Targeted Therapies in Axial Psoriatic Arthritis

Specific and high-quality evidence on the efficacy of the current targeted therapies for axial disease in psoriatic arthritis (axPsA) is still scarce. Indeed, almost all the cohorts investigated in clinical trials on PsA consisted of patients with peripheral arthritis, where a small number of them also had axial involvement. Only one randomized controlled trial was so far specifically designed to assess the efficacy of a biological disease-modifying antirheumatic drug (DMARD) in axPsA. For other biological and synthetic targeted DMARDs, the most specific evidence for treatment in axPsA is extrapolated from post-hoc analyses based on PsA patients with concomitant peripheral and axial manifestations. Furthermore, the current trials and post-hoc analysis on axPsA are affected by major limitations, including the lack of a widely accepted definition of axPsA and the lack of specific and validated outcome measures. Finally, poor data are available on the genetics of axPsA, although alleles differentially expressed in different patterns of axPsA might offer advantages in the prospective of personalized medicine in axPsA patients. Overall, this review suggests that there is an urgent need for more reliable evidence derived from studies specifically designed for axPsA and based on a validated definition of axPsA and on specific outcome measures

Gene expression profiling of monozygotic twins affected by psoriatic arthritis

Introduction: Psoriatic Arthritis (PsA) is a multifactorial disease, where the relative burden of genetic, epigenetic and environmental factors in clinical course and damage accrual is not yet definitively clarified. In clinical practice, there is a real need for useful candidate biomarkers in PsA diagnosis and disease progression, by exploring its underlying transcrip-tomic and epigenomic mechanisms. This work aims to profile the transcriptome in mono-zygotic (MZ) twins with psoriatic arthritis (PsA) highly concordant for clinical presentation, but discordant for the radiographic outcomes’ severity. Methods: We describe i) the clinical case of two MZ twins; ii) their comparative gene expression profiling (HTA 2.0 Affymetrix) and iii) signal pathways and pathophysiological processes in which differentially expressed genes are involved (in silico analysis by the IPA software, QIAGEN). Results: One hundred sixty-three transcripts and 36 coding genes (28 up and 8 down) were differentially expressed between twins, and in the brother with the most erosive form, the transcriptomic profiling highlights the overexpression of genes known to be involved in immunomodulatory processes and on a broad spectrum of PsA manifestations. Discussion: Twins’ clinical cases are still a gold mine in medical research: twin brothers are ideal experimental models in estimating the relative importance of genetic versus nongenetic components as determinants of complex phenotypes, non-Mendelian and multifactorial diseases as PsA

Expression analysis of HLA-E and NKG2A and NKG2C receptors points at a role for natural killer function in ankylosing spondylitis

Background. Ankylosing Spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of HLA-B27 alleles. HLA-E are non-classical MHC class I molecules that specifically interact with the natural killer receptors NKG2A (inhibitory) and NKG2C (activating), and have been recently proposed to be involved in AS pathogenesis. Objectives: To analyze the expression of HLA-E and the CD94/NKG2 pair of receptors in HLA-B27 positive AS patients and healthy controls (HC) bearing the AS-associated, B*2705 and the non-AS-associated, B*2709 allele. Methods: The level of surface expression of HLA-E molecules on CD14 positive peripheral blood mononuclear cell was evaluated in 21 HLA-B*2705 patients with AS, 12 HLA-B*2705 HC, 12 HLA-B*2709 HC and 6 HLA-B27 negative HC, using the monoclonal antibody MEM-E/08 by quantitative cytofluorimetric analysis. The percentage and density of expression of HLA-E ligands NKG2A and NKG2C were also measured on CD3-CD56+ NK cells. Results. HLA-E expression in CD14 positive cells was significantly higher in AS patients (587.0 IQR 424-830) compared to B*2705 HC (389 IQR 251.3-440.5, p=0.0007), B*2709 HC (294.5 IQR 209.5-422, p=0.0004) and HLA-B27 negative HC (380 IQR 197.3-515.0, p=0.01). A higher number of NK cells expressing NKG2A compared to NKG2C was found in all cohort analysed as well as a higher cell surface density. Conclusion: The higher surface level of HLA-E molecules in AS patients compared to HC, concurrently with a prevalent expression of NKG2A, suggests that the crosstalk between these two molecules might play a role in AS pathogenesis accounting for the previously reported association between HLA-E and AS

