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A Review of Systemic Biologics and Local Immunosuppressive Medications in Uveitis

April 2022
Journal of Ophthalmic and Vision Research 17(2)

DOI:10.18502/jovr.v17i2.10804

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CC BY 4.0

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Uveitis is one of the most common causes of vision loss and blindness worldwide. Local and/or systemic immunosuppression is often required to treat ocular inflammation in noninfectious uveitis. An understanding of safety and efficacy of these medications is required to individualize treatment to each patient to ensure compliance and achieve the best outcome. In this article, we reviewed the effectiveness of systemic biologic response modifiers and local treatments commonly used in the management of patients with noninfectious uveitis.

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Review Article

A Review of Systemic Biologics and Local

Immunosuppressive Medications in Uveitis

Neesurg S. Mehta, MD; Parisa Emami-Naeini, MD, MPH

            

ORCID:

  

  

Abstract

             

         

         

           

           

         

         

Keywords:   

       

INTRODUCTION

       

        

     

        

     

        

  

    

  

       

Correspondence to:

       

    

Email: 

   

Access this article online

Website: 

DOI: 

     

       

   

       

     

     

     

   

    

       

     

      

       

         

      

        

   

How to cite this article:       

        

   

276                        

      

     

     

      

    

Systemic Biologics

    

    

     

     

  

     

     

   

   

     

       

   

Tumor necrosis factor-a inhibitors

       

       

    

       

       

    

     

      

       

        



      

    

     

   

     

     

      

         

        

      

     

       

     

     

       

       

     

    

     

   



 ®    

   

       

      

        

    

      <  

≥     ≥  

      

      

    

      

       

     

      

     

       

      

       

      

 >       

    

      >  

∼      

      

        

     

       

    

     

      

      

     ∼  

      

     

   

      

     

       

            277

      

       





 ®     

      

        

      

       

   <     

         

      

       

       



    

     

        

      

       

       

      < 

       

      

        

       

       

      

      

       

       

      

       

      

         

        

         

     

 

     

     

      

   

     

     

       

    

     

      

      

    

     

        

         

        

         





 ®    

     

      

      

     

       

      

       

 

 ®    

     

      

      

         

      

     

     

      

       

     

     

        

    



 ®     

     

      

         

        

    

278            

      

Anti-interleukin-1

  

 ®     

   ®   

      

      

       

     

     



      

     

    

       

    

       

      

      

      

    

Anti-interleukin-2



 ®    

      

        

   

       

    

   

       

       

    

Anti-IL-interleukin-6



 ®   

    

      

     

      

       

      

     

      

    

       

        

       

     

        

        

       

       

      

      

     

    



 ®    

      

   

      

        

     

       

     

      

       

      

       

      

       

     

    

     

   

Anti-interleukin-17

 ®    

     

   

       

      

      

     

    

     

            279

      

    

    



Anti-interleukin-23

 ®    

       

    

     

     

    

     

    

   

Anti-CD20

 ®    

     

     

      

  

  

     

          

     

       

      

     

       

       

    

      

     

    



Selective costimulation modulator

 ®    

       

     

        

   

        

       

     

      

    

     

      

    

Interferons

      

     

      

      

       

      

     

     

      

    

     

    

  

Janus kinase inhibitors

 ®     

   

     

     

     

      

    

    

       

   

       

      

      

       

       

      

     

     

    

Local Treatments

    

     

280            

      

       

      

      



Periocular or intraocular corticosteroid

injections

      

      

      

     

   

 

     

       

     

®   

       

®    

  ®  

     

®      

       

      

     ®

       

       

      

     

       

    

      

       

    

   

  

   ®  

    

     

      

        

      

    

       

    

     

        

      

   

      

      

   >     

        

        

  >      

      

       

      



   



    

®     

     

       

       

     

   

       

     

        

        

     <  

      

         

       

     

         

       

       

   

  ®   

    

       

       

    

     

            281

      

     

     

       

       

       

       

      

       

 

 

     

      

      

      

   

   

    

      

      

       

        

     

     

      

        

       

       

 𝑇 𝑀    

       

    ®

        

  

Non-steroidal injections



     

       

    

    

     

     

        

      

   

   

   

     

       





       

     

    

       

    

      

   

     

