This live webinar will cover the basics and treatment paradigm of corticosteroid therapy (topical, regional, intraocular, and systemic) as well as the treatment paradigm for the use of immunomodulatory therapy in the treatment of noninfectious uveitis. We will review specific drugs (anti-metabolites, alkylating agents, biological) and their indications, contraindications, dosing, and side effects.
Lecturer: Dr. Ramana Moorthy, Ophthalmologist, Indiana, USA
[Bob] Good morning, everybody! My name is Bob Moorthy, Ramana Moorthy. I’m going to be giving your talk today on uveitis therapeutics as it applies to non-infectious uveitis. And there’s a lot of material. Must of the material that I’m presenting won’t be things that you will necessarily use, but I wanted you, who see uveitis patients, to be familiar with those entities and treatment options that may be available through the help of a rheumatologist or if there is an ocular immunologist or person who’s an expert in uveitis management that may be appropriate for them to be involved in the care of patients that require these treatments.
I’m going to start by sharing the slide deck here with you and here we go.
I’ve been a uveitis specialist since 1993. I’ve been in, I practice also medical and surgical retina in the Indianapolis, Indiana area. Today we’re going to talk about the treatment guidelines of systemic therapy. How do we use systemic therapy? I will also talk about some of the other things like cycloplegics, and non-steroidals, and corticosteroids, and then we’ll spend some time on immunosuppressive agents and some of the biologic response modifiers.
The treatment guidelines start out with indications. When we have identified that the uveitis, and we’ve already talked about the non-infectious versus infectious uveitis, now we’ve identified that this is not an infectious entity. If it’s non-infectious and it’s causing inflammation in the eye, how do we treat this? The indications, in terms of systemic therapy, are first of all that has to be non-infectious. And other diseases in which an inflammatory component exists, where there’s already been therapy against the Infectious cause. So for example, if somebody has tuberculosis you’ve already treated with anti-TB therapy but they have persistent inflammation, in those situations we need to consider systemic therapy and or local corticosteroid therapy. But the goal of therapy is to control the inflammation and eliminate the risk to vision from structural and functional complications from uncontrolled inflammation.
For me, control of inflammation means no cells if I can achieve that. That’s my goal, that’s the prime goal. No cells in the anterior chamber if there’s anterior chamber inflammation and really no macular edema, and stabilization of posterior segment disease. It’s very difficult to get rid of vitreous cells so I’m skirting around that issue. Vitreous cells may remain, be stable and be minimal for many years in chronic inflammation that involves the vitreous, like intermediate uveitis and pan uveitis. It should improve but you may not get rid of all the cells in the vitreous and we’ll talk about that in a second.
The choice of agent is based on the specific diagnosis. And whether or not there are concurrent ocular systemic diseases present. And the level of functional compromise. And in other words, if the patient has really good vision and has adult onset, mild intermediate uveitis, so 20/20 vision and floaters, those patients may not need to be treated as aggressively and they can be monitored, in some cases, to monitor for the progression of the disease course. Some people with that entity may not need any treatment at all.
Then monocular versus binocular disease will tell you how aggressive do I need to be? And similarly, a one-eyed patient versus a patient who has two functional eyes, in those situations also the aggressive nature of the therapy is determined. And also, of course, the patient’s desires and their past experience and what they want from the treatment. It may involve everything from their ability to tolerate the side effects of the treatment to the likelihood that they’re of childbearing age and they want to have children, that may also determine the kind of therapy you choose.
The paradigm, initially, of this therapy is to control the inflammation rapidly and then corticosteroids are really the most effective agents, with one possible exception which I’ll cover. But corticosteroids are the most rapid way of getting inflammation well-controlled, used topically, regionally, or systemically. And we’ll talk about each of those things.
How do we know that corticosteroids are the most effective agents? The good news is that there’s a randomized control superiority trials that compared systemic anti-inflammatory therapy versus the fluocinolone acetonide implant. And by systemic anti-inflammatory therapy we’re talking about corticosteroids initially, then to corticosteroid-sparing immunosuppression. Let me know from the MUST clinical studies that initially at the five-year data there was really no difference between the fluocinolone implant versus systemic anti-inflammatory therapy. But as the study progressed and the 7-year data, and now the 10-year data is coming out, we see that there may be some advantages, particularly in patients with bilateral disease to systemic immunosuppressive or immunomodulatory therapy. Systemic therapy with aggressive use of corticosteroid-sparing immunosuppression, in general, appears to be well tolerated with very few long term side effects requiring discontinuation of therapy in the MUST trial. And this is a very Important trial that was conducted in multiple centers around the world, around the globe, and so this is important information for you. And this is an ongoing evaluation with the MUST treatment trial.
For certain conditions, such as mild scleritis, nonsteroidal anti-inflammatory agents may also be used. There are some conditions where early initiation of immunomodulatory therapy, that is corticosteroid-sparing therapy, might be considered. And this is one of those expectations where we see rapid onset of anti-inflammatory activity faster than steroids. And that’s, for example, in the treatment of Behcet’s disease of the posterior segment. Agents such as infliximab or Remicade, can be with explosive onset Behcet retinal vasculitis, that can be extremely helpful in controlling inflammation very rapidly, when given intravenously as intravenous infusion.
Behcet’s is one of those conditions where we consider immunosuppression and immunomodulatory therapy starting early in the course and early initiation. It’s a sympathetic ophthalmia, necrotizing scleritis with systemic vasculitis, and serpiginous choroiditis or choroidopathy where there’s site-threatening involvement. In some cases we may want to initiate early immunomodulatory therapy.
There are other things like birdshot uveitis, juvenile idiopathic arthritis with chronic uveitis that’s steroid dependent. Multifocal choroiditis, and panuveitis, and Vogt-Koyanagi-Harada disease. These are also other conditions where we may consider early initiation of immunosuppression.
Initially, what we do with treatment is to, with corticosteroids, when we start with corticosteroids, before we start the immunomodulatory therapy, corticosteroids are the mainstay. So we start at high levels. So for example, with systemic corticosteroids we start at 1 mg per kilogram per day of prednisone for prednisone equivalent. So we’re talking about 60 to 80 mg of prednisone daily. And prednisone is gradually then tapered by 10 mg. Very typically, very slowly, I typically go down by 10 milligrams every two weeks with initial pulse therapy of the corticosteroids. And I often, if I think that the patient has one of those conditions where we want to start early immunosuppression, I may start the immunosuppression within one or two weeks of starting corticosteroid therapy.
If control cannot be achieved as you are tapering therapy, and you can’t get, for example, if I can’t get the patient controlled unless I’m using every two hour corticosteroid drops, if I’m using drops to control anterior uveitis and they still have two plus cells, and they’ve been compliant with the medicine, and are getting the drops in every two hours. In that situation I’m going to be considering, hey, I have to be more aggressive. If it’s unilateral disease, I may move on to periocular corticosteroid therapy if it’s not infectious or I may start oral corticosteroid therapy. But if oral corticosteroids themselves are failing and you cannot control the inflammation, unless the patient is on 20 or even 30 mg of maintenance prednisone which is not good. Because that’s associated with substantial increased risk the patients developing secondary complications from corticosteroids including things like hypertension, secondary diabetes. And in postmenopausal women, in particular, developing osteoporosis and bone loss, then we need to be considering the initiation of second-line therapy with immunomodulatory agents.
In second line therapy, again, a safe dose of corticosteroid is, in my opinion, probably under 10 mg of prednisone daily, typically 5 to 7 1/2 milligrams daily. That’s respectable. If you can control patience with that amount of corticosteroid who have chronic disease, that’s good and that may be required. But again, I would prefer even less than that if at all possible. And again, a lot of the decision about second-line therapy is based on even five mg daily if the patient is having a lot of intolerable side effects of prednisone, that may push me in the direction of wanting to add the second line therapy.
Let me backup for just a second. There is a general feeling, I think, among ophthalmologists and I think because of the nature of the diseases that we typically take care of, that we feel like, hey, this person has already had so many weeks of therapy they should be cured by now. And I should be able to take them off steroids. Remember that chronic diseases, unfortunately, chronic uveitis requires chronic therapy. For example, you don’t treat hypertension for one day and say it’s cured. You don’t treat diabetes with a single injection of insulin and say, “Well you’re done, you’re finished, diabetes is cured, it’s out of your body!” That’s a ridiculous statement. So when I see patients where multiple attempts are made to try to wean some small amount of steroids off and the patient keeps getting recurrences and flare wraps, I tell them, “You’ve done this for six months, how many times is it going to take you for you to realize that this disease is chronic?” It’s not going to be going away unless you have some baseline amount, the lowest possible dose of corticosteroid that is required. Whether it’s topical, regional, or systemic corticosteroid that may be required to control this inflammation.
Second-line therapy, even in acute or limited duration disease where corticosteroid therapy really has failed and has not worked, we may consider that. Or if the individuals are unable to tolerate corticosteroid therapy.
There are multiple classes of drugs in second line therapy. Generally, however, the randomized clinical trials are lacking. However, we have a lot of retrospective data that’s very useful from the SITE studies, that’s S-I-T-E studies, which I’ll refer to in a moment, and that will help us determine the selection of an agent. There are some very important studies that were done recently in multicenter studies done in India and the United States, evaluating the difference in efficacy between methotrexate and CellCept. It appears that maybe methotrexate, as a second line agent, as an anti-metabolite, may be a little bit more effective in the treatment of inflammatory disease compared to CellCept or mycophenolate mofetil. Methotrexate might be a very appropriate second line agent as a corticosteroid-sparing second line agent as a first choice of medication for anti-metabolite.
