Should we stop hydroxychloroquine even if the disease seems to have a great risk of a flare?
Hydroxychloroquine must be stopped illico.
Ocular side effects of antimalarials are either reversible or irreversible.
Maculopathy is irreversible. Stop the drug before it gets worse.
HCQ should be stopped as its half life in retina is very long, and hence its effects are literally irreversible. However, should you want to continue anti malarials, quinacrine would be a safe alternative.
I agree, stop hydroxychloroquine. Consider corticosteroids for flare.
Thank you all for your answers but the problem is the prescription of immunosuppressors while there is no real indication to that ( no kidney flare or no neurological or hematological indication)
Of course, one must stop the drug IMMEDIATELY. But another question comes to mind: if this is already symptomatic maculopathy, why did the maculopathy develop and progress this far? Why was there no the appropriate screening along the way? Based on the calculated "mg/kg" dosing, duration of therapy and total drug burden, could the high likelihood of maculopathy not have been predicted and then prevented?
I agree, stop hydroxychloroquine.
The earliest retinal abnormalities are asymptomatic and can only be detected by ophthalmologic examination. These “premaculopathy” changes consist of macular edema, increased pigmentation, increased granularity, and loss of the foveal reflex. Subtle functional loss in the paracentral retina can occur before biomicroscopic changes in the retinal pigment epithelium. Detection of changes at this stage, using techniques such as multifocal electroretinography, is desirable since they may be completely reversible upon discontinuation of the medication.
More advanced macular disease, a true retinopathy, is characterized by a central patchy area of depigmentation of the macula surrounded by a concentric ring of pigmentation, a “bull’s eye” lesion. Symptoms at this stage are generally not reversible and may include drop out of letters from words when reading, photophobia, blurred distance vision, visual field defects, and flashing lights . In such patients, continuing depigmentation and functional loss may continue for a year or more after the drug has been stopped.
Quinacrine may be preferred in patients at ocular risk.
I agree with my colleagues, HCQ must be stopped immediately and ophtalmologic examinations should be performed more frequently, even if Quinacrine is introduced in the therapy instead of HCQ for the control of SLE flare.
Thank you all for your explanations. In response to Dr Sigal I would like to say that the patient has been regularly monitored by ophthalmic examination since 2011 with a good compliance to the treatment which doses have been calculated according to a the weight of the patient but I have to say that the patient has a highly risk retina given that she is albinos
Medication should be stopped and a regular visual field follow up should be instated
Stop the hydroxychloroquine immediately. Treat the flare if and when it presents later with other meds
Dr Kechida,
The context is paramount, raising many questions.! How old is your patient and how old was she when she developed SLE? Did she have the ocular albinism syndrome only or oculocutaneous albinism? What were her clinical and serological manifestations of SLE? What is the approximate duration of her SLE and HCQ duration and daily dosage? What did her fundi or ERG look like at baseline before HCQ? HCQ was a relative contraindication from the onset. Not a relative one anymore.
In presence of an antimalarian maculopathy, I stop the hydroxychloroquine immediately. My position in the clinical practice is the same of dr. Swan Sim Yeap . The considerations that dr. Menard propose seem to be only speculative .
Like everybody else, I also do not start and certainly stop HCQ in case of any maculopathy. My point is that HCQ may have revealed/exacerbated a preexisting ocular condition due to albinism. That would be useful to know for future drug utilization.
Ok doctor Menard. Now your considerations regarding a preexisting underextimated albinism are more useful for my clinical practice !
Thanks !
Dear Drs Manzo and Kechida,
As we are at the dawn of the revolution of precision medicine, clinical practice will change significantly in the next 5-10 years. My bias is that of a clinician scientist. My job is first to ask questions to do "precise phenotyping". Let me explain.
