3.68], without heterogeneity (I2 =0%; see figure). Twelve studies were eligible for a meta-analysis of anti-TNF effect on SF36 physical form. We observed a similar and significant improvement at 12 and 24 weeks. The effect at week 24 was 6.74 [95% CI: 5.34 – 8.13], with an important heterogeneity (I2 =84%; see figure) Fatigue was evaluated in 3 studies. Adalimumab induced a significant improvement in FACIT score at 12 and 24 weeks in one study. Two studies using different scores (Fatigue Assessment Scale, BASDAI fatigue item) to assess certolizumab effect highlighted similar findings: an early improvement in fatigue at week 12, remaining significant and stable at week 24. Conclusions Anti-TNFs agents significantly improve disability, quality of life and fatigue in patients with PsA. Acknowledgements Abbvie France pharmaceutical company provided logistic support by organizing a meta-analysis methods workshop, but played no further role in the project. Disclosure of Interest None declared

AB0598 Does The Presence of Anti-Citrullinated Protein Antibodies Change The Presentation of Systemic Sclerosis?

Background Systemic sclerosis (SSc) is one of the most complex and heterogeneous systemic disease. The diagnosis can be helped by the positivity of different characteristic auto-antibodies steered toward topoisomerase I, centromeric protein, RNA polymerase and fibrillarin. Different presentations of the disease can be associated with some specificities of auto-antibodies. Recently, some studies have reported the presence of anti-citrullinated protein antibodies (ACPA) in patients with SSc. Objectives We have conducted a systematic literature review in order to define the prevalence of ACPA in SSc, and to observe their influence on clinical and paraclinical presentation of the disease. Methods Literature search was performed in PubMed Medline database on 15 february 2015. Publication were identified through a search that used the terms: (“systemic sclerosis”(MeSH) and “ACPA or anti-CCP or rheumatoid factor or cohort or value diagnostic”). In a first step, we have selected all cohorts over 50 patients with SSc and ACPA identification. In a second step we have included all studies in which the clinical profile of scleroderma was detailed according to their ACPA status. Meta-analyses were performed when there were two or more studies with similar clinical description. Results For the first question, we identified 13 observational studies merging 1231 patients with SSc. ACPAs were positive for 113 patients, giving a prevalence of ACPA in SSc of 9.2%. In a second step, we identified 9 studies reporting clinical and paraclinical aspects according to their ACPA status. Information was enough to perform a meta-analysis for arthralgia, arthritis, joint erosions, skin sclerosis, pulmonary arterial hypertension, pulmonary fibrosis and gastrooesophageal reflux. We found a significant association between ACPA positivity and the presence of arthritis (OR: 25.48 [11.82–54.47]), joint erosions on X-rays (OR: 13.06 [4.68–36.43]), pulmonary arterial hypertension (OR: 7.72 [2.38 – 25.5]), and pulmonary fibrosis (OR: 2.75 [1,21–6.24]) (Fig 1). Conclusions ACPA prevalence in scleroderma is 9.2%. Our systematic literature review shows a significant increased risk for erosive arthritis, pulmonary hypertension and pulmonary fibrosis in ACPA positive SSc. ACPA should be systematically included in the check-up of systemic sclerosis. Disclosure of Interest None declared