Abatacept reduces synovial regulatory T-cell expression in psoriatic arthritis patients

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Abatacept reduces synovial regulatory T-cell expression in psoriatic arthritis patients
Key Take-Away: 

Abatacept 10 mg/kg of body weight might be an effective treatment option for joint disease in patients with Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that exerts harmful effects on peripheral joints, enthesis and axial sites along with skin and nails. It is associated with comorbidities along with characteristic extra-articular features, such as uveitis and inflammatory bowel disease.

ABSTRACT: 
Background: 

Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that exerts harmful effects on peripheral joints, enthesis and axial sites along with skin and nails. It is associated with comorbidities along with characteristic extra-articular features, such as uveitis and inflammatory bowel disease.

It is believed that activation of T cells and production of inflammatory cytokines like tumor necrosis factors (TNF), interferon (IFN)-γ, interleuin (IL)-17 and IL-22 play a significant role in the pathogenesis of psoriatic plaques. The key players of PsA are CD8+ T cells that recognize antigen presented by human leukocyte antigen (HLA) class 1 molecules. These CD8+ T cells are abundant in synovial fluid and enthesal sites and  CD4+ T cells in the synovial tissue. Regulatory T cells (Tregs) are a subset of CD4+ CD25 high T lymphocytes that suppress the activity of T cells generating the auto immune response. These cells require forkhead box transcription factor (FOXP3) for their suppressive function. Tregs derived from thymus work by inducing a contact-dependent mechanism including cytotoxic T-lymphocyte antigen 4 (CTLA-4). Earrlier studies have reported that any dysfunction or impairment in Tregs could lead to increase in psoriatic activity.

There occurs a significant heterogeneity in PsA, and this offers a great challenge to select an appropriate treatment for an individual. Patients that do not respond well to disease modifying anti-rheumatic drugs (DMARDs) are prescribed with Apremilast or other biologic agents. This can be due to immunogenicity, poor tolerability and/or adverse events. There is a need to develop future therapies targeting other key cytokines, immunologic pathways and T cells, key mediators of PsA.

Abatacept is a soluble, fully human fusion protein consisting of the extracellular domain of CLTA-4 linked to human IgG1. It works by selectively binding to CD80/86 on antigen-presenting cells and blocks the costimulatory interaction with CD28 on T-cells. This, in turn, inhibits optimal T-cell activation and decreases the production of inflammatory cytokines such as TNFα, INFγ, IL-2, and IL-6. It is approved in rheumatoid arthritis (RA) and juvenile idiopathic arthritis, but there are no studies discussing its effect on on the skin and synovial tissues.

Rationale behind the research

  • There is a lack of data demonstrating the role of Abatacept in the skin and synovial fluid, so this study was conducted to evaluate the efficacy of this drug in PsA.

Objective

To evaluate the changes occurring in immunohistochemical markers of synovial and skin inflammation, including FOXP3 expression, after introducing Abatacept treatment in PsA.

Methods: 

 

  • Outcomes measures
  • Assessment of clinical outcomes and magnetic resonance imaging (MRI) changes over time
  • Evaluation of the impact of a short period of Abatacept 3 mg/kg of body weight treatment compared to placebo (PBO)
  • Investigation of cell markers of synovial inflammation, if, correlate with disease activity measures and MRI synovitis scores.
  •   Time Points:  Baseline, 2 and 6 months
Results: 

Figure 1. Flow of patients administered with different doses of abatacept (3 mg/kg and 10 mg/kg).

 

Study outcomes

Baseline: There were no statistically significant differences observed at baseline

Outcomes:

  • There was a reduction in synovitis (P=0.016) and vascularity (P=0.039) macroscopic scores consistent with decrease in total MRI score (P=0.016) (Fig 1)
  • There was a decrease in the immunohistological expression of FOXP3+ cells (P=0.027), precisely the expression of CD4+FOXP3+ regulatory T cells (Tregs) (P = 0.008) in the synovium over 6 months on administration with Abatacept
  • There was no important clinical or immunohistological change observed in any of the skin measures

Figure 2: Reduction in synovitis and vascularity scores from baseline to 2 and 6 months

Conclusion: 

The results of this study indicated that the treatment with Abatacept 10 mg/kg of body weight can significantly improve joint-related clinical outcomes but not skin-related outcomes in biologic DMARD-naïve PsA patients. It might be an effective treatment option in patients with PsA. Different patterns of the efficacy of Abatacept were observed in joints and skin. There was a reduction in FOXP3+ T-cell expression in the synovium but not in psoriatic lesions. This indicates that there were abnormalities in Treg function in PsA with differential suppressive capacity in the synovium compared to the skin.

Clinical effectiveness of Abatacept was reported in active RA patients, including those with an insufficent response to MTX or TNF inhibitors in early type 1 diabetes mellitus, and more recently, in primary Sjögren’s syndrome. Whilst there was no major clinical response to treatment with abatacept 10 mg/kg of body weight in a phase-2 open-label 24-week trial in ankylosing spondylitis, Mease et al. reported efficacy of abatacept on joint symptoms in PsA. It was identified that a differential dosage effect of abatacept with the dose of 10 mg/kg of body weight having more therapeutic effect on arthritis than the 3 mg/kg regimen. In line with this study, the present study reported significant improvement in joint-related outcomes with the dose of 3 mg/kg of body weight, whereas the 10 mg/kg regimen led to notable improvements in most joint-related measures at 6 months. Similarly, MRI synovitis scores improved considerably over a time only after administering the dose of 10 mg/kg of body weight. Abatacept was shown to have some clinical benefit in the treatment of psoriasis.

In conclusion, this was the first study to demonstrate both synovial and psoriatic skin immunopathological changes following Abatacept treatment in PsA. There is a need of complete studies on both the distribution and function of Tregs, together with their complex interactions with the local inflammatory milieu present in the psoriatic skin lesion and inflamed synovium in PsA in future.

Szentpetery, A., Heffernan, E., Gogarty, M. et al. Arthritis Res Ther (2017) 19: 158
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