In The Fog of Medicines and Side Effects

Alright, as I am in the middle on the foggy Appalachian Mountains and almost of the peak of the fall foliage, I have decided to write another article and clear the fogginess of biologic use in rheumatoid arthritis and the risk of infections.

Previously, I have blogged the use of methotrexate in rheumatoid arthritis, and now I need to clear up many patients multiple doubts and fears with the use of  biologic treatment in rheumatoid arthritis and in other autoimmune conditions.

One of the main issues of why patients don't want to use a biologic therapy, such as Remicade, Humira, Enbrel, Orencia, etc. is the risks of infections. As I always told my patients it is worse to have an active rheumatoid arthritis disease or another inflammatory autoimmune condition than the use a biologic therapy.

I manage drug therapy for a rheumatoid arthritis (RA) patients receiving either a DMARD or biologic in the setting of a new infection.

This is a very simple issue.  For me, I almost never stop a biologic ( enbrel for example) or DMARD ( Methotrexate for example)when the patient or infusion nurse reports an infection.  I know that it's perfectly safe and normal to proceed with therapy.

However many have a blanket policy to hold all biologic, if not all DMARD, therapy when any question of infection arises - whether it be serious or non-serious infections.

It would help if we knew the rules for this situation. Unfortunately nearly all non-rheumatologist doctors, patients, neighbors, pharmacists and well intentioned clergy get all their education about biologics and infection from television advertising!  That’s right, TV ads, which are largely designed to first cover the sponsor's legal concerns, and second educate the patient according to FDA mandated advertising rules. Thus, such ads have to warn of everything from sniffles to death, because they have to cover all possibilities when covering their butts.  

The next question should ask what the danger zones are. For RA patients, this risk of infection is highest when the patient is highly inflamed, very immunosuppressed, possesses multiple comorbidities, or is taking prednisone.

• Rule #1 - Infection risk is way more related to inflammation than any specific drug risk.

• Rule #2 - Everyone gets their education about drug-related infection risk from television ads – Rheumatologists should know what the real risks are and educate their patients and other.

• Rule #3 - RA patients have a higher than normal rate of nonserious infectious events (NSIE) – occurring in approximately half of all patients each year.

• Rule #4 – the most dangerous drug influencing infectious risk is prednisone and other corticosteroids

• Rule #5 - Despite all the infection talk surrounding all biologics, there is little data to support a substantive association, meaning there is no data that is consistently statistically significant and clinically meaningful.

• Rule #6 – the highest risk for SIE with a biologic are when it is given to elderly patients with comorbidities, prior SIE and while on high dose prednisone (> 10mg/day). In such patients the risk of a SIE in the next year is over 40% (you can calculate your patients risk here:    )

• Rule #7 – my absolute rules for holding or stopping a biologic (or DMARD) is a) when hospitalized; b) with fever > 102oF or c) any fever > 101 in patients who also are highly immunosuppressed (on chemotherapy, renal transplant, severe immunodeficiency states, etc.

The Evidence

Current FDA warnings are largely directed at serious infections, not the more common non-serious infections. SIE rates on EVERY biologic are nearly double or equal to the SIE rate seen with placebo (and background therapy).

While this seems important it is never statistically significant. 

For instance the PBO SIE ( placebo serious infections events) rate may be 1% and the biologic SIE rate will be 2%. But if you look at the rate expressed in number per 100 patient-years, the PBO rate is 2/100PY and the biologic rate 3-4/100PY. 

The potential “doubling risk” of biologics becomes clinically meaningful when the patients constitutive risk is very high from steroids, comorbidities and age.

Kathryn Dao and Cush wrote an article on non-serious infectious (NSIE) risks with biologics. In that article they  point out that NSIE’s are highly frequent in RA patients.

Also, Dixon and colleagues published data from a large longitudinal RA cohort showing an NSIE rate 47.5 per 100 patient years!

That means that in one year, nearly half of all patients will have a non-serious infectious event. 

Nearly every biologic in development has shown that the number one adverse event seen in clinical trials were NSIE with rates of 35 to 55% in the biologic population and that these were not substantially different when compared to patients on placebo. 

 Moreover there is no data from these very large clinical trials that patients managed in this manner would go on to develop serious infections or infectious related deaths. 

To summarize, there is very little data that actually says patients will have more non serious infections on a biologic then on a placebo, and also there is very little data showing higher rates of serious infections on a biologic compared to placebo, both in clinical trials and registry reports.

Finally, there is no data that NSIEs are higher in patients receiving usual DMARD therapies (e.g., methotrexate, azathioprine, hydroxychloroquine or sulfasalazine).  There is data showing higher rates of SIE with cytotoxic agents and in some cyclosporine trial. 

The worse drug we use with regard to infectious risk is clearly prednisone.

I hope this clear some lagoons to our patients using biologics or are about to decide for a biologic treatment. As I write this from the beautiful Mountains of Cashiers, North Carolina, I will encourage to weight in the benefits over the risks using biologic therapy. Definitely leaving your body in an active inflammatory state is not the answer.

Hope you enjoy this read!