Is it safe to use quinacrine in SLE patients with a history of hydroxychloroquine-associated retinopathy?

To my knowledge, quinacrine, an anti-malarial, is not FDA-approved for use in the US. It may be obtained from compounding pharmacies but the FDA makes no assertions regarding either its safety or its efficacy. For lupus, it has been used primarily as adjunctive therapy for cutaneous disease, e.g. added to hydroxychloroquine if that is not producing adequate benefit. Adverse effects from quinacrine include yellowing of the skin which should be reversible, psychosis, hemolysis, aplastic anemia, and photosensitivity resulting in symptoms such as fatigue and arthralgia. It is believed to not cause retinal toxicity, but it is not clear to me how rigorously that has been studied. Many dermatologists recommend quinacrine with another anti-malarial and that would presumably not apply to your patient. My personal preference would be to find an alternative other than quinacrine for a patient with cutaneous lupus and documented retinal toxicity from an anti-malarial. If you believe that quinacrine is the best alternative, I would definitely work with an ophthalmologist to increase the frequency of screening for additional retinal toxicity.

I do use quinacrine as an alternative to hydroxychloroquine (HCQ) and chloroquine (CQ) in patients with anti-malarial retinopathy. It has been reported as not causing retinopathy (Mittal et al., PMID 28989103).

Here, I give some tips on using Quinacrine (Thomas). 

However, I must add some caveats:

• Not everyone is in agreement. I have heard Dr. Michelle Petri (who I admire greatly) state that she does not agree, because there have been a few patients seen with retinopathy while taking quinacrine. 
• However, I am not convinced these cases are 100% attributable to quinacrine. When one looks at the millions of doses that have been given during and after World War 2, why have we not seen more cases?
• Yet, I must admit that we used to say the same thing about HCQ (that HCQ-induced retinopathy was very rare). Could quinacrine not have been studied adequately regarding the incidence of retinopathy after many years of use? This is possible. Quinacrine-related retinopathy (after chronic use) may not have been adequately studied.
• A decade ago, I would have readily offered quinacrine to patients. It works relatively quickly, and if one starts with a low dose, you can avoid side effects like lichenoid reactions and untowardly skin pigmentations in most patients. Yet, today, in patients with systemic lupus (SLE), FDA-approved biologics (like belimumab and anifrolumab) would be top choices for me above quinacrine (per the 2023 EULAR SLE management guidelines). 
• Although HCQ has such a ridiculously long list of benefits (like longer survival, less visceral dz, successful births, fewer thromboses and MACE, fewer infections, fewer cancers, etc etc etc), these have not been proven with the other antimalarials such as CQ and quinacrine. 

So, when would I use quinacrine in a patient with HCQ retinopathy?

I would use it primarily in a patient with cutaneous lupus, lupus cytopenias, lupus arthritis, or lupus fatigue who does not want an immunosuppressant or biologic. For someone with isolated cutaneous lupus (without SLE) who failed HCQ or CQ monotherapy, and whose insurance covers it, it would also be a viable solution.

I would also ask the patient to see a HCQ retinopathy expert to monitor how the retinopathy is doing (using mfERG, SD-OCT and VF 10-2) while on quinacrine. If the retinopathy worsens, then discussing other possible therapies would be prudent.

However, it is also important to remember that HCQ and CQ-induced retinopathy can worsen after HCQ or CQ is stopped. Therefore, if retinopathy worsens while they take quinacrine, this does to absolutely mean that the quinacrine is making the retinopathy worse (difficult situation, in deed). 

Do not forget to check a G6PD before RXing it, and monitor the CBC closely after first starting it, and make sure to tell patients to stop quinacrine immediately if a rash occurs (the pemphigoid rash can occur before aplastic anemia but this is incredibly rare with the low doses we use today).

Quinacrine given as a single agent has a very low incidence of retinal toxicity and, in my opinion, is effective for both cutaneous and systemic lupus, particularly for patients with constitutional symptoms and fatigue.

That said, studies that have combined quinacrine with hydroxychloroquine in the past have sometimes reported retinal toxicity, perhaps in part because of using higher doses of hydroxychloroquine than we would now employ, however this raises the question of whether or not the combination of hydroxychloroquine and quinacrine might be more toxic to the retina than hydroxychloroquine alone.

Retinal toxicity from hydroxychloroquine can progress even after this medication is stopped in the setting of widespread deposition of hydroxychloroquine throughout tissues in the body and during that time it is extremely important not to risk increasing exposure to hydroxychloroquine. For this reason, I do not add quinacrine after the onset of retinal toxicity from hydroxychloroquine because of a concern, perhaps more theoretical than proven, that quinacrine might displace hydroxychloroquine from binding sites increasing hydroxychloroquine exposure.

On the other hand, for a patient with hydroxychloroquine-induced retinal toxicity who has not taken hydroxychloroquine for years, my impression is the quinacrine could be considered for a strong indication such as cutaneous lupus.