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Improved Synovial Fluid in RA Doesn't Always Lead to Clinical Response

Treatment with rituximab and infliximab reduce the expression of Carboxypeptidase B, the complement peptide C5a and osteopontin in the synovial fluid of rheumatoid arthritis patients.

Treatment with rituximab and infliximab reduce the expression of Carboxypeptidase B, the complement peptide C5a and osteopontin in the synovial fluid of rheumatoid arthritis patients, a new study finds. But these declines do not necessarily correlate with clinical response.

In a new study published online March 1 in The Journal of Rheumatology, University of Manitoba researchers recruited 14 patients who had failed at least one conventional DMARD and who were trying their first biologic treatment. Nine were prescribed infliximab, and five rituximab. Before treatment, each patient underwent a biopsy of the most inflamed knee joint. After 12 to 16 weeks of standard clinical doses of their assigned biologic, the participants underwent a second biopsy. Their rheumatoid arthritis activity was also assessed using the DAS28 monthly for three months and then quarterly for a year. Osteoarthritis synovial tissue samples from a tissue bank were used as controls.

To find out more about the results, Rheumatology Network interviewed study coauthor Stefan Edginton, a fourth-year medical student who conducted the research along with his supervisor, Hani El-Gabalawy, M.D., a professor of medicine and immunology at the University of Manitoba, and their colleagues.

What was the impetus behind this study, and why is it important to understand the responses of CPB and its substrates in rheumatoid arthritis?  

The importance of CPB and its substrates (particularly complement C5a) in RA was highlighted in a 2011 paper by Robinson et al. This study found that CPB-deficient mice developed worse inflammatory arthritis and that C5-deficient mice were resistant to the development of inflammatory arthritis. It was hypothesized that CPB acted in an anti-inflammatory manner by deactivating proinflammotory C5a.

We wanted to explore this relationship in rheumatoid arthritis to further understand where CPB is expressed in the synovium and how it changes in relation to C5a in response to biologic treatment.

What were your major findings?

We found that in pretreatment, there was a high degree of positive staining for CPB and C5a in RA synovium that correlated with the presence of inflammatory cells, particularly macrophages. Treatment with either infliximab or rituximab produced a decrease in synovial expression of CPB and C5a along with a decrease in inflammatory cells.

C5a expression in the synovium at 16 weeks was correlated to clinical response at 12 weeks and 1 year, but the overall change in expression was not correlated to clinical response.

Why might the biomarker declines not correlate with clinical response? 

There are a number of possible explanations for this. The small number of study subjects involved in the trial may not be representative of response rates as have been seen in larger clinical trials with infliximab and rituximab. In addition, we speculated that there may be a lag between synovial response and clinical response. While there may be a more rapid change in terms of the synovial microenvironment, this may not necessarily translate to a change in a patient’s functional status immediately.

What are some of the mechanisms at play here? Why might CPB have both pro- and anti-inflammatory effects? Why might you see a decline in both CPB and C5a at the same time?

One of CPB’s functions is to cleave fibrin clots. This change in fibrin’s structures prevents the binding of plasmin and tPA, thus slowing down clot lysis. The presence of fibrin in the synovium promotes an inflammatory response, and it is through this mechanism that CPB may play a proinflammatory role.

However, C5a is another substrate of CPB. C5a is produced as part of the complement cascade and has numerous proinflammatory functions. CPB works by breaking down C5a, and it is through this breakdown that CPB may have an anti-inflammatory role.

Our study found that CPB and C5a decreased together in response to biologic treatment. If C5a is a substrate of CPB, it would be expected to increase in response to drops in CPB. Our findings highlighted the complex relationship between CPB and C5a and suggests there are other factors implicated in C5a levels.

It is likely that the decline in C5a synovial expression relates to a reduction in its generation rather than an increase in its degradation. Leukocyte-derived microparticles are found in RA synovial fluid, and these have been shown to activate the complement cascade. Successful biologic treatment may lead to a reduction in the level of these microparticles and in turn a reduction in complement activation.

What are the important messages from this work for practicing rheumatologists? 

At this time, the link between CPB and rheumatoid arthritis needs further research. Once this relationship has been more thoroughly characterized, CPB or one of its substrates could potentially represent a future aim for targeted therapies.

What are the next steps in this line of work?

It would be helpful to look at CPB and C5a in RA with a larger cohort of patients. This may show a stronger link between synovial expression and clinical response.

In addition, the use of dual immunofluorescent staining would aid in co-localizing CPB expression with specific cell markers. This could confirm with more certainty which cells are expressing CPB in the synovium and could target further research.

Along the lines of C5a and its role in rheumatoid arthritis, a study looking at the effects of RA therapy on leukocyte-derived microparticles could explore an important mechanism of synovial inflammation.




Stefan Edginton, Carol Hitchon, Warren Froese and Hani El-Gabalawy.

"Effects of Rituximab and Infliximab Treatment on Carboxypeptidase B and Its Substrates in RA Synovium,"

The Journal of Rheumatology

. Published online before print March 1, 2016, doi: 10.3899/jrheum.150869 Song JJ1, Hwang I, et. al.

"Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis,"

J Clin Invest

. 2011 Sep;121(9):3517-27. doi: 10.1172/JCI46387. Epub 2011 Aug 1.