     

      

       

      

       

       

        

      

      

         

      

 >      

      

 

     

      

    

     

     

   

  

    

    

      

      

      

   

282            

      



    

      

     

    

  

Novel Technologies: Electroporation

    

      

     

      

       

       

       

       

     

        

     

     

      

≥        

    ≥   

  ≥       

        

        

      

      

       

      

Common Practice and Future Horizons

    

       

      

     

     

     

     

        

      < 

      

         

      

        

        

     

       

      

      

 

Financial Support and Sponsorship



Conﬂicts of Interest

        



REFERENCES

           

          

     

          

    



        

       

       

      

    

         

         

      

    

 

         

        

       

     

      

    

      



         

        

       

      

    

        

    

       

     



        

     

    

            283

      

          

       

      



          

        

   

          

         

    

       

 

          

       

       

 

         

       

    

           

          

     



         

         

        

      

    

          

       

      

  

          

      

     

      

    

        

    

    

             

        

       

     



         

      

       

     

     

         

         

      

     



         

       



        

         

      

     

         

       

  

           

      

    

   

          

         

    

       

 

          

       

       

 

       

     

     

     



        

      

         

       

      

       



         

        

      

       



         

      

      

  

           

         

       

        



          

        

     

    



          

        

        

 

          

        

      

       

          

      

    

          

       

       

  

284            

      

         

        

       

      

    

  

           

         

       

   

         

        

      

 

          

         

      

       



         

      



             

       

     

  

         

   

        

         

     

        

       

     

       



        

        

       

        



           

         

      

     

         

         

      

   

         

         

     

   

         

       

   

       

          

      

      



         

          

        

       

      

         

       

  

           

          

       

  

           

         

       

  

        

        

       

        

     

  

          

        

      

 

         

      

  

       

       

           

        

       

    

  

         

       

      

         

        

     

     

  

           

          

       

      

  

          

       

       



          

        

     

    

           

        

       

    

  

            285

      

         

      

       

       

      

         

          

      

        

 

        

         

     

    

     



         

         

      

       

            

       

      

 

         

        

     

    

 

        

      



          

        

    

      

  

       

      

     

    

       

     



       

      

      

     

   

          

       

      

  

          

        

     

  

        

          

      

    

       

       

      

        

 

         

         

      

      

    

        

        

        

      

  

           

          

        

   

         

         

      

    



         

        

     

     

      

   

         

         

      

     

          

 

           

       

     

      

        

     

       



           

       

      

    

 

         

       

      

 

       

       

    



       

    

 

        

         

286            

      

     

        



        

       

   

        

       

     

   

          

       

 

            

      

     



         

       

      

 

       

       

    



         

        

    



          

      

      

     



        

     

    

         

       

     

    



       

    

 

     

     

        

      

       

   

        

       

   



          

        

     

       

    



       

         

      

      



        

      

    

           

        

     

   

         

         

       

     



          

        

      

      



         

  

         

      

    

        

      



         

       

 

         

       

        

      

        

        

       

   

         

         

       

    



         

          

       

        

 

          

       

         

   

         

        

      

 

         

        

            287

      

       



         

        

      

   

        

        

      

     



         

        

       

      



           

       



         

        

   

        

       

        

     



         

       

    

          

            

        

       

  

        

     

    





         

     

      

     

     

  

          

      

      

 

        

      

     

       

         

       

      

     

 

         

      

     

   

      

       

       

       

 

       

      

    

     

        

      



        

      



          

       

       

  

           

         

      

    

          

      

      



           

       

       



        

      

     



      

     

    







          

    

       



         

         

      

      

    

 

          

        

         

       

        

       

      

         

          

288            

      

        

  

          

        

      

       

      

  

         

       

       



         

       

  

          

           

        



       

       

     

        



           

        

      

  

        

       

       

   

         

       



        

     

      

 

     

        

     





        

        

      

  

      

       

      

    

  









       

     

     

       

   

      

 

            289

Biologics in ocular inflammatory diseases - Experience from a tertiary referral eye care center in South India

