Long-term clinical outcomes of certolizumab pegol treatment in non-radiographic axial spondyloarthritis stratified by baseline MRI and CRP status.

OBJECTIVE: There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients' baseline MRI and CRP status. METHODS: C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP-, MRI-/CRP+ and MRI+/CRP+). RESULTS: Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI-/CRP+ and MRI+/CRP- patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI-/CRP+: 52.2%, MRI+/CRP-: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI-/CRP+: 62.5%, MRI+/CRP-: 65.2%). CONCLUSIONS: In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI-/CRP+ and MRI+/CRP- subgroups.

Exploring complement biomarkers in suspected axial spondyloarthritis.

OBJECTIVES: To investigate lectin pathway proteins (LPPs) as biomarkers for axial spondyloarthritis (axSpA) in a cross-sectional cohort with a suspicion of axSpA, comprising newly diagnosed axSpA and chronic low back pain (cLBP) individuals. METHODS: Serum samples from 515 participants within the OptiRef cohort, including 151 axSpA patients and 364 cLBP patients, were measured using immunoassays for LPPs (mannan-binding lectin (MBL), collectin liver-1 (CL-L1), M-ficolin, H-ficolin and L-ficolin, MBL-associated serine proteases (MASP)-1, -2 and -3, MBL-associated proteins (MAp19 and MAp44) and the complement activation product C3dg). RESULTS: Serum levels of L-ficolin, MASP-2 and C3dg were elevated in axSpA patients, whereas levels of MASP-3 and CL-L1 were decreased, and this remained significant for C3dg and MASP-3 after adjustment for C reactive protein (CRP). A univariate regression analysis showed serum levels of CL-L1, MASP-2, MASP-3 and C3dg to predict the diagnosis of axSpA, and MASP-3 and C3dg remained significant in a multivariate logistic regression analysis. Assessment of the diagnostic potential showed that a combination of human leukocyte antigen B27 (HLA-B27) and measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, however, with a concomitant loss of sensitivity. CONCLUSIONS: Serum levels of complement activation, that is, C3dg, and MASP-3 differed significantly between axSpA and cLBP patients after adjustment for CRP. Although combining HLA-B27 with measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, this seems unjustified due to the concomitant loss of sensitivity. However, both C3dg and MASP-3 were associated with axSpA diagnosis in multivariate logistic regression, suggesting an involvement of complement in the inflammatory processes and possibly pathogenesis in axSpA.

Participación laboral en espondiloartritis axial radiográfica y no radiográfica / Labor participation in radiographic and non-radiographic axial spondyloarthritis

Introducción: las limitaciones laborales son un punto importante a considerar en el tratamiento de la espondiloartritis axial (EspAax) dado que esta enfermedad afecta a las personas en la etapa más productiva de la vida. Objetivos: describir la situación laboral en pacientes con EspAax de Argentina, incluyendo la espondilitis anquilosante (EA) y la espondiloartritis axial no radiográfica (EspAax-nr), y evaluar los factores asociados a la pérdida de productividad laboral (PPL) en esta cohorte nacional y los factores asociados a estar empleado. Materiales y métodos: en este estudio transversal y multicéntrico se incluyeron pacientes con diagnóstico de EA y EspAax-nr según los criterios de clasificación de la Assessment of SpondyloArthritis international Society (ASAS 2009) y en edad laboral (≤65 años). Los objetivos principales fueron evaluar la situación laboral, el ausentismo y el presentismo, valorados por el cuestionario Work Productivity and Activity Impairment Spondyloarthritis (WPAI-SpA). Se utilizó el coeficiente de Spearman para evaluar la correlación entre las medidas de la enfermedad y la PPL. Se realizó un análisis bivariado y multivariado para evaluar los factores asociados a estar empleado. Resultados: se incluyeron 129 pacientes con EspAax, 95 (73,6 %) con EA y 34 (26,4%) con EspAax-nr. La mediana (p25-75) de edad fue de 45 (35-55) años. La duración mediana de la enfermedad fue de 62 (24-123) meses y el retraso en el diagnóstico fue de 24 (6-72) meses. Sesenta (46,5%) pacientes estaban empleados. La mediana (p25-75) de presentismo de los pacientes con EA fue del 29,6% (0-57) y del 30% (20-40) para los pacientes con EspAax-nr (p=0,02). Asimismo, la mediana (p25-75) de PPL fue del 30% en ambos grupos de pacientes. Se encontró una correlación positiva entre la PPL y las siguientes variables: ASDAS (Rho:0.60), BASDAI (Rho:0.50), BASFI (Rho:0.60), ASQoL (Rho:0.60) y ASAS health index (Rho:0.54). En el análisis bivariado, los factores asociados al desempleo fueron el diagnóstico de EA, la edad avanzada, la mayor duración de la enfermedad, las comorbilidades (hipertensión y diabetes), el menor número de años de educación, la peor calidad de vida y la menor capacidad funcional. En el análisis multivariado, una mejor función física (evaluada por BASFI) se asoció de forma independiente a estar empleado. Conclusiones: este estudio demostró que la PPL en esta cohorte nacional fue del 30% en la EspAax. Se asoció con la actividad de la enfermedad, el estado de salud, la calidad de vida y la capacidad funcional. Una mejor función física se relacionó en forma independiente con una mayor probabilidad de mantener a los pacientes con EspAax empleados.

