Safety considerations in ACR 2015 RA treatment guidelines

12 September 2016

Dr John Cush (USA) gives his opinion on some of the safety aspects of the ACR 2015 rheumatoid arthritis treatment guidelines.

This is a review of the safety considerations on the ACR 2015 RA treatment guidelines. My name is Dr John J Cush, Director of Clinical Rheumatology for the Baylor Research Institute. Today I'd like to address some of the safety concerns that were covered in the recent 2015 RA treatment guidelines published last year by the American College of Rheumatology. 

A lot of the document dealt with treatment decisions based on whether there was a naive patient or a patient with established disease, based on how much disease activity etc. I won't be discussing those treatment options, instead I am going to talk about the treatment options afforded in the context of specific comorbidities. It first should be noted that in discussing some of the comorbidities, there was no discussion and hence no guidance on what to do in patients who are pregnant. This is something of major deficit of the document, but also has to do with what will be covered in the future by the American College of Rheumatology, as they are going to develop a guideline committee, with regard to pregnancy issues in and around rheumatic diseases. 

They did discuss a number of different safety concerns. It should be stated that for all of these safety concerns, the level of evidence is very low, which means it was basically expert opinion, which is why I'm going to comment on them, because I believe that I have some expertise in this area of drug safety and that my views are not necessarily represented by these. 

So for CHF, Hepatitis B, Hepatitis C, malignancy, skin cancer and melanoma, lymphoproliferative disorders, solid tumors and serious infectious events, they make recommendations based on very little data. Specifically regarding congestive heart failure they say that you should be using combination disease-modifying anti-rheumatic drugs or a non-TNF biologic or tofacitinib. Yet they disregard the need or use of TNF inhibitors which actually have been studied extensively, and two things have been shown; one, that if you give TNF inhibitors to patients with heart failure and no arthritis the outcomes were surprising and unexpected and not necessarily good. Meaning that there was a dose-related increase in cardiovascular events and cardiovascular deaths or hospitalizations. However, when you give TNF inhibitors the patients with rheumatoid arthritis and no prior history of heart failure there was no increase at all in de novo events. Moreover, if you give this to patients who have class two or three heart disease there was also no increase, and so the reason that TNF inhibitors were excluded was because of the studies done in non-rheumatoid patients. I am not sure that's a smart idea to exclude patients from receiving maybe potentially beneficial therapy. I would use a TNF inhibitor in heart failure if the patient had class 1, class 2 and may be well-compensated well-treated class 3 disease. 

Hepatitis B and Hepatitis C, again very little evidence. For Hepatitis C they recommended a DMARD over a TNF inhibitor where there is very little sketchy use of DMARDS in patients with Hepatitis C. But, there are hundreds of patients in the literature showing that Hepatitis C can be well managed with TNF inhibition. Hepatitis B; if you have Hepatitis B surface antigenaemia and hence active disease, you should not be receiving a biologic. However, if you have an occult infection meaning that you were exposed in the past to Hep B infection, and are now Hep B surface antigen negative and Hep B core antibody positive with or without B surface antigen antibody positivity, they recommend that you receive a DMARD, more so than a TNF inhibitor. Again, there are hundreds of reports of TNF inhibition being used safely in a situation. They also recommend you monitor viral loads: something that actually hasn't been studied. 

Malignancy, for those with melanoma and non-melanoma skin cancer: the evidence again is very low, in favour of recommending using DMARD over a biologic or tofacitinib. Maybe a reasonable recommendation but again it does not take into account the large volume of research with TNF inhibitors. If you have a lymphoproliferative disorder, the evidence is very low, and they recommend rituximab or combination DEMARDs or abatacept or tocilizumab over a TNF inhibitor, yet many tens of thousands of patients treated with TNF inhibitors in the setting of lymphoproliferative disorders in the past or currently had no increase, meaning the rate associated with TNF inhibitors is exactly the rate associated with rheumatoid arthritis, hence it is the disease and not the drug. Lastly they say if you have a solid tumor, that you should receive the same therapy as you would if you didn't have a solid tumor. I received many questions this week about patients with prostate cancer or lung cancer and “can I safely use their previous biologic therapy?”, and of course you can and the evidence is actually quite good in that area. 

Finally, our one major concern, or maybe our first concern with these drugs is serious infections events or SIEs. Again the evidence supporting the ACR recommendations is very low. They suggest combination abatacept be used before TNF inhibitors again. I think that the most important thing is that inflammation drives infection risk way more than it does a TNF inhibitor. I think infliximab in high doses has a much higher risk than any of the other biologics. I think abatacept probably has the lowest risk of all the biologics and certainly a combination DMARD regimen is also going to look very good, but that's the comparator group, so again those are reasonable recommendations, but I don't think I would exclude a TNF inhibitor from consideration. Thank you very much.