Article

Full-text available

Sep 2024
Indian J Ophthalmol

Purpose To analyze the utility of biologics in noninfectious uveitis and other ocular inflammatory diseases in a South Indian patient population. Methods This was a retrospective observational study conducted at the uveitis and ocular inflammatory diseases clinic of a tertiary eye care hospital in South India between 2016 and 2023. Results Records of 76 patients on biologics were retrieved from our databases. The mean age was 34.84 ± 17.383 years. In 75% of patients, the duration of follow-up was 52.75 months. Overall, anterior nongranulomatous uveitis was the most common anatomic type of uveitis (34.21%). HLA B27-associated uveitis was the most common etiology (34.21%) in whom biologics were used. Patients <18 years of age formed 23.7% with a mean age of 10.77 ± 2.75 years. Mean duration of follow-up in patients <18 years of age was 36 months. In this subgroup, panuveitis was the most common anatomic subtype (61.1%) and juvenile idiopathic arthritis was the most common etiology (27.7%). The most commonly used biologic in this study was adalimumab (36.84%). Additional conventional immunomodulators were used along with biologics in 50 patients (65.78%), of which methotrexate was the most common (50%). Adalimumab and rituximab were biosimilars, while tofacitinib was the generic version. There was a significant decrease in the mean number of flareups post-biologics ( P = 0.001). Adverse effects were seen in 14 patients (18.42%). The success rate of biologics was low in the parsplanitis group <18 years (33.3%), Blau-associated uveitis (50%), and idiopathic uveitis (30%). Conclusion In this study, we have analyzed the results of biologics in different anatomic types of ocular inflammation and etiologies. The success rate of biologics was low in parsplanitis, idiopathic uveitis, and Blau-associated uveitis and higher in other etiologies.

Anti-Inflammatory Effects of Clarstatin, a Shared-Epitope–Antagonistic Cyclic Peptide, on Experimental Autoimmune Uveitis in Mice

Article

Full-text available

Jan 2025

Purpose Polymorphism and mutations of human leukocyte antigens (HLAs) and calreticulin are risk factors for uveitis. Here, we sought to determine the therapeutic effects of Clarstatin, a cyclic peptide antagonist of the HLA shared-epitope–calreticulin interaction, in experimental autoimmune uveitis (EAU) models. Methods Mice were injected with Clarstatin intraperitoneally and its effect was compared to that of corticosteroid. EAU was evaluated clinically and histologically. Ocular infiltration of CD45⁺ hematopoietic cells and splenocyte CD4⁺ expression were determined using immunofluorescence and flow cytometry (fluorescence-activated cell sorting [FACS]). ELISA was used to measure the ocular level of the proinflammatory cytokines. Results Clarstatin significantly ameliorated the severity of EAU in the C57BL/6J mild and the B10.RIII severe mice models. There was a significant dose and time-dependent decrease, in the range of 30% to 80%, in the clinical score (P < 0.05), histological score (P < 0.05), and number of retinal and spleen CD45⁺ cells (P < 0.05 and P < 0.001, respectively), a comparable effect to corticosteroid. Clarstatin reduced the intraocular levels of interleukin 6 (IL-6; P < 0.05) and monocyte chemoattractant protein-1 (MCP-1; P < 0.01) by 41% and 59%, respectively. Conclusions Systemic delivery of Clarstatin significantly improved mild and severe EAU. Its potential anti-inflammatory therapeutic effects represent a novel mode of treatment in ocular inflammation. It may also be a relevant treatment modality in systemic autoimmune conditions in which calreticulin plays a role in their pathogenesis.

Multifunctional Interleukin-24 Resolves Neuroretina Autoimmunity via Diverse Mechanisms