Introduction: work disability is an important outcome in the treatment of spondyloarthritis (SpA) since this disease affects people in the most productive stage of life. Objectives: to investigate working status in patients with axial spondyloarthritis (axSpA) from Argentina, including ankylosing spondylitis (AS) and nonradiographic axial SpA (nr-axSpA), and to evaluate factors associated with work productivity loss (WPL) in this national cohort and factors associated with being employed. Materials and methods: patients with a diagnosis of AS and nr-axSpA according to Assessment of SpondyloArthritis international Society (ASAS 2009) classification criteria and in working age (≤65 years) were included in this multicentric cross-sectional study. Outcomes of interest were employment status, absenteeism and presenteeism, assessed by the Work Productivity and Activity Impairment Spondyloarthritis (WPAI-SpA) questionnaire. Spearman's coefficient was used to assess the correlation between disease measures and WPL. Bivariate and multivariate analysis were performed in order to evaluate factors associated with being employed. Results: 129 patients with axSpA were included, 95 (73.6%) with AS and 34 (26.4%) with nr-axSpA. Median (p25-75) age of 45 (35-55) years. Median (p25-75) disease duration was 62 (24-123) months and diagnosis delay was 24 (6-72) months. 60 (46.5%) of the patients were employed. Median (p25-75) presenteeism of AS patients was 29.6% (0-57) and 30% (20-40) for patients with EspAax-nr (p=0.02). Median (p25-75) WPL was 30% in both groups of patients. A positive correlation was found between WPL and the following variables: ASDAS (Rho:0.60), BASDAI (Rho:0.50), BASFI (Rho:0.60), ASQoL (Rho:0.60) and ASAS health index (Rho:0.54). In the bivariate analysis, the factors associated with unemployment were AS diagnosis, older age, longer disease duration, comorbidities (hypertension and diabetes), fewer years of education, worse quality of life and lower functional capacity. In the multivariate analysis, better physical function (assessed by BASFI) was independently associated with being employed. Conclusions: this study showed that WPL in this national cohort was 30% in axSpA. It was associated with disease activity, health status, quality of life and functional capacity. Better physical function was independently associated with a higher likelihood of keeping patients with axSpA employed.

Targeting the Interleukin-23/Interleukin-17 Inflammatory Pathway: Successes and Failures in the Treatment of Axial Spondyloarthritis.

The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.

Joint anatomy in axial spondyloarthritis: strong associations between sacroiliac joint form variation and symptomatic disease.

OBJECTIVES: The aim of this investigation was to determine the prevalence of variant SI joint forms in symptomatic patients with mechanical joint disease (MJD) and axial SpA (axSpA) compared with control patients. METHOD: A total of 973 patients were included in this cross-sectional study (95 axSpA; 61 MJD; 817 controls); clinical diagnosis, age and gender were noted. An established scoring system was used to classify joint forms on CT scans of the pelvis. Frequencies of joint forms were compared between groups (axSpA; MJD; controls). RESULTS: Patients with MJD exhibited the highest proportion of atypical joints (80.3% in MJD vs 44.1% in axSpA and 37.5% in controls; P < 0.001). Overall, females had a significantly higher proportion of atypical joints than men (65.0 vs 17.8%; P < 0.001); proportions of atypical joints were significantly higher in males with symptomatic joint disease than in male controls: 32.2% in axSpA, 55.0% in MJD and 13.9% in controls; P ≤ 0.001. Two specific joint forms were significantly more prevalent in symptomatic patients than in controls: the iliosacral complex (16.2 vs 4.2%; P < 0.001) and the crescent-shaped ilium (9.1 vs 2.8%; P < 0.05). CONCLUSIONS: Our data demonstrate a strong association between atypical joint forms and symptomatic joint disease.

Preliminary Report on Interleukin-22, GM-CSF, and IL-17F in the Pathogenesis of Acute Anterior Uveitis.

Purpose:Anterior uveitis is the most common anatomic subset of uveitis. We developed a novel multi-parametric flow cytometry panel to identify immune dysregulation signatures in HLA B27-associated acute anterior uveitis (AAU) and axial spondyloarthritis (AxSpA).Methods: We used fluorescence activated cell sorting to characterize T cell cytokine expression in stimulated T cell subsets from patients with AAU (n = 4) compared to healthy controls (n = 14) or subjects with AxSpA (n = 6).Results: Positive findings among subjects with AAU included a statistically significant increase in stimulated granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, and IL-22 synthesized by CD8 cells, a trend for stimulated ILC (innate lymphoid cells)-3 cells to synthesize more IL-22 (p = .07), and stimulated MAIT (mucosa associated innate lymphoid cells)-like cells that express the T cell receptor V alpha 7.2 to express IL-17A, IL-17F, and IL-22 in a greater percentage of cells relative to controls. IL-17F, GM- CSF, and IL-22 represent potentially novel targets in AAU.Conclusion: Our report is arguably the first to implicate IL-17F or ILC-3 and MAIT cells in the pathogenesis of AAU.Abbreviations AAU: acute anterior uveitis; AxSpA: axial spondyloarthritis; BASDAI: Bath ankylosing spondylitis disease activity index; CCR: chemokine receptor; DMSO: dimethylsulfoxide; EULAR:European League Against Rheumatism; FACS: fluorescence activated cell sorter; FBS: fetal bovine serum; FSC: orward light scatter; GM-CSF: granulocyte-macrophage colony stimulating factor; HC: healthy control; ILC: innate lymphoid cell; KIR: killer immunoglobulin receptor; MAIT: mucosal associated immune T cell; ND: not detected; NK: natural killer cell; OHSU-Oregon Health & Science University; PBMC: peripheral blood mononuclear cell; SSC: side light scatter; TCR: T cell receptor.