Azathioprine also is an anti-metabolite. Typically most people have shied away from using calcineurin inhibitors, particularly cyclosporine, although some people still use tacrolimus which has less toxicity and is a more potent calcineurin inhibitor. Can be given at relatively low doses with fewer side effects. Sirolimus, as it’s going to be available probably in an intravitreal injection form, shows some promise of efficacy but it is not approved intravitreally for clinical use and I don’t use it systemically.
There are alkylating agents, also, that can be utilized for the treatment of second line agents and even third line agents. These are much more potent agents and usually are used in conjunction with a rheumatologist or more likely an oncologist. Particularly, with these two agents, because they’re much more highly likely when used inappropriately, to cause secondary cancers or proliferative and leukemic disorders. I’m sorry the slides keep changing, I’m not sure why this is happening.
And biologic response modifiers such as infliximab, adalimumabe, tocilizumab, are typically the three ones that I use as second or third line agents. And typically these are third line agents when methotrexate or CellCept or Imuran have failed. This is beyond second line therapy. Sometimes we use a combination, we add the third line of agents if the second line agent and the steroids aren’t working. And we may use a combination of drugs. And sometimes if that’s not appropriate, we may switch to surgical therapy, such as vitrectomy in pars planitis that may be effective in help controlling inflammation. We may also use other things like implantable long term steroid devices such as the Reticert implant which is a fluocinolone acetonide implant.
Pregnancy and the desire to have children, these are an important part of deciding immunosuppressive therapy. And of course, with the vaccine recommendations, generally with Covid-19, it has become particularly a difficult problem to answer. But with patients who are receiving any kind of immunosuppressive therapy should probably avoid live virus bio vaccines. But in the case of Covid-19, generally the consensus has been to go ahead and immunize those folks with Covid-19. And in fact, we’re even considering a third booster dose for those who received the BNT vaccine from Pzizer or the Moderna vaccine, we’re giving a booster dose for some of these patients even in the United States. If the patient’s already immunosuppressed, generally we want to vaccinate them against Covid. And I have been pro-vaccine for these folks. Generally I tell them that we may want to hold the second line immunosupression agent like CellCept for a few days before the vaccine and a few days afterwards and then resume. And then for the Humira, for the biologics, generally I will try to time the vaccine in between their dosing without necessarily having to stop that.
The efficacy of these vaccines, in the face of immunosuppression with Covid-19, we know is less and that is why if we have efficacies between 30 and 70% as opposed to 94%, according to clinical trials in healthy individuals, we may want to do a third booster on those patients.
There are, as I was mentioning, the SITE studies and MUST clinical trials form the basis of the decision of these agents that we use. At seven years, here’s the MUST study results, when we looked at steroids plus immunosuppressive therapy, there are better visual outcomes at seven years compared to the fluocinolone implant and with comparable quality of life and safety data. It’s safe to use systemic immunosuppressive therapy in chronic uveitis and it seems to be long term better than using just the steroid implant which often has to be replaced, et cetera.
Do immunosuppressive agents increase the risk of cancer mortality? The good news is that the cancer mortality when we use, based on the SITE studies, shows that the overall cancer mortality of using anti-metabolite medicines and the calcineurin inhibitors and corticosteroids or dapsone, these incidence rates of cancer mortality are very similar to those who have never taken these immunosuppressive drugs. So that’s very good. There’s no increased risk of cancer with these agents. However, with cyclophosphamide, overall mortality was not increased and cancer mortality was not significantly increased with cyclophosphamide. However there is, if you cross a threshold with cyclophosphamide beyond the cumulative dose of 35 grams, there appears to be a substantial increased risk of secondary lymphoproliferative or leukemic malignancies, particularly AML.
With TNF inhibitors like Humira and infliximab, adalimumab, and infliximab, there was an increased risk of a hazard ratio around two of increased risk of cancer and cancer mortality. This is important to remember, that TNF inhibitors aren’t necessarily the safest choice of drug but they’re often necessary.
I’m going to switch gears. That’s the overview and this is a long lecture and I apologize. I will try not to spend too much time and bog down on the details of the immunosuppression. I wanted to give you an overview. Because many of you, as I said, probably will refer these patients to a rheumatologist and/or a uveitis specialist if there’s one in your area. If not, I think it’s important for you to know what’s available to recommend to a rheumatologist or an oncologist. Hey, this is what you need to do for me and this is what’s typically done.
We’ll talk about the simpler things though, the day-to-day things that we often forget or don’t pay attention to. Cycloplegics are very important in the treatment of anterior uveitis. Why? Because chronic anterior uveitis in particular and severe acute anterior uveitis can result in significant edema and inflammation of the iris itself that can cause the development of posterior synechiae, which can be very extensive in severe acute disease. And we want to prevent the development of posterior synechiae, keep the pupil mobile, and prevent formation of new synechiae. We use this for anterior chamber inflammation.
We also use it to reduce pain, photophobia, that is pain due to ciliary and sphincter muscle spasm, and pain from exposure to light in these acute uveitis cases. And we also use it to break recently formed synechiae. If the patient has allergy or sensitivity to the agent, this is a contraindication, of course. And the other thing is you always need to check for angle depth to make sure the patient does not have primary narrow angles, so that they do not develop angle closure attack on the cyclopedics. That’s rare, but you can assess that when you, of course, do your slit lamp examination.
I can’t express to you the importance when you give me or give us information as Cybersight mentors, when we’re looking at these cases. When I ask you and you give me the clinical information, telling me the amount of cell and flare in the anterior chamber under a slit lamp examination, telling me the nature of the vitreous and vitreous findings, how much cellularity there is the vitreous which you can assess with a slit lamp, is very important. I can’t decide how to help you treat a patient unless that information is given. Many times I have information that’s sent and I can’t determine, based on the data that’s given to me, how I can help the patient, or you, in that situation. I encourage all of you, I hope you all have slit lamps, many of you may not in the field. But a slit lamp examination in uveitis patient is very, very important.
The dosage of cycloplegics is dependent on the severity of the inflammation. If a patient has severe hypopyon uveitis from HLAB27 positive uveitis, in those cases with a lot of fibrin in the anterior chamber and the patient may present with significant synechiae formation, I will start with a very potent agent such as atropine initially. And I would use it very frequently, four times daily. A higher dose should be very carefully used in children and older adults because of the risk of getting secondary psychosis, atropine-induced psychosis, which I have seen in patients. Not in uveitis patients, but in patients however where I’ve used it as a post operative drop after retinal surgery.
Scopolamine can also be used, this is also a longer acting agent. Atropine and scopolamine typically last seven to 14 days after installation. Homatropine lasts two to five days, cyclopentolate about 24 to 28 hours, and tropicamide 12 to 24 hours in duration. The most effective use is to prevent synechiae, which really requires monitoring the pupil size and shape. And one of the things that you do with the slit lamp, when you look at a chronic uveitis patient, is to, I do, I actually tell the clock hours where there are synechiae. Because in chronic disease, sometimes you think, oh, the disease is well-controlled and the patient may come back in two or three months and they have a new area of posterior synechiae. Unless you’ve documented where it is, you may not be able to tell. This is something that you need to do.
I’ve talked about psychosis from cycloplegics, but because of their antimuscarinic effects, you can develop tachycardia, fever, urinary retention, those kinds of things. And cyclopedia, of course, induced blurred vision. When you’re using it chronically, I tell people to take it as a bedtime regimen or once weekly regimen one the inflammation is controlled. And occasionally I will just have them stop it if they have acute disease and the acute disease is gone.
Also, one thing you have to be careful about is if you use a very long-acting agent like atropine long term, the patient sometimes develops a large fixed dilated pupil because there’s posterior synechiae formation. And a dilated pupil, which is very problematic because it induces a significant amount of photophobia and other monocular diplopia and other complaints that may occur. Atropine may cause a widely dilated pupil that’s fixed due to posterior synechiae if you’re not careful. Once the acute inflammation process is under control, the atropine can be switched out to something milder like cyclopentolate, which is what I typically use.
First question that we have. Poll question. Which of the following agents is associated with the longest duration of pharmacological dilation of the pupil? Tropicamide, scopolamine, cyclopentolate, or homatropine? Let’s see if you guys were paying attention, I mentioned it. Oh, okay, not so good here. Yes, scopolamine is like atropine, it lasts seven to 14 days. It’s a very long acting cycloplegic agent. Homatropine is about two to five days in 5% homatropine. Scopolamine is a longer acting agent.
Cycloplegic induced psychosis is most likely to occur in which age group? Pediatric, young adult, elderly, or late-teens? We just briefly talked about this. This is more to see if you guys are paying attention. The right answer is pediatric, so most of you got that right, that’s good.