Article

Full-text available

Oct 2022
INT J MOL SCI

IL-24 is a multifunctional cytokine that regulates both immune cells and epithelial cells. Although its elevation is associated with a number of autoimmune diseases, its tolerogenic properties against autoreactive T cells have recently been revealed in an animal model of central nervous system (CNS) autoimmunity by inhibiting the pathogenic Th17 response. To explore the potential of IL-24 as a therapeutic agent in CNS autoimmunity, we induced experimental autoimmune uveitis (EAU) in wildtype mice and intravitreally injected IL-24 into the inflamed eye after disease onset. We found that the progression of ocular inflammation was significantly inhibited in the IL-24-treated eye when compared to the control eye. More importantly, IL-24 treatment suppressed cytokine production from ocular-infiltrating, pathogenic Th1 and Th17 cells. In vitro experiments confirmed that IL-24 suppressed both Th1 and Th17 differentiation by regulating their master transcription factors T-bet and RORγt, respectively. In addition, we found that intravitreal injection of IL-24 suppressed the production of proinflammatory cytokines and chemokines from the retinas of the EAU-inflamed eyes. This observation appears to be applicable in humans, as IL-24 similarly inhibits human retinal pigment epithelium cells ARPE-19. In conclusion, we report here that IL-24, as a multifunctional cytokine, is capable of resolving ocular inflammation in EAU mice by targeting both uveitogenic T cells and RPE cells. This study sheds new light on IL-24 as a potential therapeutic candidate for autoimmune uveitis.

Seronegative spondyloarthropathy-associated inflammatory bowel disease

Article

Full-text available

Jan 2023
WORLD J GASTROENTERO

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

Targeting ocular tissues with intravenously administered aptamers selected by in vivo SELEX

Article

Oct 2024

Ocular diseases create a significant economic burden and decrease in quality of life worldwide. Drugs and carrier molecules that penetrate ocular tissues after intravenous administration are needed for more efficient and patient-friendly treatment of ocular diseases. Here, ocular barrier-penetrating aptamers were selected through the utilization of in vivo SELEX and intravenous injection in rats. Three aptamers—Apt1, Apt2, and Apt5—were chosen based on their specific accumulation in vascularized ocular tissues and further characterized for their in vivo biodistribution using quantitative reverse-transcription PCR (RT-qPCR). A statistically significant difference between ΔCt values of ocular and control tissues with Apt2 (p < 0.0001) and Apt5 (p < 0.0001) was observed. Interestingly, Apt1 was the most abundant aptamer in the sequencing pool, but it did not show a statistically significant difference in in vivo biodistribution between ocular and control tissues. Overall, this study established a functional in vivo SELEX method for discovering ocular tissue targeting aptamers.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats

Article

Apr 2024
INT J PHARMACEUT

Recent advances in uveitis therapy: focus on selected phase 2 and 3 clinical trials

Article

Dec 2023

Introduction: Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract. It is a leading cause of blindness in developed countries and exerts significant psychological, social, and economic impact on both patients and the larger society. While there are numerous pharmacotherapy options, posterior segment noninfectious uveitis remains a significant challenge to treat due to its severity, chronicity, and high recurrence rates. Areas covered: The index review highlights the unmet needs of uveitis pharmacotherapy and its research and the shortcomings of existing ocular and systemic therapeutic options for noninfectious uveitis. The more promising novel ocular drug delivery methods and therapeutic targets/drugs are discussed, and evidence from the clinical trials is evaluated. Expert opinion: There has been incredible growth in the number of treatment options available to uveitis patients today, especially with the new generation of biologic drugs. Available evidence suggests that these newer options may be superior to conventional immunosuppressive therapies in terms of efficacy and side effect profiles. Further high-quality research and additional clinical trials will be needed to clarify their roles in the stepladder treatment approach of noninfectious uveitis.

Vitreoretinal Lymphoma

Article

Full-text available

Aug 2021

Vitreoretinal lymphoma (VRL) is a rare variant of primary central nervous system lymphoma (PCNSL), mostly of diffuse large B cell lymphoma, which affects the retina and/or the vitreous with or without optic nerve involvement. The disease course is aggressive. Up to 90% of the patients develop central nervous system lymphoma within one year. The diagnosis of VRL is challenging due to nonspecific chronic and relapsing uveitis and is made by anterior chamber tab or vitreous aspirate biopsy. There is no established treatment protocol for VRL patients with bilateral involvement without CNS involvement. There are suggestions to use only intravitreal chemotherapy with methotrexate and/or rituximab. Alternatively, systemic high-dose MTX treatment or external beam radiotherapy is used. Further studies are needed to prove and confirm the prophylactic systemic therapy in preventing CNS involvement in limited VRL.