In most clinical milieux, antimalarial maculopathy has become a rarity because of preventive awareness and because we now know that HCQ side effects are dose-related while benefits are not. For a clinician, that translates into long term low dosage and rigorous pre-existing ocular status and regular ocular follow-up. Hence my questions about the exact dosage of HCQ. In adults, we do not calculate HCQ dosage in mg/unit weight because the hard data supporting that approach is lacking. Empirically, for an adult, we never go over 200 mg/day for maintenance after 2-3 months of loading at 400 mg/day, Irrespective of weight, except if it is in the child range, where we would cut it by 50%, always empirically. I do not treat children but I recognize that pediatricians like the mg/wt or surface area script.
I have never seen a case of ocular albinism and I would not know the extra risk of using HCQ in such a case. Dr Kechida suggests it is likely high. I would agree based on common sense but is there any hard data on that? Was the dose reduced accordingly? For which specific lupus manifestation was it used? Why risk it?
Finally, I am not aware of a uni- or bi-directional relationship between SLE and albinism. Is there one? Could SLE without HCQ make ocular albinism worse? If so, in which kind of SLE context? Hence my clinical questions about the lupus process in order to learn more from that unique patient and later speculate.
I had a case of SLE with porphyria cutanea tarda. I though HCQ would do great for the skin lesions. In fact, I was wrong and there is now a sound metabolic explanation well known in dermatology but totally absent from our rheumatology textbooks. Since then, I try to collect more than less clinical info before advising in a highly personalized medicine unique case, like this one.
Here we have a patient who IN SPITE of all precautions (taken by him/herself, Dr Kechida and the ophthalmologist) is developing a maculopathy. To stop HCQ immediately is the first thing to do but the second is to clarify how/why it happened and learn from it.
Thanks to all for allowing me to participate in that interesting discussion.
How many people would use up to the maximum dosage of 6.5mg/kg/day of hydroxychloroquine for adults?
Dear Dr Yeap,
What follows is totally empirical based on ~ 48 years of practice in a Caucasian population.
- For a 50 kg patient which would be at the lower end of the Canadian adult weigth range, 6.5 mg/kg/day means Plaquenil 325 mg/day. Not one of my patients is using that much during long term maintenance which for me is 200 mg/day. They would only reach that maximal level for a short period, during the loading phase at 400 mg/day for 2-3 mths. For a 70 kg person, that would mean, 455 mg/day. Not one of my patient. For a person like me at 90kg (working hard to loose some😊), that would mean almost 600 mg/day. At that dosage we used to frequently see maculopathy.
- HCQ like most DMARDS, does not obey the usual dose-response rule of pharmacology except for side effects. Either because they have a hit and run mechanism on long lived inflammatory cells or because they have a third storage space from where once loaded, they are slowly released and dosage is only needed for maintenance. That was shown for gold salts where one can find gold in tissues years after stopping the drug. The interval between therapeutically efficient gold shots could go for several months. I suspect there is also slow release of antimalarials in the retina and skin basal membrane. Further, the good effects continue for weeks to months after stopping until the bad cells return or the amount of released drug is too low.
I believe that most current RA or SLE treatment is still largely empirical in spite of the advent of designer drugs that we STILL use totally empirically as long as PRIMO NON NOCERE.
Best to all.
HM
Thank you Dr Ménard for your opinion and your explanation they are very helpful. I have to tell more about my patient, she was in fact diagnosed with lupus since 2011 at the age of 18, she has albinism (retina and skin). her diagnosis criteria were vespertilio erythema, thrombopenia at 90 000, lymphopenia, lupus nephritis class 1, anti DNA (+), ANA(+). She was treated with steroid and HCQ at 6.5mg/kg/day.( 400 mg / day, her weight was 60 kg) I should also say that in my department we have the habit to prescribe HCQ 5 days per week with a good outcome and a poor rate of maculopathy. Perhaps, in this case, given that the patient has a high risk retina, we would have prescribed the HCQ 200 mg*2 during the first 3 months as Dr Ménard said and then would have withdrawn the dosage to 200 mg/day. I don't have the experience to treat patients with albinism and lupus, this is the first case I have seen, perhaps I should see in the literature, as Dr Menard suggested, are there any similar cases and if albinism is a risk factor of antimalarial maculopathy. What incited me to ask the question in fact is how can I stop this drug which is very important as a treatment of lupus in a patient with a high risk of a renal flare? and what can I prescribe in place in a case of flare? I thank you all for your responses
Dear Dr Kechida,
I think with retinal problems from albinism an anti-malarial may be contra-indicated simply on caution grounds anyway. There may be few if any other cases. I am not sure that you should assume that an anti-malarial is important as a protection against lupus nephritis. I am not sure that we know it is all that potent anyway. I never had a major lupus practice as a consultant but I set up the first trial of rituximab in lupus and got familiar with colleagues practice. I think if you are worried about renal disease the key thing is regular monitoring of BP, urinary protein etc and use of more powerful drugs if needed. Sometimes we give patients treatment because we feel we should be doing something when logically it would make sense to watch and wait.