Biologics and Targeted Synthetic Drugs Can Induce Immune-Mediated Glomerular Disorders in Patients with Rheumatic Diseases: An Updated Systematic Literature Review

Objective: Our objective was to update the understanding of the development of paradoxical immune-mediated glomerular disorders (IGDs) in patients with rheumatic diseases treated with biologics and targeted synthetic drugs (ts-drugs). Methods: A systematic literature review was performed by searching PubMed for articles published between 1 January 2014 and 1 January 2020 reporting on the development of IGD in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or systemic lupus erythematosus (SLE) who were receiving biologics or ts-drugs. IGDs were classified on the basis of clinical, laboratory and histopathological data as (1) glomerulonephritis associated with systemic vasculitis (GNSV), (2) isolated autoimmune renal disorder (IARD) or (3) glomerulonephritis in SLE and in lupus-like syndrome (GNLS). The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment was applied to evaluate the causal relationship between IGD and specific drugs. The classification was based on a six-category scale, where the “certain” and “probable” categories were deemed clinically relevant relationships. Results: The literature search retrieved 875 articles. Of these, 16 articles reported IGD data, for a total of 25 cases. According to the WHO-UMC assessment, the strength of the causal relationship between IGDs and investigated drugs was higher for anti-tumor necrosis factor-α agents (a clinically relevant relationship was found in four of six cases), abatacept (one of two cases), tocilizumab (two cases), ustekinumab (one case) and tofacitinib (one case) than for rituximab (nine cases), belimumab (three cases) or secukinumab (one case), which showed a weak causal relationship with these paradoxical events. No cases associated with apremilast or baricitinib were found. The retrieved cases were classified as 11 GNLS, seven IARD and seven GNSV. Conclusions: Biologics and ts-drugs can cause IGDs. These events are rare, and the causative effect of a specific drug is hard to establish. When a patient is suspected of having an IGD, the drug should be discontinued, and treatment for the new-onset renal disorder should be promptly started

Current smoking predicts inadequate response to methotrexate monotherapy in rheumatoid arthritis patients naïve to DMARDs: Results from a retrospective cohort study

Identifying predictors of inadequate response to methotrexate (MTX) in rheumatoid arthritis (RA) is key to move from a "trial and error" to a "personalized medicine" treatment approach where patients less likely to adequately respond to MTX monotherapy could start combination therapy at an earlier stage. This study aimed to identify potential predictors of inadequate response to MTX in RA patients naïve to disease modifying anti-rheumatic drugs.Data from a real-life cohort of newly diagnosed RA patients starting MTX (baseline, T0) as first-line therapy were analyzed. Outcomes, assessed after 6 months (T1), were defined as failure to achieve a disease activity score 28 (DAS28) low disease activity (LDA) or a good/moderate response to MTX, according to the European League Against Rheumatism (EULAR) response criteria. Logistic regression was used to assess the associations between baseline variables and the study outcomes.Overall, 294 patients (60.5% females, median age 54.5 years) with a median disease duration of 7.9 months were recruited. At T1, 47.3% of subjects failed to achieve LDA, and 29.3% did not have any EULAR-response. In multivariate analysis, significant associations were observed between no LDA and current smoking (adjusted odds ratio [adjOR] 1.79, P = .037), female gender (adjOR 1.68, P = .048), and higher DAS28 (adjOR 1.31, P = .013); and between no EULAR-response and current smoking (adjOR: 2.04, P = .019), age (adjOR: 0.72 per 10-years increases, P = .001), and higher erythrocyte sedimentation rate (adjOR: 0.49; P = .020). By contrast, there were no associations between past smoker status and study outcomes.In summary, in our real-life cohort of disease modifying anti-rheumatic drug naïve RA patients, current smoking habit independently predicts inadequate response to MTX. This, together with other independent predictors of response to treatment identified in our study, might assist with personalized monitoring in RA patients. Further studies are required to investigate whether smoking quitting strategies enhance the therapeutic response to MTX