A Review of Ocular Drug Delivery Platforms and Drugs for Infectious and Noninfectious Uveitis: The Past, Present, and Future

Article

Full-text available

Aug 2021

Uveitis refers to a broad group of inflammatory disorders of the eye that often require medical and surgical management to improve or stabilize vision and prevent vision-threatening pathological changes to the eye. Drug delivery to the eye to combat inflammation and subsequent complications from uveitic conditions is complex as there are multiple barriers to absorption limiting availability of the needed drug in the affected tissues. As such, there has been substantial interest in developing new drugs and drug delivery platforms to help reduce intraocular inflammation and its complications. In this review, we discuss the challenges of drug delivery, novel technologies recently approved for uveitis patient care and promising drug delivery platforms for uveitis and sequelae of ocular inflammation.

Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA)

Article

Full-text available

Feb 2021

Purpose To evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU). Design Open-label, prospective multicentre safety study. Participants Thirty-eight subjects with NIU, with and without macular oedema (MO). Methods Treatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations. Main outcome measures The main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST). Results Based on a CST of ≥300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; two of which were deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period. Conclusions Suprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.

Medication-induced Uveitis: An Update

Article

Full-text available

Jan 2021

Drug-induced uveitis is an uncommon but important cause of ocular inflammation. Uveitis can be seen in association with various systemic, topical, and intraocular medications. In this article, we review common medications associated with uveitis. Most cases of drug-induced uveitis resolve with termination of the suspected medication with or without administration of topical or systemic steroids. It is important for clinicians to readily identify medications that may cause uveitis in order to provide rapid treatment, avoid consequences of longstanding inflammation, and prevent costly and excessive laboratory testing.

Rituximab in the treatment of Susac’s syndrome: Report of a case

Article

Full-text available

May 2020

Significance Susac’s syndrome is a rare retinocochleocerebral immune-mediated endotheliopathy and clinically manifests as a pathognomonic triad of encephalopathy, hearing loss, and branch retinal artery occlusion. This triad is rarely present at symptom onset, thus, it is often initially misdiagnosed. To date, Susac’s syndrome has persisted as an elusive entity and there are numerous treatment regimens proposed with varying effectiveness mainly based on case series. Purpose To report our 12-month follow-up experience in the treatment of Susac’s syndrome with rituximab. Case report A 25-year-old female presenting with headache, paresthesias, tinnitus, peripheral vertigo, and a branch retinal artery occlusion. The patient had a personal history of anxiety-depressive disorder. After discarding other infectious/autoimmune conditions and magnetic resonance imaging suggestive findings of Susac’s syndrome, we observed a prompt response to the combination of intravenous immunoglobulin, corticosteroids, and rituximab. Conclusion A standard treatment paradigm is lacking in Susac’s syndrome as randomized controlled trials do not exist. There are no definitive scores to predict its outcome, and early diagnosis is important as the organs involved can easily become irreversibly damaged. Thus, patients with Susac’s syndrome must be treated promptly and aggressively. Our report highlights the possibility of positive long-term prognosis with an early use of rituximab. However, a systematic therapeutic approach on the basis of controlled trials is mandatory to develop a consensus.

The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients with axial spondyloarthritis: 48-week interim results from C-VIEW

Article

Full-text available

Apr 2020

Background Acute anterior uveitis (AAU) is the most common extra-articular manifestation in patients with axial spondyloarthritis (axSpA). C-VIEW investigates the impact of the Fc-free TNF inhibitor certolizumab pegol (CZP) on AAU flares in patients with active axSpA at high risk of recurrent AAU. Methods C-VIEW ( NCT03020992 ) is a 96-week ongoing, multicentre, open-label, phase 4 study. Included patients had an axSpA diagnosis, a history of recurrent AAU (≥2 AAU flares, ≥1 flare in the year prior to study entry), HLA-B27 positivity, active disease, and failure of ≥2 non-steroidal anti-inflammatory drugs. Patients received CZP 400 mg at Weeks 0/2/4, then 200 mg every 2 weeks up to 96 weeks. This 48-week pre-planned interim analysis compares AAU flare incidence in the 48 weeks before and after initiation of CZP treatment, using Poisson regression to account for possible within-patient correlations. Results In total, 89 patients were included (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean axSpA disease duration: 8.6 years). During 48 weeks’ CZP treatment, 13 (15%) patients experienced 15 AAU flares, representing an 87% reduction in AAU incidence rate (146.6 per 100 patient-years (PY) in the 48 weeks pre-baseline to 18.7 per 100 PY during CZP treatment). Poisson regression analysis showed that the incidence rate of AAU per patient reduced from 1.5 to 0.2 (p<0.001). No new safety signals were identified. Conclusions There was a significant reduction in the AAU flare rate during 48 weeks of CZP treatment, indicating that CZP is a suitable treatment option for patients with active axSpA and a history of recurrent AAU.