HCQ is an important drug in SLE but as Dr Edwards wrote, it is not essential, acting as a facultative add on to more critical interventions like steroids, immunosuppressive and anti- B cell therapy. Unlike its side effects, it will never give a result spectacular enough to remember. The good results are incremental and if you withold it, the long term end results are worse either because of worse renal disease or more frequent exacerbations. (See the NEJM Plaquenil withdrawal study of John Esdaile & al that finally convinced nephrologist of something rheumatologist had been doing empirically for years).. The proof of that concept was statistical from a cohort study where N=100. It cannot apply strictly in N=1 like in this case. So better to use HCQ but if you can't, you don't !!! By the way you are probably, amongst all of us, the most experienced doctor with SLE and albinism. So, be especially diligent in your clinical observation as we will all learn from it. Best.
HM.
Dear Dr Menard,
Thank you for your helpful comments. As a matter of practice, I do use the 6.5mg/kg/day calculation as a guide for the maximum dose for our Asian patients, to a maximum of 400 mg daily. At this dose, the incidence of retinopathy is very rare.
However, your point about the lack of dose-response with hydroxychloroquine would explain why there is sometimes no response to the higher dose.
Thanks and regards.
Interesting. We have three different posology for HCQ:
- a short, fixed loading dose of 400mg/day for 2 mths followed by a fixed low maintenance dose of 200 mg/day for the long term (mine in Canada);
- a continuous fixed 6.5 mg/kg/day but not more than 400mg/day (Dr Yeap in Malaysia);
- a continuous fixed 6.5 mg/kg/day but on week days only ( Dr Kechida in Monastir)
- I am quite sure that. If we were to get the practice of those who participated in this exchange, we would get as many.
I am almost sure that if we were to do a critical journal club to assess the paper where the "6.5 mg/kg/day maximum" rule came from, we may find enough flaws to invalidate part or all of it. Can somebody give us that reference so that we do the exercise?
Have a nice week-end
It's manifest that we are in presence of different point of view regarding HCQ therapy.
I use, in my clinical pratice, a schedule very similar to dr. Menard' one : a short loading dose of 400 mg/day for 4 months (instead of two) followed by a fixed low manteniance dose of 200 mg/day (even for life, in absence of side-effects). Most of Italian rheumatologist use this HCQ schedule, according to my knowledge. Certainly, the risk of HCQ maculopathy is strongly related to HCQ dosages and it is very high when we use dosages more than 400 mg/day.
I don't rule out the possibility that the patients dr. Yeap treat can heave particular characteristics : for example, they are not fat whereas this is the rule in my experience.
I don't understand because dr. Kechida propose to use 6.5 mg/kg/day on week days only. Is it able to ameliorate the outcomes of our patients ? What is the logic for this operative proposal ?
Certainly, HCQ has a long time time for removing, even in the retina. And the SLE manifestations in which we can use HCQ are indicated in the principal international guidelines.
But in addition to the international guidelines there are our personal experiences and I think that these experience are not less important.
So I am very happy for this interesting confrontation !
In our practice giving HCQ 6.5 mg/kg/day on days week only allows us to have intermediate doses between Dr Menard or your's schedule and Dr Yeap schedule. and with this schedule we have poor rates of maculopathy. But it will be interesting if we can make a trial with these 3 schedules and try to find which one is associated with the lowest rate of maculopathy and the lowest rate of flares