Joaquim Polido Pereira

Non-classical human leucocyte antigens in ankylosing spondylitis: possible association with HLA-E and HLA-F

Objectives Ankylosing spondylitis (AS) is the most prevalent form of spondyloarthritis, with a known genetic association with the HLA-B27 molecule. The aim of this study was to assess the contribution of the HLA-G, HLA-E and HLA-F to AS susceptibility/protection in Portuguese patients with HLA-B27 AS and HLA-B27 unaffected controls. Methods High-resolution typing of HLA-G, HLA - E and HLA - F was performed in 228 patients with HLA-B27 AS and 244 HLA-B27 unaffected controls. Allelic, genotypic and haplotypic frequencies were compared between cohorts. To replicate the results, single nucleotide polymorphisms (SNPs) in HLA-E and HLA-F genes were typed in Australian cohorts. For further confirmation, a group of European-descent patients with AS and unaffected controls were genotyped for Major Histocompatibility Complex SNPs using the Illumina microarray. Results In the Portuguese population, no significant differences were found in HLA-G. For HLA-E, a significant difference was detected for the genotype HLA-E*01:01:01/01:03:01 (p=0.009; pc=0.009; OR=0.51), with a protection effect. For HLA-F, significant differences were detected in the allele HLA-F*01:01:02 (p=0.0049; pc=0.0098; OR=0.60) and corresponding SNP rs2075682 (p=0.0004; pc=0.0008; OR=0.53), suggesting protection and in the genotype HLA-F*01:01:01/01:03:01 (p=0.011; pc=0.043; OR=2.00), suggesting a susceptibility effect. Three G-E-F haplotypes with significant differences were detected but occur in a very small number of individuals. The only significant differences detected in the replication studies were for HLA-E rs1059510 in the Australians and for HLA-F rs1736924 in the European-descent cohorts. Conclusion Our results reveal suggestive AS protective and susceptibility effects from both HLA-E and HLA - F loci, however with population differences. To our knowledge, this is the first study showing association of HLA-F with AS.

Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic immune-mediated inflammatory disease that affects predominantly females during childbearing age (Lateef and Petri Best Pract Res Clin Rheumatol 27(3):435–447, 2013). Fertility in SLE patients is considered to be normal (Clowse et al. Arthritis Care Res (Hoboken) 64(5):668–674, 2012; Ekblom-Kullberg et al. Scand J Rheumatol 38:375–380, 2009) but several known factors may negatively influence fertility. Immune mechanisms are also thought to be an important cause of premature ovarian senescence, characterized by reduced ovarian reserve markers such as anti-Müllerian hormone (AMH) (Oktem et al. Obstet Gynecol Surv 70(3):196–210, 2015; Bermas and Sammaritano Fertil Res Pract 1:13, 2015; Østensen Int J Clin Rheumtol 8(1):27–37, 2013; Ulug et al. Am J Reprod Immunol 72(1):85–88, 2014; Lawrenz et al. Lupus 20(11):1193–1197, 2011). We evaluated the ovarian reserve of women in reproductive age with SLE, by measuring AMH levels and we compared it to that of non-SLE women. We also analyzed the association of SLE disease characteristics with AMH levels. AMH levels were decreased in this population of SLE women, accounting for a high proportion of women with criteria for low ovarian reserve. Age and SLE damage were associated with abnormally lower AMH levels in our SLE patients. In this way, SLE may have a negative influence on the ovarian reserve.