Effect of an Fluocinolone Acetonide Insert on Recurrence Rates in Noninfectious Intermediate, Posterior, or Panuveitis: 3-Year Results

Article

Full-text available

Apr 2020
OPHTHALMOLOGY

Objective To examine the 36-month efficacy and safety of a 0.2 μg/day fluocinolone acetonide insert (FAi) to treat noninfectious intermediate, posterior, or panuveitis (NIU-PS). Design Phase 3, prospective, double-masked, multicenter study (clinicaltrials.gov, NCT01694186). Subjects Adults (≥18 years old) with a diagnosis of NIU-PS in ≥1 eye for ≥1 year and ≥2 recurrences of uveitis requiring systemic corticosteroid, immunosuppressive treatment, or intraocular corticosteroids. Methods Participants were randomized 2:1 to FAi or sham (injection plus standard of care) treatment. Main Outcome Measures The primary outcome was the difference between the proportion of FAi-treated and sham-treated patients who had a uveitis recurrence. Secondary outcomes included time to first recurrence, number of recurrences, best corrected visual acuity (BCVA) change from baseline, resolution of macular edema, and number of adjunctive treatments. Results 129 participants (n=87 FAi-treated; n=42 sham-treated) were enrolled. Over 36 months of treatment, cumulative uveitis recurrences were significantly reduced with FAi compared with sham (65.5% vs. 97.6%, respectively; P<0.001); time to first recurrence was commensurately longer (median 657.0 and 70.5 days, respectively; P<0.001). The number of recurrences per eye was significantly lower in the FAi- compared with sham-treated group (mean 1.7 vs. 5.3, respectively, P<0.001). At 36 months, more FAi-treated eyes had a ≥15-letter increase in BCVA from baseline and fewer FAi-treated eyes had investigator-determined macular edema at Month 36, compared with sham-treated eyes (33.3% vs. 14.7% and 13.0% vs. 27.3% for BCVA and macular edema, respectively). Fewer FAi-compared with sham-treated participants required adjunctive treatments (57.5% vs. 97.6%, respectively). Intraocular pressure (IOP) was similar for both study groups at Month 36 (mean ± standard deviation 14.5±5.1 and 14.8±5.3, respectively), and approximately half as many eyes in the FAi-treated group when compared with the sham-treated group underwent IOP-lowering surgery (5.7% vs. 11.9%). Cataract surgery was required more frequently over 36 months in the FAi- compared with the sham-treated group (73.8% vs. 23.8% of eyes, respectively). Conclusions FAi-treated eyes had significantly reduced uveitis recurrence rates throughout the study duration, significantly increased recurrence-free durations, fewer recurrence episodes among those with recurrences, less adjunctive therapy, and an acceptable side-effect profile compared with sham-treated eyes.

Efficacy and Safety of Intravitreal Sirolimus for Non-Infectious Uveitis of the Posterior Segment: Results from the SAKURA Program