Non-steroidal anti-inflammatory agents can be utilized for the treatment of very mild scleritis and episcleritis. Even topical NSAIDs may be a benefit for very, very mild episcleritis. Because episcleritis is usually just a red eye with no pain. Scleritis, on the other hand, often requires systemic therapy and sometimes local therapy in carefully selected cases. It may be useful as a steroid-sparing agent, according to some studies for JIA-associated uveitis. That has not, and HLAB27 disease, I have been cautious in interpreting the data from the study that suggested this. But there is probably some role for a very, very mild disease where you don’t need, necessarily immunosuppression, but you could use this as an opinion for adults or even some children. And it can also be useful, of course, with postoperative cystoid macular edema or pseudophakic patients who may have uveitic macular edema, you can use topical NSAIDs like ketorolac or bromfenac or nepafenac. Those are agents that are readily available these days.
There are some contraindications to systemic non-steroidals, patients who have renal insufficiency, or peptic ulcer disease, or allergies, or have underlying bleeding disorders. There is some potential risk for COX-1 inhibitors that we know of for causing cardiovascular and thrombotic disease, so we have to be very careful about that.
I apologize for my cursor, I’m not sure exactly why the slides are skipping. I don’t think I’m doing anything wrong with this, but I’m not sure why this is happening.
The other things that complications can include, caustic and peptic ulcers with non-steroidals given systemically. Remember that the increased risk of gastric and peptic ulcer disease occurs when non-steroidals are combined in particular with systemic corticosteroids. But systemic corticosteroids alone probably have less risk of inducing peptic ulcer disease compared to non-steroidals alone. And certainly, non-steroidals combined with corticosteroids probably have the greatest risk, about a 20 fold greater risk than corticosteroids alone or non-steroidals alone in causing gastric or peptic ulcers. That’s very, very important to keep in mind. Occasionally you may see liver function abnormalities and clotting disorders with these agents.
In topical non-steroidals, you can absolutely see corneal epithelial breakdown and thinning, so some patients are particularly prone to having really severe keratopathy and toxicity from non-steroidal use. Be careful when you put patients on this, you need to monitor them carefully to make sure they’re tolerating it early on. I have had some patients that develop very severe corneal thinning on non-steroidal therapy that did affect their vision very, very badly. And it’s rare, I have maybe one or two patients in all the thousands of patients that I’ve treated with these agents. But it’s very important to keep in mind. It can delay wound healing and cause conjunctival hyperemia in some cases. That’s counterintuitive, right? Because we use it to treat episcleritis, but it can cause conjunctival hyperemia.
Here’s a question that I’m going to give you on which of the following is most likely to induce peptic ulcers? Systemic steroids, systemic non-steroidal anti-inflammatories, systemic corticosteroids combined with NSAIDs, or all are equally likely? We just talked about this, literally two seconds ago. Yeah, you got it. Combined systemic corticosteroids and NSAIDs are really, that’s when you’re at greatest risk. Probably 20 fold greater risk than either agent alone. You have to be very careful and probably use H2 blockers or other agents PPI inhibitors when patients are using the combination of steroids and non-steroidals in particular.
Corticosteroids we already touched on, when we use them for non-infectious uveitis or infectious uveitis as an adjunctive therapy combined with antimicrobials. Or diseases where there may be, the primary etiology has been treated but there’s an inflammatory component.
Contraindications are infections etiologies. And there’s several caveats to this. If a patient has, for topical corticosteroids, if the patient has an infectious keratitis with epithelial breakdown, you should not be using topical steroids. If the patient has an infectious herpetic retinitis, syphilitic uveitis that is untreated with antimicrobials, tuberculous uveitis that’s untreated with anti-tuberculosis therapy, those patients should not be treated with corticosteroids alone until appropriate antibiotic coverage has been given. And for appropriate periods of time. If the patient has poorly controlled diabetes, that’s a significant contraindication, especially a brittle diabetic who’s insulin dependent. Those patients can be thrown into a nonketotic hyperglycemic coma from corticosteroids. Blood sugars can go up to 600 to 800 milligrams per deciliter. Very, very high levels of sugars.
And of course, if the patient has very severe peptic ulcer disease or erosive gastritis already. And then when you have non-steroidals already being used, concomitant use of corticosteroids increases the risk of this peptic ulcer disease. And corticosteroid-induced intraocular pressure elevation may be a relative contraindication if you know this, especially if the patient has severe underlying glaucoma.
There are numerous topical preparations of corticosteroids. Difluprednate is very potent. It’s twice as potent as prednisolone acetate. Difluprednate also has a substantially greater risk of steroid-induced ocular hypertension and glaucoma. And also has a greater risk of causing steroid-induced cataract. Particularly in children, there is a potential that in difluprednate, 50% or more of children on topical difluprednate develop steroid-induced ocular hypertension. And I believe that this is a great drug to use acutely, but not a good drug to be used for chronic maintenance therapy. It’s very difficult to leave a patient on chronic maintenance difluprednate and expect that their intraocular pressures are not going to go up.
With any corticosteroid, with long term use, topical, regional, systemic, any of those can cause intraocular pressure elevation at any point during the course of treatment. In fact, a periocular corticosteroid injection, in rare cases, has been shown to cause intraocular pressure elevation years after it has been given. And it is thought that these patients may have some underlying predisposition to developing glaucoma or high pressures, and the steroids throw them over the edge.
I think it’s very, very important to monitor the intraocular pressures. Even in stable patients, in stable chronic uveitis, the longest interval I go between examinations, typically, is four months. And that’s because I have had patients at the six month interval develop dramatic glaucomatous optic disc cupping, intraocular pressure, when they have been stable for years. And I kick myself in those situations when that happens. And some patients have lost a lot of vision as a result of that. I am very, very cautious even with topical corticosteroids being used as maintenance therapy as low as one time daily. And I rarely use Durezol as a maintenance therapy. It’s great for acute control but not for it.
Other agents that are milder, I tend to use Durezol as my initial agent for severe disease, prednisolone as my initial agent for milder, and then step down therapy to prednisolone if I used difluprednate initially. And then finally fluorometholone is my third agent. I don’t use prednisolone sodium phosphate, I just don’t think it works as well. It doesn’t penetrate the cornea as well, in my experience, getting to the anterior chamber. I do not use topical dexamethasone because of its intraocular pressure issues and it’s efficacy. And rimexolone is just, I don’t use it. It’s not available for us and most of our insurance carriers don’t cover it.
Local injections of corticosteroids we’ve alluded to, but triamcinolone is the typical agent that I use. It’s a depo steroid that’s given either subconjunctivally or in the posterior sub-Tenon space. It lasts for several weeks and it can be given as frequently as every two to three weeks. But typically I give it monthly if I’m going to give it repeatedly in an eye. This is considered particularly useful in unilateral disease, unilateral chronic disease, or unilateral acute severe disease because the patient doesn’t necessarily need systemic therapy but needs more than topical drops.
Intraocular corticosteroids, I am very cautious about their use in uveitis initially. I typically will use this in selected cases where there’s foveal threatening inflammation such as foveal threatening serpiginous choroiditis responds very well to intravitreal triamcinolone. And the risks include a substantial risk of intraocular pressure elevation and cataract formation with repeated use. There are some patients who are not tolerant of steroids given systemically and intraocular steroids are the only way you can control them. But they come with substantial risk with repeated use. Of course, intraocular antibiotics and intraocular anti-VEGF inhibitors are used in selective cases for uveitis-related complications and in infections uveitis, of course.
There are other periocular preparations such as DepoMedrol that are used and shorter acting agents like betamethasone and so forth, that I rarely, if ever, use.
There are any ways to deliver regional corticosteroids. I typically will give a posterior sub-Tenon’s injection. This is a patient of mine where I’m having her look down and in and I give it in the superior temporal quadrant. I will use the lacrimal gland as a guide to where I put the needle entry, just anterior to the edge of the lacrimal gland, the palpebral lobe of the lacrimal gland. And very gently use a sweeping motion as described by Dr. Robert Nozit many years ago. Using a short, ⅝ inch 25 gauge needle with a 3cc syringe. I use a 3cc syringe because the plunger does not have to be so far back compared to a Tuberculin syringe. My hands are fairly short and small and so it’s convenient. I know I’ve gotten the feel of how that is supposed to feel as I inject.
I have seen complications from this that can be devastating. I have seen two patients that I performed periocular corticosteroids that developed intra-arterial embolisation of the corticosteroid. One patient who has orbital disease that had a severely inflamed sarcoid-related inflammatory lacrimal gland and orbititis. And I gave her a corticosteroid injection after an orbital biopsy surgery. And the patient developed intra-arterial embolisation into the choroidal vessels as well as the retinal vessels and became NLP. The patient fortunately recovered completely to 20/20 vision about a week later. I gave her intensive corticosteroid therapy, emergent paracentesis, and was able to move most of those corticosteroid particles and there were very few.
I’ve had another patient, unfortunately, where that happened too, where she lost most of her vision and did not recover. That can happen. Ao I always retract the plunger once I’ve gotten to the point, I advance the hub of the needle, and retract the plunger to make sure there’s no blood that comes back, and make sure there’s not much resistance. If you feel a lot of resistance, you’re in the wrong spot. You may be near a vessel, you may be in a position where that… And the bevel of the needle is always pointed down towards the globe as I’m advancing.
If you don’t feel comfortable with this, and many people don’t, the other approach is to do a retroseptal approach with a short 27 gauge needle. A 27 gauge needle and 3cc syringe. And you’ll go directly, there’s no, you go transcutaneously and this is very well-tolerated with a 27 gauge needle. I would not use a 25 gauge needle here, that’s more painful. And go directly feeling the margin of the globe and just staying below the globe and go directly through the orbital septum perpendicular to the orbital septum, just inferior to the globe.
