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Rules for Drug Cessation with Infection

I recently received an email asking me how I would manage drug therapy for a rheumatoid arthritis (RA) patient receiving either a DMARD or biologic in the setting of a new infection.

If you know the data, this is very simple issue.  For me, I almost never stop a biologic or DMARD 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 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 I wrote an article on non-serious infectious (NSIE) risks with biologics. In that article we point out that NSIE’s are highly frequent in RA patients. 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. 

You should also know that 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. 

Also important is the fact that in developmental clinical trials for biologics, an NSIE occurrence did not mandate study drug suspension. Such patients were managed and the drug was continued; no further problems occurred. 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.

References: 

Dixon WG, et al.  Ann Rheum Dis. 2011;70(6):956-60. 

 Dao KH, Herber MA, Habal N, Cush JJ. Rheum Dis Clin North Am. 2012; 38:707-25

 

Join The Discussion

Can I get a copy of this? Trouble accessing it online. Dao KH, Herber MA, Habal N, Cush JJ. Rheum Dis Clin North Am. 2012; 38:707-25
sorry...I dont have any reprints on this. JJC

Oscar Arill, MD

| Oct 19, 2017 9:55 am

What about hospitalizations for worsening/ exacerbated interstitial lung disease. It is difficult to r/o infection in these patients and equally difficult to "prove" that the biologic is or is not contributing to the ILD.

Barry Waters

| Oct 30, 2017 11:47 am

This is your best post ever - and they are all great. Wish this was published in the WSJ or made into a segment on 60 minutes.

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Disclosures
The author has no conflicts of interest to disclose related to this subject
Dr. Cush is the Executive Editor of RheumNow.com and also Co-Edits the online textbook RheumaKnowledgy.com. 
  
Dr. Cush's interests include medical education, novel drug development, rheumatoid arthritis, spondyloarthritis, drug safety, and Still's disease/autoinflammatory syndromes. He has published over 140 articles and 2 books in rheumatology.
 
He can be followed on twitter: @RheumNow