The corneal ulcer should be treated topically if possible first, especially if the arthritis is well-controlled with MTX. However, there are various ways to determine if the arthritis is truly under good control, and if the arthritis is not in remission, then an increase in MTX would be warranted. Systemic therapy for the corneal ulcer alone would be started if it cannot be controlled on topical therapy, or if there was very severe corneal disease or if there are recurrent attacks. 

Thank you Dr Swam for your answer. my patient is in full dose of MTX and his corneal ulcer is very severe that it couldn't be controlled topically according to ophtalmologists given the risk of perforation. So could we indicate the anti TNF alpha even if the articular lesion of rheumatoid arthritis seem to be well controled

Dr. Kechida - what level and type of invovlement does the patient have with the eye? My concern is involvement of the corneal-conjunctival junction. Another concern is possible infectious etiology that will need to be ruled out first (which I am sure has already been considered).

In my opinion, TNFs dont have a clearly established recommendation for eye involvement and it can be considered on a case by case basis...

If methotrexate is already on board, we can try increasing or adding oral glucocorticoids in addition to local ocular therapy to immediate benefit. You might need higher doses depending on what the level of eye involvement is....

Gaurav

Thank you Dr Gulati for you interest.  It's about a patient who had a paracentral corneal ulcer which is very deep with a high risk of perforation. given that the patient was diabetic with a poor diabetes control and that she was in a full dose of methotrexate with a sufficiant articular control we prefered not to add oral glucocroticoids and to add ciclosporine until we can get anti TNF alpha. I think that these patients should not be considered as on remission given that there are extra articular symptoms who are on flares and anti TNF should be given to controle the hole manifestations of the disease even if articular symptoms are sufficiently controled

1. The very first step is to rule out herpetic infection (Herpes Simplex or Herpes Zoster) which might cause such an ulcer.

2. If it is determined that the ulcer is due to RA complications such as Sjogren Syndrome or vasculitis, then aggressive therapy is mandatory. We cannot call RA well controlled just because arthritis is in check: systemic extra-articular complications will dictate more aggressive treatment.

Options:

1. Cyclosporin local ophthalmic drops is a safe and less costly option.

2. Biologic therapy can be given off label because guidelines are not yet well defined.

Rituximab has been shown to improve most parameters in Sjogren Syndrome. Its effect on tear secretion has been inconsistent in different studies.

It has a good safety profile and is easy to administer (Two IV infusions two weeks apart. May be repeated after 6 months if improvement occurred).

Rituximab is given with methotrexate. So the previous treatment for the patients will be kept.

if the patient has adequate control of articular symptoms, then i would rule out dryness of eyes probably due to secondary sjogrens which can be treated with topical agents or pilocarpine and additionally cyclosprine eye drops. as for DMARD, the preferred biologic would be rituximab after taking due precautions.

Thank you Dr Khoury and Dr Kundu for your answers. But don't you think that topic cyclosporin is associated with a risk of perforation?

RA itself can lead to corneal perforation. so it becomes a comparision of risk of perforation by RA Vs CsA. basically, eye problems should be treated by ophthalmologist. CsA is used in autoimmune corneal ulcer. of course i don't think you plan to use it indefinitely. weaker preparations can be used of course. 

Thanks for this interesting question, which is very important to improve patient's safety. As clinical pharmacist specialist usually deal with these problems (ADRs, DDIs ...) in my hospital and primary setting. 

According to the evidence-based medicine the involvement of patient in to the pharmacotherapy is an essential step. I would suggest to include patients more actively to pharmacotherapy. We should present to the patients the benefits and risks and therefore patient's opinion is very important (e.g. to continue this pharmacotherapy with MTX or switching to anti TNF alpha.