There are complications with both of these techniques. You can see ptosis develop with this technique with the posterior sub-Tenon’s technique. The retroseptal technique you can see orbital festoons develop and the subcutaneous orbital prolapse.
The oral agents typically that I use are prednisone, I alluded to this early. One milligram per kilogram per day starting dose and then gradually taper. With the topical steroids and with oral prednisone, the idea, the paradigm of treatment is to start at high doses and gradually taper. Most episodes of inflammation, like it or not, and you may disagree with this, this is just an observational thing. For example, HLAB27 disease, anterior uveitis lasts 12 to 16 weeks. If you’re tapering these patients off in two weeks, they’re going to reoccur. Be careful. I would rather over treat an acute episode and monitor the patient and gradually taper them off, than for them to have a recurrence which will become recalcitrant of therapy and then become chronic. And that happens often in HLAB27 disease. It’s very important to remember that and keep that in mind.
Oral agents, prednisone is typically what I use. Intravenously, you can give methylprednisolone for the most severe diseases. We used to use, for example, explosive onset Behcet’s or severe VKH disease, I will use high doses of IV steroids for three days and then transition to oral corticosteroids. patients often needed to be admitted to the hospital. Sometimes we can do this outpatient. But the blood pressure and blood sugars should be monitored very carefully when you’re giving intravenous therapy with these agents.
There are ocular complications from steroids of any form, including posterior subcapsular cataract and intraocular pressures. With systemic use there are many short-term complications including weight gain, mood swings, acute hyperglycemia, manifestations of latent diabetes where you may have a person who has glucose intolerance that becomes frankly diabetic, exacerbation of hypertension, fluid retention, worsening of congestive heart failure, potassium loss, hypokalemic alkalosis, and hypertension, all these things are risks.
Patients who receive high doses of corticosteroids, over 60 milligrams a day, may be particularly at risk, although idiosyncratically, for the development of aseptic necrosis of the femoral and humeral heads. A devastating complication that is rare, but can definitely happen with higher doses. I have seen it with corticosteroids. If a patient develops hip pain on a high dose of corticosteroid therapy, they need to be, the corticosteroid probably needs to be stopped fairly rapidly. And the patient needs to be referred to an orthopedic specialist and have an MRI of their hips to look for aseptic necrosis.
There may be other things that are common, many different side effects. Every possible systemic side effects associated with the human body, I think, has been reported with corticosteroids. If you have infections that are untreated, they can get worse on steroids. Long term use, osteoporosis in post menapausal women, especially if it begins to develop within three to four months of corticosteroid systemic therapy. Once the patient is on maintenance steroids, annual bone density studies to look for osteoporosis is very important.
There’s imparied wound healing with chronic corticosteroid use. You can develop many other problems, everything from fatty liver to chronic pancreatitis, peptic ulcer disease, et cetera. You can reactive latent tuberculosis when inappropriately or inadequately TB may be present in patients in TB endemic areas in particular. Pathologic fractures of long bones, fat redistribution, and the development of the humpback and Cushingoid features from chronic steroid use are well-known.
Regional corticosteroids, I’ve already told you about injections of the retinal or choroidal circulation, perforation of the globe, that can occur in hypotenous eyes, in particular. It can occur with retroseptal as well as posterior sub-Tenon’s injection. I have seen both. And I’ve done one, fortunately with a happy outcome but it can be very, very significant. Can create significant problems. So be very, very cautious in patients. Ptosis and proptosis we’ve already talked about, orbital fat prolapse we’ve talked about. Patients can develop subconjunctival hemorrhage with the injection, a periorbital hemorrhage can occur as well. Although corticosteroids, when given in the periocular space, don’t typically cause systemic problems, they still get absorbed systemically. They can affect blood sugars, they can affect blood pressure in some patients who are prone to having problems.
Intravitreal corticosteroid implants like Retisert or the Yutiq, for example, that are used for the treatment of uveitis and uveitic cystoid macular edema, last for a long time. And Retisert, in particular, is associated with cataract formation within two years after implantation in 100% of phakic patients. Cataract will occur in two years, guaranteed. And 40% of patients may need surgical intervention for glaucoma, 50% will need glaucoma topical medications with these sustained release implants, particularly this is mainly referring to Retisert. Similar data, although less severe, has been reported even with the Yutiq implant, Yutiq brand of low dose fluocinolone acetonide implant.
Vitreous opacities and vitreous hemorrhage are very common postoperatively and these usually spontaneously resolve. Endophthalmitis is a potential risk because you’re doing surgery and conjunctival erosion of the anchor suture can occur with the Retisert implant. Again, with the Retisert implant you have to start managing their immunomodulatory therapy in corticosteroids and start tapering them and get them off these agents relatively rapidly once you have done the Reticert implant placement.
Reticent implant, by the way, the retail price in the United States is $19,000. That is very difficult in private practice to have a surgery center obtain this, so we often have to fight with the insurance companies to get this approved before a patient can get this implant. It is still a product that has a role to play in the management of chronic uveitis, and posterior uveitis in particular.
We’ve already talked about many of these other things. External infection disease in the conjunctiva is a contraindication to topical corticosteroid use. Some patients with topical corticosteroid use chronically can develop recurrence of conjunctival hemorrhages which can be a nuisance for the patient. You need to monitor these patients carefully, we’ve already talked about some of these monitoring issues.
Next question, if a patient was treated with, I’m sorry, I can’t see the question, with 60 milligram daily for a week for uveitis and the prednisone dose was tapered and discontinued over a six week period thereafter, which of the following complications of corticosteroids would be least likely to occur during this period of treatment? Weight gain, aseptic necrosis of the hip, hypertension, or mood disturbance? We touched on this, this is a little bit more difficult question. Let’s see if you’ve come up with an answer. Yeah, you’re right, aseptic necrosis of the hip is pretty uncommon. It’s a severe and devastating problem but it’s very idiosyncratic and it occurs usually in patients who are receiving more than 60 milligrams a day, but in high dose therapy.
All right, the following tests need to be performed for the patients on maintenance therapy of oral prednisone of less than 10 milligrams daily. Monthly SGOT/SGPT liver function tests, Monthly BUN and creatinine, annual complete blood count, or annual bone density scan? When you’re on maintenance corticosteroids, we talked about this as well. Especially in postmenapausal women, we worry about what? That’s right, most of you got it. That’s excellent. You worry about osteoporosis, so you want to do an annual bone density study if it’s available in your community.
We’ll move on now and talk about the second line agents beyond corticosteroids. Let’s say that you’ve got the patient, a patient who has bilateral, and we’ll make it simple, I don’t want, there’s any exceptions to all of these. I don’t want to get bogged down on the details here. Bilateral chronic inflammatory disease, you can’t go below 20 milligrams of prednisone before they start flaring up. They have chronic cystoid macular edema, it’s just not responding to steroids alone. They’re also developing a cataract, they have intraocular pressure problems, and you need to do something to get them off. What are your choices? My first choice is usually to go to an anti-metabolite. Methotrexate may be my first agent, although for me, it has been personally for the last 10 years, I’ve been using mycophenolate mofetil for the last 15 years. Mycophenolate mofetil, usually, one gram BID to one and a half grams BID, that’s a total dose of three grams per day. And then the other possibility is starting at a relatively moderate dose of methotrexate and increasing rapidly based on response.
A couple of things we’ll talk about each of these agents. If these fail, I sometimes will then move on, or I’ll add a TNF inhibitor these days. Because of the data results we’ve talked about from the visual studies, Visual I and Visual II, which are beautiful studies that actually probably are the cornerstone of great clinical trials, in my opinion. Really well done, because I think the uveitis specialists that were involved with this to design these studies really had a great idea on how to conduct these trials and really understood uveitis.
There are some patients who are treated for mild ocular cicatricial pemphigoid, they can be treated with non-steroidal medications like Dapsone or sulfasalazine for mild OCP. But corticosteroids are really the first line therapy. We talked about second line therapy as being anti-metabolites and then other things. And then third line therapy is usually anti-TNF therapy and in some cases Rituxan.
The mechanisms of these anti-metabolites, in particular, are really directed towards interference with cell division, particularly with inflammatory cell division directed towards inhibition of T-cell replication. And that’s where the target really is. They’re broad, right, they’re given orally, so they affect all the cells that are dividing in the body. But their most profound effects we see are typically going to be as a result of their effects on inhibition T-helper cell replication which is one of the fundamental concepts of autoimmune uveitis, or non-infectious uveitis development. We have these agents, steroids work at the level of the antigen presenting cell as also the cell nuclear level in terms of transcription, translation. And with the cyclosporine and tacrolimus are calcineurin inhibitors that subsequently can affect DNA replication and transcription and translation.
And then mycophenolate and azathioprine and to a great extent, also methotrexate, those are inhibitors of the cell cycle and we’ll talk about methotrexate a little bit more in detail. But mycophenolate and azathioprine, in particular, are purine synthesis analog inhibitors. And they have a specific role, similarly in inhibiting T-helper cell proliferation.
When I start immunomodulatory theory, I will typically get a complete blood count and liver function tests, and a metabolic profile on patients. If I’m using azathioprine, I used to check for Thiopurine methyltransferase activity because there are heterozygous and homozygous mutations for this particular enzyme that can cause liver toxicity from azathioprine. Although this is a very expensive test, I sometimes do it. But I will usually start at low doses of azathioprine and monitor liver function tests very closely because you’re going to be able to tell fairly quickly within a few weeks of therapy how the patient’s going to respond and whether they have a heterozygous or homozygous mutation for TPMT.
