Inhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases

Treatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFN gamma were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS

Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study

Objectives: To describe the evolution of radiographic abnormalities of the spine in patients with ankylosing spondylitis (AS). Methods: Patients with AS were followed prospectively with 2 yearly radiographs for 12 years. The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) was scored by two readers (R1 and R2). New syndesmophytes at uninvolved vertebral corners were computed. Radiographic progression was investigated using generalised estimating equations. Results: 809 radiographs (presenting 520 at 2 yearly intervals) from 186 patients (70% men, mean age 43 (SD 12) years, mean 20 (SD 12) years since symptom onset and 83% HLA-B27 positive) were included. Mean mSASSS at baseline was 11.6 (16.2). While the course of progression in individual patients was highly variable, and still occurred in patients with decades of symptom duration, mean 2 year progression was 2.0 (3.5) mSASSS units. Over the entire follow-up, at least one new syndesmophyte was found in 55% (R1) and 63% (R2) of patients (38% (R1) and 39% (R2) of all intervals). In 24% of patients (39% of intervals), there was no progression. A progression >= 5 mSASSS units occurred in 22% of patients (or in 12% of intervals). At the group level, a linear time course model fitted the data best, with a constant rate over the entire 12 year interval of 0.98 mSASSS units/year. Radiographic progression occurred significantly faster in men, in HLA-B27 positive patients and in patients with a baseline mSASSS >= 10. Conclusions: Long term radiographic progression in AS is highly variable in the individual patient, more severe in HLA-B27 positive men and still occurs after decades of disease. At the group level, however, progression in AS follows an approximately linear course

Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort

Objectives: To analyse the long-term relationship between disease activity and radiographic damage in the spine in patients with ankylosing spondylitis (AS). Methods: Patients from the Outcome in AS International Study (OASIS) were followed up for 12 years, with 2-yearly clinical and radiographic assessments. Two readers independently scored the X-rays according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Disease activity measures include the Bath AS Disease Activity Index (BASDAI), AS Disease Activity Index (ASDAS)-C-reactive protein (CRP), CRP, erythrocyte sedimentation rate (ESR), patient's global assessment and spinal pain. The relationship between disease activity measures and radiographic damage was investigated using longitudinal, autoregressive models with 2-year time lags. Results: 184 patients were included (70% males, 83% HLA-B27 positive, mean (SD) age 43 (12) years, 20 (12) years symptom duration). Disease activity measures were significantly longitudinally associated with radiographic progression. Neither medication nor the presence of extra-articular manifestations confounded this relationship. The models with ASDAS as disease activity measure fitted the data better than models with BASDAI, CRP or BASDAI+CRP. An increase of one ASDAS unit led to an increase of 0.72 mSASSS units/2 years. A 'very high disease activity state' (ie, ASDAS >3.5) compared with 'inactive disease' (ie, ASDAS = 18 years symptom duration (0.84 vs 0.16 mSASSS units per ASDAS unit). Conclusions: This is the first study showing that disease activity contributes longitudinally to radiographic progression in the spine in AS. This effect is more pronounced in men and in the earlier phases of the disease

The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study

OBJECTIVE: To assess the incidence and risks of common extra-articular manifestations (EAMs), that is, acute anterior uveitis (AAU), psoriasis and inflammatory bowel disease (IBD), in patients with ankylosing spondylitis (AS) compared with population-based controls. METHODS: All incident patients with AS (n=4101) from the UK Clinical Practice Research Datalink (1987-2012) were matched with up to seven control subjects without AS by year of birth, sex and practice (n=28 591). Incidence rates, cumulative incidence rates and adjusted (adj) HRs for the development of EAMs were calculated, with time-dependent adjustments for age, sex, comorbidity and medication use. RESULTS: At diagnosis of AS, the proportion of patients with an EAM was 11.4% for AAU, 4.4% for psoriasis and 3.7% for IBD. Incidence rates of EAMs were 8.9/1000 person-years for AAU, 3.4/1000 person-years for psoriasis and 2.4 /1000 person-years for IBD in AS. The 20-year cumulative incidence was 24.5%, 10.1% and 7.5%, respectively. Risks of EAMs were 1.5-fold to 16-fold increased versus controls, with an adj HR of 15.5 (95% CI 11.6 to 20.7) for AAU, adj HR of 1.5 (95% CI 1.1 to 1.9) for psoriasis and adj HR of 3.3 (95% CI 2.3 to 4.8) for IBD. For psoriasis and IBD, the highest risks were found in the 1st years after diagnosis, while developing AAU continued to be increased also 10 years after diagnosis of AS. CONCLUSIONS: The risk of, in particular AAU, but also of psoriasis and IBD, is significantly increased in patients with AS compared with controls. Hazard patterns are different for each of the EAMs

Ankylosing Spondylitis Spine Score (mSASSS) or the Radiographic Ankylosing Spondylitis Spinal Score

Scoring radiographic progression in ankylosing spondylitis: should we use the modified Stok

A physically demanding job may amplify the effect of disease activity on the development of syndesmophytes in patients with ankylosing spondylitis

Pathophysiology and treatment of rheumatic disease

Gender-attributable differences in outcome of ankylosing spondylitis: long-term results from the outcome in ankylosing spondylitis international study

Pathophysiology and treatment of rheumatic disease

Do extra-articular manifestations influence outcome in ankylosing spondylitis?: a 12 year follow-up study

Pathophysiology and treatment of rheumatic disease

Characteristics associated with the presence and development of extra-articular manifestations in ankylosing spondylitis: 12-year results from OASIS

Objective. The aim of this study was to identify characteristics associated with the presence and development of extra-articular manifestations (EAMs) in a prevalence cohort of patients with AS. Methods. Twelve-year follow-up data from the Outcome in Ankylosing Spondylitis International Study (OASIS) were used. In addition, medical charts were checked for the presence of acute anterior uveitis (AAU), IBD and psoriasis. Demographic, clinical and radiographic characteristics associated with the presence of (any) EAM at baseline or new development during follow-up were identified. Results. Two hundred and sixteen patients were included [mean age 43.6 years (S.D. 12.7), 154 (71%) men, mean symptom duration 20.5 years (S.D. 11.7), mean follow-up 8.3 years (S.D. 4.3)]. At baseline, 39 (18%) patients had AAU, 15 (7%) had IBD and 9 (4%) had psoriasis. The history of AAU was univariably associated with increased age [odds ratio (OR) 1.04 (95% CI 1.01, 1.07)], longer symptom duration [OR 1.05 (95% CI 1.02, 1.08)] and more radiographic damage [OR 1.02 (95% CI 1.00, 1.04)]. The history of psoriasis was associated with greater age [OR 1.05 (95% CI 1.00, 1.11)] and lower CRP [OR 0.77 (95% CI 0.59, 1.00)]. At follow-up, 27 patients developed a new EAM. Newly developed IBD was associated with a higher time-varying AS Disease Activity Score [hazard ratio (HR) 2.80 (95% CI 1.43, 5.52)], worse physical function [HR 1.40 (95% CI 1.09, 1.80)] and worse patient global well-being [HR 1.46 (95% CI 1.10, 1.93)]. Newly developed AAU was associated with an elevated time-varying CRP [HR 1.02 (95% CI 1.01, 1.04)]. Conclusion. Development of EAMs was infrequent in this cohort, despite relatively long follow-up. In particular, markers of disease activity were associated with the development of IBD