Article

Full-text available

Apr 2020
OPHTHALMOLOGY

Purpose To evaluate the efficacy and safety of intravitreal sirolimus in the management of noninfectious uveitis of the posterior segment (NIU-PS). Design Combined analysis of two phase III, randomized, double-masked, multinational, 6-month studies (SAKURA Program). Participants Adults with active NIU-PS (intermediate, posterior, or panuveitis; defined as vitreous haze [VH] ≥ 1.5+ on modified Standardization of Uveitis Nomenclature [SUN] scale). Methods Subjects were randomized 1:1:1 to receive intravitreal sirolimus 44-μg (n=208), 440-μg (n=208), or 880-μg (n=177) on Days 1, 60, and 120. Subjects discontinued medications for NIU-PS except for systemic corticosteroids, which were tapered according to protocol. Enrollment in the 880-μg group was terminated after interim results found no significant difference in efficacy compared to the 440-μg dose. Main Outcome Measures The primary efficacy endpoint was the percentage of subjects with VH = 0 response at Month 5 in the study eye without use of rescue therapy. Secondary efficacy endpoints included VH = 0 or 0.5+ response, corticosteroid-tapering success, and changes in best-corrected visual acuity (BCVA). Safety measures included ocular and non-ocular adverse events (AEs). Results A total of 592 subjects were randomized. In the SAKURA Program analysis, significantly higher proportions of subjects treated with 440-μg compared with 44-μg achieved VH = 0 (21.2% vs 13.5%; P = 0.038) and VH = 0 or 0.5+ (50.0% vs 40.4%; P = 0.049) at Month 5. BCVA was stable (absolute change <5 ETDRS letters) or improved >5 letters in 80.1% and 80.2% of subjects in the 440-μg and 44-μg groups, respectively. At Month 5, corticosteroids were successfully tapered in 69.6% and 68.8% of subjects in the 440-μg and 44-μg groups, and among these subjects, VH = 0 or 0.5+ response was achieved by 43.5% and 28.1% in the 440-μg and 44-μg groups. Both doses were generally well tolerated. Mean changes from baseline intraocular pressure (IOP) in the study eye at each analysis visit were minimal in all treatment groups. Conclusions Intravitreal sirolimus 440-μg improved ocular inflammation, as measured by VH, compared to the 44-μg dose, with minimal impact on IOP, while preserving BCVA.

Certolizumab pegol – Tumor necrosis factor inhibitor for refractory uveitis

Article

Full-text available

Feb 2020

Purpose The purpose of our study is to report our experience with the use of certolizumab pegol in patients with refractory non-infectious uveitis. Observations We present a case series of three patients with non-infectious uveitis, treated with twice-monthly subcutaneous certolizumab pegol. All of our patients had different types of uveitis and different underlying etiologies. All of our patients had previously failed various immunomodulatory therapies and/or were intolerant to at least one tumor necrosis factor (TNF) inhibitor agent. Following initiation of therapy with certolizumab pegol, all three patients showed significant clinical improvement of their ocular inflammation. No adverse events from treatment with certolizumab pegol were observed. Conclusions and Importance: We observed positive outcomes using the TNF inhibitor certolizumab pegol for the treatment of patients with refractory, non-infectious uveitis, in whom therapy with other TNF inhibitors was inadequate or in which there were tolerance issues. Patients who have failed other TNF inhibitors may benefit from treatment with certolizumab pegol.

Effectiveness and safety profile of anakinra in a HLA-B27 positive patient with multiple sclerosis-associated uveitis

Article

May 2020

Multiple sclerosis (MS) is a chronic demyelinating disorder of central nervous system (CNS) leading to neurological disability. A wide variety of ophthalmic and neuro-ophthalmic manifestations have been associated with MS. Although this link is well recognized, controversial is still the risk of developing MS in patients with ophthalmic manifestations. Intermediate uveitis followed by panuveitis are the most common manifestations among the ophthalmic involvement in MS. Timely management of uveitis, is a crucial step to prevent irreversible visual impairment. A multidisciplinary team including ophthalmologists together with other specialists is required in the majority of cases for an adequate diagnostic and therapeutic approach of uveitis. Corticosteroids represent the mainstay of therapy in the acute phase, whereas conventional immunosuppressive drugs such as azathioprine may allow a steroid sparing effect. Increasing evidence from anti-CD 20 monoclonal antibodies such as rituximab have proven the efficacy on clinical and radiological outcomes in MS, on the contrary anti-Tumor Necrosis Factor (TNF) monoclonal antibodies such as infliximab and adalimumab are contraindicated in patients with demyelinating disorders, as they seem to worsen disease and neurological clinical symptoms. On this basis, MS-associated uveitis may deeply influence the therapeutic choices suggesting targeting inflammatory cytokines different from TNF. Recently, interleukin (IL)-1 blockade has been investigated as possible therapeutic tool in several inflammatory eye conditions such as Behcet's disease related uveitis, strengthening that IL-1 is also critical for the development of uveitis. Herein, we report our experience in a HLA-B27 positive patient with MS-associated uveitis successfully treated with the short-acting IL-1 receptor antagonist anakinra.