The routine monitoring, initially, once they start immunosuppressive therapy with anti-metabolites or alkylating agents is CBC and liver function tests at least monthly, initially. And then once they’re on a stable dose, every two to three months or less. And often I’ll have the internist and a rheumatologist follow along with me. I prescribe my own anti-metabolite and anti-TNF therapy for Humira. If I need infusion therapies, Rituximab or if I need chlorambucil, I may rely on rheumatologist or an oncologist, particularly for chlorambucil therapy.
There’s special consideration, fetal risk consideration for immunosuppression. There are certain drugs that are allowed during pregnancy. Glucocorticoids or corticosteroids are allowed, azathioprine and 6-Mercaptopurine are allowed during pregnancy and TNF inhibitors are allowed. In childbearing age, those are agents that may be more safe to consider. Cyclosporine and tacrolimus also have been used during pregnancy and they have relatively low maternal and fetal risk.
But moderate fetal risk and harm, of course, is what cyclophosphamide, methotrexate is moderate to high risk because it’s a category X medication, was originally an abortifacient. It is not something that you want to use in childbearing years, unless the patient is practicing two forms of contraception. Mycophenolate mofetil, similarly, leflunomide similarly, this is rarely used. This is an agent I rarely if ever use. And then of course, in the third trimester, use of aspirin and non-steroidals you have to be careful.
There are certain unknown risks during pregnancy, specifically the Rituxan and some of these other agents. Tocilizumab we don’t know.
Let’s switch to anti-metabolites, we’ll talk a little bit quickly. I don’t expect you to know all of these things, but basically methotrexate works as a inhibitor of dihydrofolate to tetrahydrofolate, so dihydrofolate reductase enzyme, that’s one step. It can also be important in terms of extracellular release of adenosine which also has anti-inflammatory properties. And it is important in transmethylation reaction and division and it also affects the thymidylate synthase pathway as well. All of which, basically, inhibit purine de novo synthesis and inhibit cell replication and DNA synthesis and subsequently transcription and translation.
The pharmacokinetics typically we give orally or subcutaneously and it’s a slower action agent, tends to last long and so it’s given weekly. It takes up to three to six months, really six months to have full intraocular effect. Level II data and now Level I data, that I eluded to early, shows that in the SITE data there was ⅔ of patients had no inflammation at one year and 58% were able to reduce their prednisone dose to less than 10 milligrams daily. And now we have additional data from a randomized clinical trial that has shown that methotrexate is probably a little bit more effective than mycophenolate. But again, the choice of agents is really based on an individual basis. Nobody is going to criticize you if you use mycophenolate over methotrexate. And so those two agents, methotrexate is probably a little bit more effective in controlling uveitis. And being able to allow the taper of oral prednisone, compared to mycophenolate itself.
There are no long term increased risk of neoplasia or secondary cancers with methotrexate. But you can develop liver function enzyme elevation with treatment that needs to be monitored in children, especially. And with long term use you can develop cirrhosis with high dose methotrexate if you follow the liver enzymes carefully. And you can also develop secondary pulmonary fibrosis which is a rare complication of methotrexate. Sometimes seen in chemotherapy for cancer when high dose methotrexate is used.
You prevent complications by avoiding alcohol, avoiding other medicines that affect the liver, appropriate contraception in women of childbearing age and men of childbearing age also. And, of course, use of folic acid supplementation for citrovorum rescue. Typically folic acid of one to two milligrams per day is given to avoid serious side effects like lethargy, generalized malaise, and stomach pain, those types of side effects that are very common, and fatigue, that are common with methotrexate.
Imuran, again, inhibits the de novo purine synthesis by, again, affecting the thiopurine methyltransferase enzyme and when you use this medication you incorporate abnormal purine analogues into the DNA that results of stopping of DNA replication and subsequently cell division will stop. Again, we discussed the TPMT deficiency. Usually I use 100 to 200 milligrams per day as the typical dose of Imuran. And we reduce the doses if the patient has a known heterozygous TPMT deficiency. With homozygous TPMT deficiency, I don’t use it at all. It’s very rare, but I don’t use Imuran at all. Again, the SITE data shows some definite efficacy for this agent. And 62% have no inflammation up to one year of Imuran use on the SITE study. And 42% were able to reduce their prednisone below 10 milligrams daily maintenance.
Leukopenia elevation liver function tests are complications. Mycophenolate mofetil is an inosine monophosphate dehydrogenase inhibitor. It is a purine analogue kind of, its effects are that it inhibits purine synthesis and DNA synthesis ultimately.
Here you have the dosing is usually 1,000 to 1,500 milligrams twice daily and patients typically are going to be complaining of gastrointestinal disturbances if they don’t take the medicine properly. Unlike prednisone, mycophenolate has to be given two to three hours prior to or after food on an empty stomach. That’s very important. GI disturbances like diarrhea and constipation and nausea are very common and account for the most common side effects that require discontinuation of therapy. I really make sure I drive home the point that they need to take this medicine on an empty stomach. And you can develop leukopenia. There is some increased risk in the rheumatologic literature of lymphoma or leukemia and progressive multifocal leukoencephalopathy is an idiosyncratic reaction that has been reported with CellCept.
There is substantial Level I evidence, as well as Level II evidence from SITE data to suggest that there is substantial positive effect from the use of mycophenolate in the control of inflammation. As I mentioned earlier, the most recent study looking at methotrexate versus mycophenolate, shows that methotrexate may be slightly more effective in the treatment of non-infectious uveitis and allowing a great ability to reduce prednisone dosage and have better long term control. And so there’s good data to suggest that, however, that mycophenolate is still effective and still a good choice of an anti-metabolite.
Calcineurin inhibitors work differently. They do affect the translation and transcription of IL-2. And they are considered IL-2 inhibitors through a primary pathway inhibiting calcineurin, which inhibits NFAT dephosphorylation. And in that particular nuclear factor is then important in IL-2 gene synthesis so it can impact and cause reduction of IL-2 release. IL-2 is, of course, you know is a very important cytokine for T-helper cell proliferation. And so this is how the cyclosporine… Cyclosporine is a byproduct of a fungus, was discovered accidentally. And is a terrific agent, really is very highly useful in organ transplant patients. And now it’s been replaced, for the most part, by tacrolimus which works in a similar mechanism.
The dosage of cyclosporine is two to five milligrams per kilogram per day. When it’s used in combination with other anti-metabolites, for example, it’s used at a lower dosage. It’s usually two and a half milligrams per kilogram per day. And again, I typically just follow renal functions on cyclosporine as well as liver function tests. We used to monitor trough levels of cyclosporine which were very difficult to do using a radioimmunoassay. That isn’t necessary anymore, it’s found to be just as effective to monitor renal functions in those patients rather than trough levels.
Tacrolimus is a more potent agent and you can use a lower dose of .1 to .15 milligrams per kilogram per day. I have very little experience with tacrolimus. I have some experience with cyclosporine, but I don’t use cyclosporine very much anymore. There is modest efficacy and good Level I evidence of its use in organ transplantation. The SITE data is good Level II evidence to suggest that at one year more than half the patients do have no inflammation on this agent.
It is difficult to wean patients off of cyclosporine. It’s almost as dose-dependent long term use as prednisone is so that’s another reason I don’t like to use it. And there’s lots of complications that occur with hypertension, renal function problems with higher doses, hirsutism, gingival hyperplasia, trembling, paresthesias, there’s neurologic complications of it. So I like to avoid this agent.
In really severe cases of systemic vasculitis and necrotising scleritis, I will use alkylating agents such as cyclophosphamide. These are typically, and/or chlorambucil. Chlorambucil is also used in very profound, severe uveitis that has not been responsive to anything else. In these situations, the efficacy of these agents is based on the fact that they axially cause alkylation, or cause DNA crosslinking, and ultimately cause cell death. There are toxic metabolites of Cytoxan or cyclophosphamide, which is acrolein. Acrolein can cause hemorrhagic cystitis in the bladder. And so you have to make sure that patients who are being treated with Cytoxan intravenously or orally, receive very substantial fluid hydration prior to and during therapy.
Orally, Cytoxan is given at 100 to 150 milligrams daily. Maximum of 200 milligrams daily with a maximum cumulative dose of 35 grams, at which point I stop. Typically that takes about six months to achieve. immunosuppressive pulse therapy can be given monthly for six to 12 months as well. I know some folks in India, some of the Europeans do use this in the hospital setting. Again, this is done through an oncologist. Highly effective agents in terms of Level II evidence from the SITE studies for ocular cicatricial pemphigoid and systemic vasculitis. Shows that more than three quarters of patients will have no inflammation within a year and most patients are able to reduce their prednisone dependency.
Chlorambucil is a much slower acting agent but we can use short term high dose therapy for three to six months. That’s highly effective. And I’ve used this on a couple of very recalcitrant patients in the last couple of years. Two, actually, during the pandemic who did very, very well. But you have to be very careful with these alkylating agents because of opportunistic infection risk. Bactrim is usually given daily as prophylaxis for pneumocystis. You have to watch for cyclophosphamide induced hemorrhagic cystitis and maintain adequate hydration, as I mentioned. Neoplastic risk, you need to monitor CBC and liver function tests very carefully and sometimes weekly, particularly with high dose chlorambucil therapy. That’s why you need to have an oncologist in the care of these types of patients where you’re considering these agents. The patients can develop severe gonadal suppression and permanent sterility with these agents as well.
