VEXAS syndrome: A 2-case series report.

VEXAS syndrome is a rare entity secondary to UBA1 gene mutations, located on the X chromosome. This mutation generates, as a consequence, a characteristic vacuolation on haematopoietic stem-cells. It is characterized by multiple autoinflammatory and haematologic manifestations, which respond and end up being dependent on corticosteroid treatment. In this publication we present a 2-case series diagnosed at our hospital and make a brief literature review of the published evidence so far.

Real-world effectiveness and persistence of secukinumab in the treatment of patients with psoriatic arthritis.

Introduction: Psoriatic arthritis (PsA) is a complex and heterogeneous inflammatory disease. Secukinumab, a biologic disease-modifying antirheumatic drug (bDMARD), has extensive clinical evidence of efficacy and safety in the treatment of PsA but data in clinical practice are still limited. This study aims to provide real-world evidence on secukinumab use, effectiveness, and persistence in PsA. Methods: A retrospective, multicenter study was conducted on patients diagnosed with PsA and treated with secukinumab up to June 2021 at 12 centers in the Valencian Community (Spain). Data on DAS28-CRP, DAPSA, Tender and Swollen Joint Counts (TJC, SJC), enthesitis, dactylitis, skin and nail involvement, pain, patient and physician global assessment (ptGA, phGA) using 100-mm visual analog scale (VAS), and persistence for up to 24 months were collected. Results: A total of 178 patients were included (49% men; mean [standard deviation, SD] age: 51.4 [10.5] years; 39% obese). Secukinumab was used as a first-, second-, or ≥ third-line bDMARD in 37, 21, and 42% of patients, respectively. The percentage of patients achieving at least low disease activity (DAS28-CRP ≤ 3.2) increased from 25% at baseline to 66% at month 6 (M6) and was maintained (75%) up to M24. Mean (SD) DAS28-CRP baseline values (3.9 [1.2]) decreased to 2.9 (1.1) (p < 0.001) at M6 and remained low through M24 (2.6 [1.1]) (p < 0.001). Secukinumab also improved peripheral arthritis increasing the percentage of patients with TJC = 0 (20% baseline; 57% M24) and SJC = 0 (37% baseline; 80% M24). Treatment reduced the percentage of patients with enthesitis (25% baseline; 6% M24), dactylitis (20% baseline; 4% M24), and skin (70% baseline; 17% M24), and nail (32% baseline; 2% M24) involvement. Additionally, we observed improvements in the mean pain VAS (-26.4 mm M24), ptGA (-26.2 mm M24), and phGA (-24.8 mm M24). Secukinumab showed an overall 24-month persistence rate of 67% (95% confidence interval [CI]: 60-74%). Patients receiving first-line secukinumab showed the highest 24-month persistence rate (83, 95% CI: 73-92; p = 0.024). Conclusion: Secukinumab showed long-term effectiveness across the six key PsA domains thus reducing disease activity and pain, which are major treatment goals. This was accompanied by high persistence rates, especially in bDMARD naive patients.

The complex HLA-E-nonapeptide in Behçet disease.

Introduction: The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. Objective: This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. Methods: We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Discussion: Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Evaluation of the sexual sphere in patients with psoriatic arthritis.

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory disorder that primarily affects the joints and entheses. In addition, it is associated with depressive syndrome (DS), cardiovascular disease, hypertension (HT), diabetes mellitus (DM), obesity and psoriasis (Pso). There are few studies aimed to analyze the association of the involvement of the musculoskeletal system with sexual function (SF). METHODS: A cross-sectional observational study was proposed in patients diagnosed with PsA, to whom self-administered validated questionnaires were applied to determine alterations in SF: MGH-SFQ and CSFQ-14, which assess the 4 domains of sexual function; Qualisex and DLQI designed for joint and dermatological pathology respectively, which explore sexual aspects. The objective was to describe the existence of altered sexual function in patients with PsA; analyze the association between sociodemographic characteristics, comorbidities (Pso, DS, cardiovascular risk factors) and the treatments of patients on SF; and describe differences of SF according to gender. RESULTS: 72 patients were evaluated. It was observed that the variables of patients with PsA that were associated with lower scores in SF were gender and age in the CSFQ-14 and MGH-SFQ; annual incomes, treatment with NSAIDs, DL and depression were associated with worse results in some domains of the sexual sphere. CONCLUSIONS: Patients with PsA had impaired SF, especially women, elder patiens, those with low annual incomes, DL and emotional disorders. Anti-inflammatory treatments were associated with better SF. Globally, the chronic disease and the psychological burden behaved as factors associated with sexual dysfunction.

Treatment With Tofacitinib in Refractory Psoriatic Arthritis: A National Multicenter Study of the First 87 Patients in Clinical Practice.