A10.5 Comparative Effectiveness of Biological Therapies in Rheumatoid Arthritis is Influenced by Response Measures and Disease Activity State

Background and Objectives Several biological therapies have become available in the last years in the management of rheumatoid arthritis (RA). Two of the most common drug classes include anti-tumour necrosis factor (TNF) and anti-interleukin-6 (IL-6) agents, which target central cytokines in the disease pathway. We have previously shown that the proportion of patients achieving remission was higher in the tocilizumab group, an anti-IL-6 agent, compared to anti-TNF therapies, but the magnitude of the effect was associated with the disease activity measure used, namely DAS28, CDAI or SDAI. The aim of this study is to assess whether this difference remains significant in other RA disease activity states. Materials and Methods We included biologic-naïve RA patients registered in the Rheumatic Diseases Portuguese Register, Reuma.pt, who have started therapy with anti-TNF (adalimumab, infliximab, golimumab) and anti-IL-6 (tocilizumab) monoclonal antibodies after 1st January 2008. Our primary outcome was the proportion of patients in each disease activity state (remission, low, moderate, high) at 6 months, applying DAS28, CDAI and SDAI. Univariate and multivariate logistic regressions were performed to compare the groups. Results 220 RA patients were enrolled, 180 treated with anti-TNF monoclonal antibodies and 40 treated with tocilizumab. Both groups had similar baseline characteristics but tocilizumab-treated patients had significantly higher SJC, DAS28, SDAI and CDAI as well as shorter disease duration. At 6 months, a significantly higher proportion of patients in the tocilizumab group had reached the DAS28 (n = 21, OR 0.16, p < 0.0001, 95%CI 0.06–0.38) and SDAI (n = 9, OR 0.29, p = 0.03, 95%CI 0.09–0.91) remission thresholds, but no significant difference was seen for CDAI (n = 8, OR 0.41, p = 0.12), in the adjusted logistic multivariate model. Moreover, the proportion of patients with moderate (n = 85, OR 3.49, p = 0.006, 95%CI 1.44–8.43) and high disease activity (n = 30, OR 6.13, p = 0.028, 95%CI 1.32–30.89) was higher in the anti-TNF group only according to DAS28. No differences were seen in the low disease activity class. Conclusions Globally, tocilizumab-treated patients had better disease activity outcomes, but the magnitude of the effect was dependent on the disease activity measure used, confirming our previous results and underlining the pronounced reduction of inflammatory markers such as ESR and CRP, translated by lower DAS28 and SDAI, respectively. Furthermore, this effect was also related to the disease activity state considered. This may be explained by the fact that these different indexes distinctly weigh the different components and/or do not classify the same patients in the same disease activity state.

Predictors of response and anti-TNF drugs comparative efficacy

Methods Analyses were performed upon Reuma.pt. Response to therapy was defined according to EULAR criteria. Probability of response was modeled. Multivariate logistic regression model predicting response over 1 year with all variables and automated stepwise selection models were built. In addition, we performed analyses using propensity score 1:1:1 nearest neighbor matching algorithms to obtain comparable groups regarding baseline features.

Predictors of chronicity and the discriminative value of the new ACR/EULAR rheumatoid arthritis classification criteria in an untreated polyarthritis cohort with less than 6 weeks of disease duration

Thirty-seven patients were included. During the follow up most of the patients evolved into RA (57%). The median age of the patients of the RA-group was similar to the median age of the non-RA group (median (IQR) 47 (31-58.5) vs 43 (34-69) years, p=0.74). At the initial visit the DAS 28 in the RA group was significantly higher than in the non-RA group, as well as the VAS and the number of swollen joints. The ESR values did not differ significantly between RA and non-RA groups (Table 1).

Mycophenolate mofetil use in refractory juvenile systemic lupus erythematosus

The optimal immunosuppressive treatment in patients with systemic lupus erythematosus (SLE) remains controversial [1]. Mycophenolate mofetil (MMF) has proved to be an efficacious and safe therapy in adult lupus nephritis [2]. Recently, this drug has been suggested as a possible new alternative treatment for juvenile-SLE, especially in cases of lupus nephritis refractory to treatment with corticosteroids, cyclophosphamide azathioprine, methotrexate and/or cyclosporine [3-4]. In this review we describe our experience with six children diagnosed with SLE and treated with MMF.