When we failed with anti-metabolites or calcineurin inhibitors, we often go to biologic response modifiers even before we consider alkylating agents. And biologic response modifiers typically are done with the help of a rheumatologist. Although now with the approval of Humira for primary non-infectious intermediate and posterior panuveitis, we have been able to prescribe this ourselves, but with caution. There are some pre-procedure things that you need to do, pre prescription things that you need to do to evaluate the patient. Such as making sure that they have a hepatitis screen, making sure they don’t have active or chronic active hepatitis C or hepatitis B, and make sure they do not have HIV, of course, make sure they do not have a history of multiple sclerosis, congestive heart failure, underlying history of lupus, because these agents can also induce lupus-like syndromes. All of these need to be considered.
These are not off-label for ocular disease anymore. That slide needs to be changed, I apologize, I thought I got that out of there. Because of the visual studies particularly for Humira. You got to make sure that you’re not dealing with an infectious condition. And finally, you’ve got to make sure that the patient doesn’t have TB, or other fungal illnesses like histoplasmosis. If the patient has latent TB or a history of TB, that kind of thing, you have to make sure that they’ve been adequately treated and that’s been assessed by an infectious disease specialist before you use biologic response modifiers.
There are many, many, many biologic response modifiers that are now available. Many of them are monoclonal antibodies, if they say -mab at the end, that’s what it means. The -cept, C-E-P-T, are usually receptor analogues. And then the pegols are usually pegylated polyethylene glycol conjugates of antibodies are also being utilized. The naming of these agents are based on their chemical structure and how they’re engineered.
There’s numerous clinical trials now showing that there have been efficacy in the use of the TNF-alpha inhibitors. How does TNF-alpha inhibitors work? They really do inhibit at a very high level the induction of IL-1 and many of the pro-inflammatory cytokine releases from inflammatory cells, including the CD4 helper cells, T-helper cells, as well as macrophages. They work at the antigen presenting cell level, the post antigen presenting cell, activated macrophage level, as well as the T-helper cell level in terms of inhibiting inflammatory disease.
Infliximab will bind membrane-bound TNF-alpha and also the soluble TNF-alpha is bound by Infliximab. Infliximab is a chimeric antibody, it has a murine component that’s the variable region and a human IgG Fc component. Whereas adalimumab, again a monoclonal antibody, that is completely humanized. And etanercept, which we typically don’t use primarily for the treatment of uveitis, and in fact, etanercept has the clouded history of potentially being a cause of the de novo uveitis in patients who don’t have a history of uveitis. We avoid it. But it’s a receptor analogue and it has a human Fc component and a human chain, a TNF receptor chain that binds solubilized TNF-alpha.
Etanercept is no better than placebo in the treatment of uveitis, we have Level I evidence of that. Infliximab there was Level II evidence and there’s strong evidence for use in explosive onset Behcet’s disease. Adalimumab now has Level I evidence for the treatment and efficacy of non-infectious intermediate posterior and panuveitis. There is evidence of some of these other ones but it’s weak. Certolizumab and Golimumab are not agents that we typically use for the treatment of uveitis. They may be used for other autoimmune diseases.
Complications include hypersensitivity reactions and infusion reactions with use of infliximab, but you can have exacerbation of demyelinating disease, congestive heart failure, exacerbation of TB, drug-induced lupus, and secondary neoplasia, and heart failure. All of these are potential risks of TNF-alpha inhibitors. Those are important things for you to remember.
Adalimumab, in particular, I’m going to cover because we use this frequently, in my experience, as a third line agent, occasionally as a second line agent for the treatment of uveitis. Visual I and Visual II studies show that adalimumab increases the interval to the treatment failure from 13 to 24 weeks, it increases the interval of flare from 4.8 months to 10 months as oral corticosteroid doses are tapered, and reduces the risk of vision loss. FDA improved this drug in 2016 for non-infectious intermediate, posterior uveitis, and panuveitis. These are important Visual I and Visual II trials, are important. They were published in “Lancet” and “New England Journal of Medicine”, so that tells you the level of import of the study findings.
The hazard ratio time to treatment failure between adalimumab versus placebo is .5. Therefore the risk to fail was about 50% for adalimumab compared with the standard of care therapy in placebo with steroids. The median time to treatment failure was prolonged by 87%, as I said up to 24 weeks, as steroids were tapers. This is remarkable efficacy. We know how well it works. Is it a cure? No. But it’s extremely effective in controlling inflammation.
It really significantly reduces worsening of AC cell grade and reduced development of new lesions as corticosteroids were tapered. And the primary end point time to treatment failure, again, the median time to treatment failure was 8.3 months for the placebo but was not estimable with adalimumab, as fewer as half of the ADA-treated patients, adalimumab-treated patients, experienced treatment failure. This is a remarkably effective thing. This trial is ongoing, so you’ll see from additional information published here soon, if it’s not already been published.
There is definitely efficacy in use of these medications. Compared to placebo, adalimumab is very, very effective. In patients with active non-infectious uveitis, adalimumab significantly lowered the risk of uveitic flare as the prednisone is tapered or best corrected visual acuity loss. And patients on adalimumab had lower risk to fail and fewer criteria for treatment failure were met, and worsening of AC cell grade, vitreous haze, and best corrected visual acuity from best state was achieved, as well as the occurrence of new lesions were reduced with adalimumab compared with placebo. It was highly effective compared with placebo with just steroid taper.
Adverse events data were similar between placebo and adalimumab groups. And the safety profile was very well compatible with what was already known about the safety profile of adalimumab. And the FDA approved it across these indications for uveitis.
There are numerous secondary endpoints to this study, I won’t go into the details of it. Needless to say, that even the secondary endpoints suggested that TNF-alpha inhibitors were very highly effective compared to placebo.
Rituxan is used in very severe selected cases of inflammatory disease, particularly in the management of GPA granulomatosis with polyangiitis and systemic vasculitis for severe and rapid control of disease. This is like giving a bone marrow transplant with an IV infusion. Rituxan knocks out all the CD20 positive B-lymphocytes and really has a profound lymphopenic effect and really reduces inflammation in patients with vasculitis. It’s also very effective in the treatment of primary intraocular lymphoma as an intravitreal agent as well as a systemic agent.
And so this is where it’s very useful from a refractory scleritis, associated systemic vasculitis or systemic vascular disease in general, and we can also use it for selective cases of OCP, severe orbital inflammation, and pediatric uveitis. There can be profound lymphopenia, infusion reactions can occur, and hypersensitive reactions can occur.
I have a few questions and then I’ll try to wrap things up. I do have some cases. It’s going to go on, this is a very lengthy lecture. If you want me to stop, because it’s getting late in the day, I can certainly do that. I appreciate your attention. But we’ll do these questions quickly.
Which of the following immunosuppressive agents is used to treat ocular inflammatory disease most clearly associated with increased risk of malignancy? Cyclosporine, azathioprine, methotrexate, or cyclophosphamide? Yes, cyclophosphamide because it’s an alkylating agent. Especially after 35 gram cumulative dose, you’re going to increase the risk of malignancy.
Next, the daily dosage should be adjusted based on which of the following laboratory tests of cyclosporine? Hematocrit, platelet count, creatinine, or glucose? Yeah, exactly, renal function testing is very important so creatinine level is what you need to check in patients who are given systemic cyclosporine because of its potential toxicity profile.
Next, what does monoclonal antibody infliximab target? Let’s see if you were paying attention. Interleukin-2, cyclo-oxygenase, choroidal melanoma cells, tumor necrosis factor-alpha? (chuckles) This is an easy question, right? Everybody should get this one. Yeah, it targets TNF-alpha, it’s a TNF-alpha inhibitor. Remicade or infliximab. We talked about adalimumab and infliximab, those are the two agents that are most commonly used in the treatment of uveitis, as second or third line agents.
Which of the following is not a contraindication for TNF-alpha inhibitors? Multiple sclerosis, uveitis in a child younger than 10 years of age, TB, or heart failure. Which is not a contraindication? Where would you use a TNF-alpha inhibitor? The answer is yes. TNF-alpha inhibitors, they can cause exacerbation of underlying multiple sclerosis or cause de novo demyelinating disease. They can cause worsening or exacerbation of heart failure. They can cause a reactivation of latent tuberculosis. Those are all contraindications. But we use Remicade and Humira in the treatment of uveitis in children very commonly, so that’s not a contraindication, that’s the answer.
Most common side effect of mycophenolate mofetil? Is gastrointestinal disturbances like diarrhea, myelosuppression, elevation of liver function tests, or nephrotoxicity? The most common side effect of mycophenolate, it was in a slide in yellow, 18% developed this side effect in clinical studies. Diarrhea or gastrointestinal side effects are the most common, that is correct.