I would like to add some important remarks:

- if this adverse event is very serious and dangerous (If I see it is), drug switching is preferable than continue with the same dose of MTX,

- with anti-TNF alpha we do not have much evidence about this adverse event (minus),

- even disease can cause these affects (not only MTX) and therefore effect could be additive (to distinguish effect of drug and disease is very important step),

If I conclude, If a remission has been established i suggest (first) to taper the dose MTX (maybe these effect is dose depenent), although we should wait for a effect, because C ss of MTX in steady state already has been established (maybe months). This can cause sudden worsening of the disease and therefore a great caution is required. Maybe to add a Rituximab to small-medium doses of MTX would be the best option. If a remission will be established then you can taper the dose of MTX (If this serious adverse event is still presented). When there is no improvement occured (ADR) there is disease related AR (or idiosyncratic reaction, type C). MTX is well known about its idiosyncratic reactions and therefore adverse event still has been occured although MTX is discontinued.

If I sum up, to add a Rituximab to small-medium doses of MTX would be the best option first. After, if this is a dose dependent ADR then we can expect serious improvements in few months (because of distribution of MTX in all 3 body spaces). If this adverse event is idiosyncratic reaction (not discontinue although we discontinue with MTX) then anti-TNF alpha is maybe the best option (e.g. i would not suggest to switch to leflunomide BCS its efficacy and long half life). To add VITAMIN A and ophthalmologist is very good idea to improve patient's safety. However, we should talk with the patient and present to him/her all benefits and harms and to interview patients about her/his priorities and check the drug patient's drug ADHERENCE/COMPLIANCE first, because patient maybe took to many tablets (often see in patients treated with MTX). To include clinical pharmacist specialist would be also a great option, especially if this patient is treated with polypharmacy, because MTX can interact with several important medications and self-medications (e.g. ciprofloxacin).

Regards,

Mathew

Thank you all for your responses

Good evening Dr Kechida,

first, I would like to recognize the thoughtful contribution of Dr M Khoury to rule out viral or amebic infections in the clinical problem you raised.  I further want to assure her of our best wishes during the hardship and turmoil that her country is going through.  We all hope for a solution if that is still a possibility.

Ulcerative keratitis is not part of run-of-the-mill RA in an adult.  So the first thing to establish is that the patient really has RA and second, if so, that the keratitis is due to RA.  So, be sure of the correct rheum and ophthalm diagnoses.

If the patient has RA,

1.  Clinically, severe keratitis may be part of either RA vasculitis, secondary sicca or associated with peripheral ulcerative keratitis (see PUK in Google for differential diagnosis).  In the former, scleromalacia perforans is more expected than deep keratitis and in the first two, there should be evidence of vasculitis and severe sicca elsewhere, respectively. To be noted, that arthritis and vasculitis are often reciprocally active/inactive in RA.  So here, the "MTX-controlled arthritis" does not necessarily mean that the rheumatoid process is controlled.

2.  Serologically,  the only (high titer) specific marker for RA vasculitis is the Euroimmun anti-Sa (citrullinated-vimentin) ELISA and that for severe sicca, the more likely, if not entirely specific, is anti-La/SS-B.  RF, anti-CCP and other ANA-sub-specificities can be positive in both.  PUK is a clinical diagnosis that can be either sero-RA +, sero-SS + or sero-negative.  ANCA and APLA should be negative.

3.  Local treatment is best left to Ophthamologists.  I would not push for any kind of medicated drops like steroids or cyclosporine and favour natural tears or gels with/without antibiotics.  Just for comfort!  R/O infection...

4.  Systemic treatment is that of vasculitis: IV or PO cyclophosphamide, IV and/or PO corticosteroid boluses and RTX.  ANTI-TNF ARE BEST AVOIDED IN RA VASCULITIS OR SS.

5.  Empirically, once, I used successfully in PKU, long term (1y) treatment with a low dose daily tetracycline (for its anti-collagenase action).  It allowed the acceptance of a corneal graft after an unsuccessful attempt.

That is a complex problem and for everybody to learn, you should give us 6-mth follow-ups. 

Sorry for the length of that response but most of it is not found in textbooks.  Bonne chance!

Henri A. Ménard MD, FRCP (C)

Emeritus Professor of Medicine, McGill U.

Thank you so much Dr Ménard. It's a very helpful answer. It becomes more clear for me now

Hello,

I Strongly agree with Dr.Ménard, rule out other possible etiology (infectious, inflammatory) and I would get  Ophthalmology consultation.

 Best regards.