OBJECTIVE: Tofacitinib (TOF) is the first Janus kinase (JAK) inhibitor approved for psoriatic arthritis (PsA). It has shown efficacy in patients refractory to anti-tumor necrosis factor-α in randomized controlled trials (RCTs). Our aim was to assess efficacy and safety of TOF in clinical practice. METHODS: This was an observational, open-label multicenter study of PsA patients treated with TOF due to inefficacy or adverse events of previous therapies. Outcome variables were efficacy, corticosteroid dose-sparing effect, retention rate, and safety. A comparative study of clinical features between our cohort of patients and those from the OPAL Beyond trial was performed. RESULTS: There were 87 patients (28 women/59 men), with a mean age of 52.8 ± 11.4 years. All patients were refractory to biologic disease-modifying antirheumatic drugs (DMARDs) and/or to conventional synthetic DMARDs plus apremilast. TOF was started at 5 mg twice daily after a mean follow-up of 12.3 ± 9.3 years from PsA diagnosis. At first month, Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) decreased from median 4.8 (IQR 4.1-5.4) to 3.7 (IQR 2.8-4.7, P < 0.01), Disease Activity Index for Psoriatic Arthritis from median 28 (IQR 18.4-34.1) to 15.5 (IQR 10.1-25.7, P < 0.01), and C-reactive protein from median 1.9 (IQR 0.3-5.0) to 0.5 (IQR 0.1-2.2) mg/dL (P < 0.01). Also, TOF led to a significant reduction in prednisone dose. Mild adverse effects were reported in 21 patients (24.13%), mainly gastrointestinal symptoms. TOF retention rate at Month 6 was 77% (95% CI 65.2-86.3). Patients in clinical practice were older with longer disease duration and received biologic agents more commonly than those in the OPAL Beyond trial. CONCLUSION: Data from clinical practice confirm that TOF seems to be effective, rapid, and relatively safe in refractory PsA despite clinical differences with patients in RCTs.

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept.

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

Behçet's disease and genetic interactions between HLA-B*51 and variants in genes of autoinflammatory syndromes.

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p.Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P = 0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P = 0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.

Validation study of genetic biomarkers of response to TNF inhibitors in rheumatoid arthritis.

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.

Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A Next Generation Sequencing approach.

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis.

INTRODUCTION: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. METHODS: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. RESULTS: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. CONCLUSION: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.

Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: a EUSTAR case-control study.

OBJECTIVE: To estimate the prevalence, determine the subgroups at risk, and the outcomes of patients with systemic sclerosis (SSc) and gastric antral vascular ectasia (GAVE). METHODS: We queried the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) network for the recruitment of patients with SSc-GAVE. Each case was matched for cutaneous subset and disease duration with 2 controls with SSc recruited from the same center, evaluated at the time the index case made the diagnosis of GAVE. SSc characteristics were recorded at the time GAVE occurred and the last observation was collected to define the outcomes. RESULTS: Forty-nine patients with SSc and GAVE were included (24 with diffuse cutaneous SSc) and compared to 93 controls with SSc. The prevalence of GAVE was estimated at about 1% of patients with SSc. By multivariate analysis, patients with SSc-GAVE more frequently exhibited a diminished (< 75%) DLCO value (OR 12.8; 95% CI 1.9-82.8) despite less frequent pulmonary fibrosis (OR 0.2; 95% CI 0.1-0.6). GAVE was also associated with the presence of anti-RNA-polymerase III antibodies (OR 4.6; 95% CI 1.2-21.1). SSc-GAVE was associated with anemia (82%) requiring blood transfusion (45%). Therapeutic endoscopic procedures were performed in 45% of patients with GAVE. After a median followup of 30 months (range 1-113 months), survival was similar in patients with SSc-GAVE compared to controls, but a higher number of scleroderma renal crisis cases occurred (12% vs 2%; p = 0.01). CONCLUSION: GAVE is rare and associated with a vascular phenotype, including anti-RNA-polymerase III antibodies, and a high risk of renal crisis. Anemia, usually requiring blood transfusions, is a common complication.

[Popliteal aneurysm simulating a Baker's cyst in a patient with rheumatoid arthritis: a case presentation]. / Aneurisma poplíteo que simula quiste de Baker en un paciente con artritis reumatoide: a propósito de un caso.

Baker's cyst is the most common mass located in the back side of the knee, the popliteal fossa, in patients with degenerative and inflamatory disease of the knee. Popliteal mass may also be due to proliferation of adipose tissue, popliteal artery aneurysm, thrombotic vein, or tumor. These lesions are rarer and may easily be misinterpreted as cysts. We show a man with rheumatoid arthritis who is presenting a palpable mass in the popliteal fossa. Ultrasonography examination demostrated a popliteal artery aneurysms.

Is there a role for TNFα antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique.

OBJECTIVES: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. METHODS: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. RESULTS: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-α inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNF-α antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-α antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-α antagonists for arthritis associated with SSc. CONCLUSIONS: Most of the experts do not recommend the routine use of TNF-α antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-α antagonists are needed before general recommendations can be given.