Let’s see, I think we’re coming down to the end here. Which anti-metabolite has the most rapid onset of therapeutic immunosuppressive activity? Methotrexate, chlorambucil, mycophenolate, or azathioprine? Just a hint, methotrexate and azathioprine take six months to be most effective. The answer, this is a tough one, methotrexate takes very long, it’s not the most rapid. Mycophenolate is the most rapid. Mycophenalate, in my experience, within a couple of months we can see its anti-inflammatory effects in the eye, two to three months. Methotrexate longer. Chlorambucil is a tricky one because if you use a high dose/short term therapy, you may see an efficacy of inflammatory control within the first two to three months. But it’s variable in its effect. I would have accepted either chlorambucil or mycophenolate, high dose chlorambucil or mycophenolate as the answer. But mycophenolate is the answer in that slide.
There are many other biologic response modifiers. Tocilizumab is used as another useful agent when our traditional TNF-alpha inhibitors fail. And I have had some experience with the use of that agent. Some of these other agents such as IL-6 inhibitors and Th17 inhibitors, I have less experience with. Many of these are still undergoing clinical trials and so and they’re used for treatment of other autoimmune conditions.
Secukinumab is an IL-17 inhibitor, it has sustained inhibitor activity for two months after treatment. This is something that is being evaluated still and may have some role, along with tocilizumab and the treatment of ocular inflammation.
The goal of treatment for uveitis is A, start with corticosteroids. Topical, regional if it’s unilateral, and then orals if it’s bilateral at high doses and then gradually taper very slowly. And if they can’t be tapered to reasonable dosage to control the inflammation with chronic disease, then you have to institute immunomodulatory therapy. In the most severe cases, especially in severe chronic disease, you need to institute immunosuppressive therapy sooner. Immunosuppressive therapy and/or steroid therapy requires vigilance and close monitoring and therapy may be required for many years. We know when to start therapy, mostly, but we don’t know when to stop therapy. When do you predict that a patient has achieved durable remission? We don’t know.
I’m going to go through these cases very quickly. This is a patient who presents with severe pain and has had flattening of her nasal cartilage and auricular cartilage pain. This is a case of the diagnosis, you see these white areas is where the pain is most intense, the entire eye is very injected. This patient also has significant joint pain but has noticed her bridge of her nose is flattened and she has pain in her ear cartilage. This is relapsing polychondritis associated with necrotising scleritis. The treatment of this is rapid, we use corticosteroids with rapid induction of immunosuppressive therapy. Usually with this we use alkylating agents and/or nowadays, Rituxan, which is associated with a good response to systemic vasculitis and necrotizing scleritis.
This is a patient who presents with acute, red, photophobic painful eye. Vision is count fingers with the plasmoid aqueous and a small hypopyon. And he has this psoriasis. The diagnosis here is HLAB27 positive, hyperacute anterior uveitis with plasmoid aqueous and hypopyon. This patient should also be tested for syphilis and it’s negative. In this case we started aggressive topical steroid therapy and also instituted oral steroids because of the severity of the ocular inflammation and we tapered the oral steroids over three months and the topical steroids over 16 weeks. And was evaluated by rheumatology for the further treatment of the systemic psoriasis, psoriatic arthritis.
This patient can be treated with corticosteroids alone and with heavy doses can be controlled without necessarily using immunosuppressives for the treatment of uveitis. Inadequate control of inflammation in this kind of a case can result in chronic disease, at which point they become recalcant to steroid therapy, and at which point they will require immunosuppression. Also, aggressive use of atropine in a case like this, in the early cases, to cycloplege and dilate the pupil is important. And once the inflammation is better controlled we can switch to atropine to cyclopentolate which is a milder mydriatic agent. Frequent topical steroid drops tapered very slowly, periocular steroids can also be done if it’s unilateral, oral corticosteroids can be done. Watch out for recurrent and chronic disease.
This is a patient who presented like this with poor vision in both eyes and she was five years old. This was a tragic case. This is a patient who had calcific band keratopathy, chronic posterior synechiae, she also had some mild joint pains in her knee and ankle. She has chronic anterior uveitis associated with juvenile idiopathic arthritis. She was ANA positive and also had oligoarticular disease. We’ve ruled out infectious causes and the patient was started on topical steroids and cycloplegics, but rapidly was started on immunosuppressive therapy with methotrexate and TNF-alpha inhibitors.
Here’s another patient with a classic disease. This is a patient, when you look at it, you know what the diagnosis is, right? This is a patient who has birdshot uveitis, birdshot retinochoroiditis, disc edema, multiple birdshot-like lesions, vascular leakage and CME, and disc staining. This patient can be treated initially with oral corticosteroids. But most, since they have bilateral disease, will require long term immunosuppression. We can use anti-metabolites with or without TNF-alpha inhibitors. Some folks feel that management of these patients can be done with Retisert implantation, which is not unreasonable. But because it’s a lifelong disease, these implants last three years, they need to be replaced every three years. And 100% will develop cataracts with Retisert and 40% may develop glaucoma requiring surgery.
Here is a patient who has shortness of breath, weight loss, and presents with these conjunctival nodules. And there’s the biopsy of the nodule and this granulomatous inflammation in the anterior chamber with mutton fat KPs. And the posterior segment shows taches de bougie perivascular infiltrates, and vitreous snowball opacities, and a severe panuveitis. The diagnosis? This is pretty easy, I’m giving you everything. The diagnosis is sarcoid uveitis. Sarcoid, in my experience, tends to be exquisitely steroid responsive. And it can be managed often with corticosteroids alone. Occasionally when that fails, immunosuppressive therapy may be necessary.
This is a classic presentation of a patient who has an ephemeral hypopyon, a hypopyon that goes away if they shake their head, oral aphthous ulcers, and presentation with vasculitis, retinal vasculitis in one eye, and retinal hemorrhages affecting the veins and arteries. And also in the fellow eye of this type of appearance was almost a retinitis type of appearance. This patient has what syndrome? Everybody probably knows this. This is Behcet’s disease. This patient requires anti-TNF therapy because of the retinal vasculitis and it needs to be treated aggressively with long term immunosuppression as well. Topical corticosteroids and regional steroids can also be utilized for acute control.
Next, this is a patient who’s HIV positive who presents with sudden onset of floaters and severe peripheral visual field loss. We know that he has AIDS, actually. CD4 count is zero. This patient has? By definition this patient probably has infectious uveitis. This is not a patient that I’d recommend starting steroids on, obviously. This is not a patient that we can treat only with topical steroids, et cetera, to treat their inflammation. The eye is white, there’s not much cell in the anterior chamber because the CD4 counts are low. The diagnosis is made based on aqueous PCR. I would do an aqueous tap, send for PCR evaluation for viruses. We find that he had varicella zoster virus. I would start him empirically on systemic antivirals. And then I would avoid oral steroids if they have AIDS. If they don’t have AIDS, and they have necrotizing herpetic retinitis, you can add oral steroids when they have antiviral cover to control the inflammation. This is handled very differently. Here you see that it’s infectious, you treat the infectious condition with anti-infective agents and then you can use the steroids to control the inflammation if their immune system is normal.
Here’s a patient who’s HIV positive with CD4 counts of 10, who presents with sudden vision loss in the left eye and floaters. This patient has frosted branch angiitis from cytomegalovirus. This patient is likely HIV positive and/or has iatrogenic immunocompromise. PCR testing will be necessary to confirm that it’s cytomegalovirus. Intravenous and intravitreal antivirals may be recommended until immune reconstitution. And avoid systemic and regional steroids in these patients.
Those are the cases that I have. It looks like there are 30 Q&As, let me see if I can rapidly go through the questions and answers.
Immunomodulatory therapy in VKH is started relatively quickly, especially with severe presentation. I usually start them on high dose oral corticosteroids and within a couple of weeks will start them on an anti-metabolite such as methotrexate or mycophenolate.
Same day with TAB prednisone. According to Professor Jabs, a dose of 7.5 milligrams is considered a safe dose with no side effects. What are your thoughts? Yeah, so Dr. Jabs is, I have a great respect for Doug and he’s fantastic and one of the fathers of modern uveitis, I consider him, even though he’s not that old. He’s terrific. I have followed many of his advice and approaches. And I agree. I think, really, my approach is to try to get below 7.5 if I can. Anything below 10, especially 7.5 or less, I consider a relatively safe dose. And long term if you look at the risks of long term complications at 10 milligrams versus 7.5, there’s a substantial reduction at 7.5 or five milligrams compared to 10. Our adrenal gland makes an equivalent of about five milligrams of prednisone daily. When we get down to that level, the patient may become still steroid dependent, but it’s a safe level and unlikely to cause long terms issues such as severe osteoporosis, aseptic necrosis, worsening of diabetes and hypertension, those kinds of things are less likely to happen.
Next question is reduce side effects of anti-TNF, we combine with methotrexate but if not available methotrexate can I use anti-metabolite or cyclosporine instead of methotrexate? You can use other anti-metabolites if methotrexate is not available. I have used CellCept with TNF-alpha inhibitors as well. You can use cyclosporine or tacrolimus. I have less experience with that in the face of TNF inhibitors. Because of the neurologic complications of cyclosporine, I tend to avoid it. Especially with TNF-alpha inhibitors because if there’s a risk of demyelinating disease and then you have other neurologic issues that you can’t tell that are side effects of the cyclosporine, it just becomes too confusing.
Is there a role of sulfasalazine in uveitis? Not in my experience. I think it’s great for the treatment and management of symptomatic inflammatory bowel disease and maybe inflammatory bowel disease associated arthritis. But it does very little, I think, for the management of uveitis. I have seen some rheumatologists try to use that but it doesn’t make any difference in terms of, in my experience, in terms of uveitis recurrences. There are some publications about it. I think Dr. Foster has written about its use, but I think it has some limited value.
