Thread by @chriswincup

🧵 Short summary thread on our recent publication looking at the impact of Anti-Rituximab Antibodies in #SLE with our recent manuscript published in @RheumJnl

This has been a story that we have been looking at for a few years now

💻 Link - academic.oup.com/rheumatology/a…

In spite of failing to meet primary endpoints in the LUNAR and EXPLORER trials, a number of Open Label studies have shown benefit of B cell depletion with Rituximab in #lupus

In England, we have access to the drug for severe and refractory cases 💊 💉

england.nhs.uk/wp-content/upl…

During my time at @uclmedsci I was interested as to why patients receiving rituximab for #SLE occasionally developed infusion reactions to treatment, whilst I did not see this in patients receiving the drug for rheumatoid arthritis 🤔

I was then lucky to speak with @Jury_Lab @MadhviM and @Mauri_group about some data on anti-rituximab antibodies and we found that a detectable circulating anti-rituximab antibody predicted subsequent infusion reactions

💻 link in @ARD_BMJ - ard.bmj.com/content/78/8/1…

Anti-drug antibodies (ADA) were associated with subsequent infusion reaction on retreatment with rituximab. Most reactions were mild but in the rare severe cases this was seen in those with higher ADA titre. Switching to humanised anti-CD20 therapy was well tolerated though

Next up we were interested to learn more about the formation and long term impact of anti-rituximab antibodies in #lupus

We wondered
🔴 Do ADA persist for months or years post-treatment?
🔵 How prevalent are ADA to rituximab in #SLE?
🟢 Do ADA impact treatment response?

This resulted in the study we have just published in @RheumJnl

We identified 35 patients receiving rituximab for #SLE at UCLH with serum samples collected early post-treatment (1-3 months), 6, 12 and 36 months post-treatment ⏰

Anti-rituximab antibodies were measured by @Fogdell_lab and @nickydunn_ We also measured serum rituximab level and whether anti-drug antibodies were capable of neutralising the drug in vitro 🧫

This way we aimed to see whether these antibodies impair rituximab therapy in #SLE

We found

🚨 Anti-rituximab antibodies are COMMON (64.3% of patients had persisting ADA three years post treatment)

🚨 As with our previous study, younger patients had a higher risk of developing anti-rituximab antibodies (22% reduction in risk for each year older)

Unsurprisingly ADA were detected earlier and at higher titre in those previously treated with rituximab when compared with those who were treatment naive

We also found ADA positive patients had significantly lower circulating rituximab levels at 3 & 6 months post-treatment

Our in vitro assays showed that anti-rituximab antibodies were able to neutralise rituximab, which potentially explains why drug levels were lower in ADA positive patients

But what does this mean clinically?

At 3 months post-treatment BILAG response was broadly similar between ADA negative and ADA positive but relapses were exclusively seen those who were ADA positive at 6 months after treatment

At 12 months, major BILAG response was more common in ADA negative patients

So we suggest that anti-rituximab antibodies can neutralise the drug, resulting in ⬇️ rituximab levels and result in earlier relapse. They also associate with infusion-related reactions

‼️ So anti-rituximab antibodies are a major limitation for therapy in #SLE ‼️

Finally, this work could only have been done with massive input from a number of amazing collaborators who I am very grateful to including @Jury_Lab @MadhviM @Mauri_group 🇬🇧 @Fogdell_lab of the @karolinskainst 🇸🇪 and colleagues from Université Côte d’Azur, Nice 🇫🇷

Also big shout out to co-first author @nickydunn_ 🇳🇿
Thanks also to @ARD_BMJ and @RheumJnl for publishing our work and to @LUPUSUK and @VersusArthritis for funding these studies

CC-ing in case of interest @bcells_rosser @kidneydoc101 @edvital @LupusForum @lupus_hub @Lupusreference @lauraandreoli80 @EricFMorand @MuhammadShipa @EhrensteinLab @Dr_JohnR @APSsupportUK @RMD_clinic @alessia_alunno @cristianasieiro @IoannisParodis @gomezg_alvaro @EMEUNET @alhkim