Toward the renal vesicle: Ultrastructural investigation of the cap mesenchyme splitting process in the developing kidney

Background: A complex sequence of morphogenetic events leads to the development of the adult mouse kidney. In the present study, we investigated the morphological events that characterize the early stages of the mesenchymal-to-epithelial transition of cap mesenchymal cells, analyzing in depth the relationship between cap mesenchymal induction and ureteric bud (UB) branching. Design and methods: Normal kidneys of newborn non-obese diabetic (NOD) mice were excised and prepared for light and electron microscopic examination. Results: Nephrogenesis was evident in the outer portion of the renal cortex of all examined samples. This process was mainly due to the interaction of two primordial derivatives, the ureteric bud and the metanephric mesenchyme. Early renal developmental stages were initially characterized by the formation of a continuous layer of condensed mesenchymal cells around the tips of the ureteric buds. These caps of mesenchymal cells affected the epithelial cells of the underlying ureteric bud, possibly inducing their growth and branching. Conclusions: The present study provides morphological evidence of the reciprocal induction between the ureteric bud and the metanephric mesenchyme showing that the ureteric buds convert mesenchyme to epithelium that in turn stimulates the growth and the branching of the ureteric bud

ERAP1 and ERAP2 Haplotypes Influence Suboptimal HLA-B*27:05-Restricted Anti-Viral CD8+ T Cell Responses Cross-Reactive to Self-Epitopes

The human leukocyte antigen (HLA)-B*27 family of alleles is strongly associated with ankylosing spondylitis (AS), a chronic inflammatory disorder affecting the axial and peripheral joints, yet some HLA-B*27 variants not associated with AS have been shown. Since no major differences in the ligandome of associated compared to not-associated alleles have emerged, a plausible hypothesis is that the quantity rather than the quality of the presented epitopes makes the difference. In addition, the Endoplasmic Reticulum AminoPeptidases (ERAPs) 1 and 2, playing a crucial role in shaping the HLA class I epitopes, act as strong AS susceptibility factors, suggesting that an altered peptidome might be responsible for the activation of pathogenic CD8+ T cells. In this context, we have previously singled out a B*27:05-restricted CD8+ T cell response against pEBNA3A (RPPIFIRRL), an EBV peptide lacking the B*27 classic binding motif. Here, we show that a specific ERAP1/2 haplotype negatively correlates with such response in B*27:05 subjects. Moreover, we prove that the B*27:05 allele successfully presents peptides with the same suboptimal N-terminal RP motif, including the self-peptide, pDYNEIN (RPPIFGDFL). Overall, this study underscores the cooperation between the HLA-B*27 and ERAP1/2 allelic variants in defining CD8+ T cell reactivity to suboptimal viral and self-B*27 peptides and prompts further investigation of the B*27:05 peptidome composition

B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure.

OBJECTIVE: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi-IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0-9) and of CD20+ B cell infiltrate (on a scale of 0-4). B cell scores were validated by digital image analysis and B cell lineage-specific transcript analysis (RNA-Seq) in the early RA (n = 91) and TNFi-IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). RESULTS: Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage-specific transcripts. B cell-rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi-IR cohort (P = 0.025). B cell-rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti-citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell-rich patients were demonstrated in both cohorts. CONCLUSION: We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell-rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Background: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. Methods: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). Findings: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). Interpretation: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. Funding: UK Medical Research Council and Versus Arthritis