For which immunomodulatory drug was live viral vaccine a contraindication? Really, I would avoid live viral vaccine in any immunomodulatory therapy. I would avoid it. Live viruses potentially carry substantial risk of causing some severe problems. Always choose to go with a killed or a non-live viral vaccine.
How to differentiate old and new vitreous cells? How long can cells go away? Yeah, this is a difficult thing. Most old vitreous cells become pignotic and may become pigmented over time? And they become suspenses in the vitreous in the formed vitreous. And they gradually they take a long time to go away, sometimes years. And as long as they’re not, and you have to be really careful in terms of deciding how effective it is when you’re looking at the vitreous inflammation. There isn’t SUN criteria or Standardization Uveitis Nomenclature Criteria for determining what is the number of vitreous cells that you look at in the slit lamp. We all have our own way of doing it. Vitreous haze, I think is a much more gross measure because many patients who have vitritis may not have much haze, but we still treat the vitritis.
In the SITE study, methotrexate is most effective than other anti-metabolites in posterior uveitis. May you give an example of posterior uveitis when methotrexate is more effective than other anti-metabolites? I know when associated with scleritis, methotrexate may be more effective, but in a case of posterior uveitis? For example, if you have somebody who has sarcoid uveitis who’s steroid resistant or requires higher doses of corticosteroids, that may be a case where I would consider methotrexate use. You can also use it as an adjunctive agent in somebody who has serpiginous choroiditis. I have done that. I use it in birdshot as posterior uveitis, it may be effective for birdshot as a second line therapy. Those are the situations where we can use it.
And the newest data suggests that methotrexate probably is a little bit more effective than CellCept. But again, doesn’t mean you’re wrong to use CellCept or mycophenolate. Please don’t get me wrong, I’m just telling you that the data is highly suggestive that methotrexate is effective. And there is synergy of methotrexate with TNF-alpha inhibitors. That’s why we use it together. I think the synergy of the anti-inflammatory effects are fairly significant in children, especially we see it.
When IMT is used in pregnancy, is it harmful in breastfeeding? Yes. We talked about Imuran being safe, TNF-alpha inhibitors being safe. With breastfeeding, I believe that I would avoid any immunomodulatory therapy if the person is actively breastfeeding. But I do think that TNF-alpha inhibitors are probably relatively safe in breastfeeding. These are things that should be discussed with the obstetrician or with the pediatrician/neonatologist.
When you use phenylephrine, can you use phenylephrine as a dilating the pupil? Maybe? (laughs) We use it during cataract surgery and in the operating room but never alone because its efficacy, it’s very short-lived. It lasts only a few hours and it doesn’t result in complete cycloplegia. It’s good at dilating but not cycloplegia.
How do you treat posterior uveitis in patients with adrenal insufficiency? Well, in adrenal insufficiency, obviously if their posterior uveitis is non-infectious, and it’s very important to make sure that if it’s non-infectious, you treat it the same way. They have adrenal insufficiency, they’re not making any hydrocortisone at all or cortisone-related derivatives, cortisol-related derivatives, so they need corticosteroids. And they may need immunosuppression based on how they respond.
Do we need drug level monitoring in uveitis? No, generally not. We don’t monitor Humira levels. Although we do monitor autoantibodies against Humira. Autoantibodies against other monoclonal antibody drugs can be checked. It’s a very expensive test. But can be useful in patients who feel have achieved non effectiveness with the drug. Because remember, 20% of us have autoantibodies already in our body. So we can mount an immune response against monoclonal antibodies that are given for therapy. This is interesting and I think it’s a great question. But we don’t need to monitor drug levels of cyclosporine, you can just monitor serum creatinine usually.
Can you give a posterior example where methotrexate is most effective? Already talked about that. The choice of immunosuppressive agent is still in my mind, one where after 30 years of doing this I can tell you that I don’t know that I can tell you, “Oh, this drug is going to work great with this.” There are some expectations. For example, retinal vasculitis or vasculitis, I tend to find that if it’s severe, systemic vasculitis, alkylating agents and/or Rituxan are going to be very useful with long term use of agents like Imuran or mycophenolate. Mycophenolate is good for isolated retinal vasculitis. It’s all kind of…
Loteprednol preferred? No, I don’t use loteprednol. I usually use fluorometholone if I’m worried about intraocular pressure.
Can we combine more than two IMTs? Yes, you can. But I typically avoid using the same class. For example I’d avoid using two anti-metabolites together, although sometimes you don’t have a choice. But typically if I’m using methotrexate or mycophenolate then I would add a calcineurin inhibitor at low doses. Or add a TNF-alpha inhibitor. And then of course, yes, you may have to use steroid with it. Again, you have steroids that you’re using and tapering and then adding these immunosuppressives as you’re tapering the steroids, and you’re trying to find the lowest dose of steroid to keep the inflammation controlled while continuing the immunosuppressive agent.
Are topical cyclosporine drops effective in pars planitis and posterior uveitis? Not in my experience, no.
If the patient has non-responsive hydrosteroids, does it mean that the patient has autoimmune disease that it’s useless to try IMT? Listen, if the patient has autoimmune disease and you know it’s not infectious, then not responding to steroids, there are two possibilities. You’ve missed an infection, you’re dealing with a neoplastic condition that’s not uveitis but a masquerade syndrome, and thirdly, it’s a really bad uveitis and you’re going to have to use something like Remicade or some TNF-alpha inhibitor with the help of a rheumatologist. I think these are things to keep in the back of your mind if traditional treatments… Steroids are effective in 95% of patients. If you’re seeing no effect or it’s getting worse on steroid, then you have a problem. You made a wrong diagnosis or you’ve gone down the pathway where you may be dealing with something that’s looking like non-infectious but it’s actually infectious, or it may be neoplastic. So keep that in mind.
Remember that diagnosis of uveitis, the etiology is an evolutionary process. It’s not something that you can make immediately just looking at it. It’s rare, sometimes we can, obviously those slides that I showed you were meant to be that way.
Until now no sustained release IMT? That’s right, only the steroid. I wish there was, that would be a great thing. People are working on that intravitreal sirolimus.
If the liver function test is elevated in azathioprine, can I shift to another anti-metabolite or better to go to another group? Well, it depends. If the patient is on azathioprine and they have TPMT deficiency, you may be okay with methotrexate because that won’t be affected by TPMT deficiency. So may be able to switch to another anti-metabolite or to CellCept. That’s one thing. You may want to check the TPMT level if their liver function tests are elevated to determine if there’s Thiopurine methyltransferase heterozygous or homozygous deficiency, enzyme deficiency or aberrancy. That would be important.
What would you use in a young female with chronic VKH, pregnant, with a baseline prednisone of 10 milligrams, doesn’t tolerate more and not tolerant of azathioprine, still minimally active. Probably Humira would be my choice for that one.
I wish we had two hours to discuss. (laughs) I’m going to two hours, it looks like.
If a patient is stable on steroid five milligrams in IMT and we want to stop gradually all medicines, which is the first to stop? The medicine or IMT? This is an excellent question. I would try to reduce the steroid, not stop it at five, but go down by one milligram at a time. I would go for four milligrams a day, three milligrams a day, very slowly over the course of several months. And then if they’re stable at that, I’d go to every other day at one milligram, or once a week at one milligram of prednisone and then gradually taper off that first. And then consider tapering the immunosuppression therapy.
If antitheta failure, do we need to do anti-TNF antibody tests? Not in all cases, but you should consider it. Especially if you’ve been using it for awhile and the patient becomes recalcitrant, you need to consider it. I have several patients who have failed Humira, who were JIA patients who I now have on tocilizumab. Tocilizumab is rapidly becoming a third line preferred agent as an anti-TNF agent that’s newer. It was originally touted to be effective for giant cell arthritis and other things. But I think it really has a niche role as an agent for recalcitrant uveitis. That’s something that your rheumatologist would need to discuss. I usually, with VKH, if methotrexate doesn’t work, I often will add TNF-alpha inhibitors.
Sarcoidosis, Behcet’s, TB, these are all questions that they had. I think people are answering the questions.
Let’s see, is there a role for vitrectomy in chronic uveitis with vitreous opacities? Yes. Patients who have toxoplasmosis with severe uveitis opacities or vitreous opacities will benefit from vitrectomy, you have to be careful of developing a secondary retinal detachment during surgery. The second issue is pars planitis or intermediate uveitis that has significant vitreous opacities that remain. There may be value for doing vitrectomy combined with endolaser and a panretinal photocoagulation treatment in these cases.
Do you treat concurrent macular edema in a chronic uveitis who’s already on oral prednisone and immunosuppressive therapy? Sometimes use of intravitreal dexamethasone implant or intravitreal corticosteroid therapy in a non-infectious uveitis can be very effective for the treatment of macular edema. That’s what they’re there for. And even the law of the fluocinolone implant, the Yutiq implant, can be effective for macular edema that is residual. That’s another treatment option that you have.
Thank you, everybody, thank you for your attention. It’s an hour and 45 minutes, this is a record. You guys are wonderful for hanging on. I hope you have a wonderful rest of your day and thank you for your attention. Look forward to maybe sometime next year giving some additional presentation. Good luck, bye bye.