Steroid Resistance - The Smoking Gun May Be a Smoking Mouse

I often wonder about ‘steroid resistance’ and think it's a poor prognostic marker in early RA.

The Hench lectureship by Professor Peter Barnes entitled, ‘Why Steroids Work in Some Inflammatory Diseases but Not in Others' was truly enlightening on the concept of 'steroid responsiveness.'

COPD was used as an illustration. Smoking can cause or worsen steroid resistance in COPD and worsen oxidative stress. But, based on evidence from animal models of 'smoking mice,' stopping smoking is not necessarily able to reverse this. If severe, more steroids are needed to improve steroid response.

An important area of research is the change in phosphorylation of HDAC2 cells, where HDAC can activate and potentiate the effect of steroids. Antioxidants can help to alleviate this, for example, N-acetylcysteine.

There are other pathways involved. Theophylline can improve sensitivity to steroids but not when it results from changes in PDE4 levels. Theophylline can favourably reverse histone acetylation when given in low doses, whereas high doses generate more side effects and may be deleterious.Steroids and theophylline administered together may improve steroid resistance in COPD but not necessarily when given individually.

The P13 kinase inhibitor pathway can also reduce steroid resistance by improving oxidative stress. This was shown by knocking out P13 kinase.

Nortriptylline, macrolides and antioxidants can help address steroid resistance. This is another good reason to prescribe a low-dose tricyclic antidepressant – to REDUCE steroid resistance.

A key take-away for me is that the smoking mouse really does help me treat patients better.

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