Severe RA and Coccidioidomycosis Save

Dr. Tesser: How would you manage a middle-aged woman with seropositive rheumatoid arthritis (RA) who has rip-roaring, active synovitis in many joints? She has failed multiple, but not all DMARDs and biologics (for instance, she hasn’t yet tried rituximab, leflunomide, tocilizumab, etc.). The problem is that she was treated for coccidiomycosis in 2012 and while on subcutaneous abatacept she disseminated again. In 2014 she was switched to tofacitinib and took daily fluconazole, but after 3 months she blew open (disseminated) her cocci as her CT scan had worsened and her serologies reverted to positive (both complement fixation and immunodiffusion). Usually maintaining such patients on an anti-fungal agent prevents resurgence of the opportunistic fungal infection. Her pulmonologist and her infectious disease consultant have forbidden her from taking any further immunosuppressants. Sulfasalazine was no help. I now have her on hydroxychloroquine and auranofin (yes – oral gold; a blast from the past). Get this – this generic lists for over $1000/month! She’s only on this latter combination a month with nothing happening so far. What would you suggest?

Dr. Cush: I have a drug safety rule that says “if no damn good can come of this (situation/problem) then don’t contribute to it”. Meaning that you shouldn’t assume the risk of a no win situation by prescribing high risk therapy on an even higher risk patient with little chance of significant improvement. I’m going to assume that such is not the case with your patient. If so, then you may want to consider the following choices:

1. Clearly a month on HCQ and auranofin is too soon to judge – another 3-5 months are needed to know the full potential of this combination.
2. Fluconazole (Diflucan) may not be the best agent for her prophylaxis. There may be better anti-fungal agents (e.g., posaconazole, itraconazole) and there are low and high dose regimens and some can be given intravenously. There is also the issue of compliance - was she really taking it? Infectious disease needs to supervise her anti-fungal therapy. While on effective, high dose prophylaxis she should be able to safely receive ANY of the non-TNF (other MOA) biologics with little or no risk.
3. There is no good evidence or scientific rationale that says rituximab, abatacept, tocilizumab, anakinra or tofacitinib would cause reactivation of her fungal infection. Reactivation lessons were learned from animal models of mycobacterial infection and taught us that TNF (and to some extent interferon-g) is needed to grow and maintain granulomas. Hence, inhibition of B cells, T cell costimulation, IL-1, IL-6 should not contribute to granuloma breakdown. Nevertheless, a patient with an invasive fungal infection will never fully clear the infection and hence the need for chronic anti-fungal prophylaxis should they need a TNF inhibitor or other biologic.
4. The safest biologic would be anakinra, then rituximab or tocilizumab, especially if used in low doses or was intermittently dosed.
5. Don’t use leflunomide - has been associated with TB infection and reactivation and the package insert says patients going on this drug require TB testing - may apply to cocci infections.
6. Suggest that she go on a gluten free diet - may help; can’t hurt. We have had some patients with inflammatory arthritis do wonderfully well on gluten free diets.
7. At all cost – AVOID STEROIDs. These are often a greater contributor to infectious risk than the biologics.
8. Fix what you can to improve health and reduce the burden of inflammation: diet, dental hygiene, smoking, lose 20-30 lbs., and a rigid low salt diet.
9. Consider apremilast (Otezla) – I’ve had several RA pts who it did great taking apremilast in usual dose.
10. Consider IVIG.

Dr. Tesser: Your response is interesting as it turns out that she has been recently switched to voriconazole, due to significant weight loss from the fluconazole. She’s cachectic from her highly active RA and cocci infection – neither make for a healthy lifestyle. There is no thoughts of starting leflunomide. Currently we have to hold off on immunosuppressants, at least until we can see some reduction of cocci activity with the voriconazole. I must say anakinra is an interesting consideration. She’s not on prednisone.

Gluten free is quite interesting as an option. I’ll advise her about that and salt reduction paying attention to dental hygiene as well. Apremilast and IVIG are also interesting considerations, but you have to wonder about getting coverage?