Autoimmune uveitis comprises a diverse group of diseases that can differ widely in clinical presentation and duration.

 Although a number of systemic autoimmune diseases can manifest as noninfectious uveitis (NIU)—for example, psoriasis, ankylosing spondylitis, multiple sclerosis, sarcoidosis, and ulcerative colitis—many cases of NIU are idiopathic. Indeed, in the US, most uveitis is of noninfectious or autoimmune origin, with a majority of those cases being idiopathic.

The autoimmune mechanisms at work in the pathogenesis of uveitis are not completely understood; but it is known that the retina contains several potent autoantigens that are expressed in the thymus and secondary lymphoid tissue, where immunological tolerance is maintained. Regulatory T cells, which help maintain self-tolerance and control immune responses, are also present in the retina.

 In the context of an autoimmune disease, local dynamics of immune cell trafficking within the eye may be altered, and the resulting remodelling may put the eye at risk of nonspecific immune activation, precipitating clinical signs of inflammation.

Uveitis is categorized anatomically as anterior, intermediate, posterior, or panuveitis, with symptoms that generally correspond to the location of inflammation. When the inflammation predominantly affects the anterior segment, patients may experience pain, sensitivity to light, and redness; posterior-segment inflammation can result in floaters, flashes, blurry vision, and blind spots. Although patients with posterior uveitis may not experience pain, it is generally the most dangerous in terms of vision, as choroidal inflammation and its resultant scarring can affect the retina, optic nerve, and macula very quickly.

In my experience, it is common for patients with NIU to present to the clinic without a previous diagnosis of systemic autoimmune disease; typically, they have experienced some worrisome vision loss or irritation that prompts their visit. They may, however, have other extraocular symptoms that they have been neglecting, such as joint pain (inflammatory joint pain is typified by exacerbation following a period of inactivity, such as wakening in the morning), nail pitting, or hair loss. Every patient new to our practice is asked to complete a 

 to help uncover ocular and systemic symptoms that he or she may not otherwise think to report.

In terms of ocular findings, diagnosis of anterior uveitis is relatively straightforward at the slit lamp; in cases of posterior-segment involvement, imaging tools such as optical coherence tomography (OCT), fluorescein and indocyanine green angiography, and fundus autofluorescence are essential adjuncts. For certain uveitic entities, visual field testing and electroretinogram can be helpful. In general, the diagnostic workup for a patient with NIU often requires time, consideration, and collaboration with other specialists. In addition to review of systems and ocular exam, we do bloodwork to rule out infection and help identify signs of systemic autoimmune activity (e.g., HLA haplotyping, antinuclear antibodies, serum angiotensin-converting enzyme, lysozyme, to name a few). Even when a systemic workup is negative for infection or clearly defined autoimmune disease, patients can be comforted that we still have effective ways of managing uveitis that is presume autoimmune, noninfectious in nature.

Our knowledge of ocular immunology has grown immensely over the past decade or two, revealing a complex web of interconnected pathways, signalling molecules, and surface markers involved in acute and chronic inflammation. In treating NIU and other autoimmune-mediated diseases, it is rarely as simple as blocking a single molecule and turning a single switch on or off. Still, in recent years, targeted biologic treatments for autoimmune disease have been approved, including some specifically for NIU.

Humira (adalimumab, AbbVie) is the first FDA-approved biologic therapy for noninfectious uveitis affecting the posterior segment. Most of the other systemic immunosuppressive therapies used to treat uveitis are off-label, including methotrexate, mycophenolate, azathioprine, and cyclosporine. Although these therapies have been used for many years, they do not have FDA approval for this indication and lack the support of randomized controlled trials.

Through clinical experience, we know that these are excellent steroid-sparing medications. Although these therapies are well accepted today, in the past, many considered them as overly aggressive. Now, uveitis has become a “mainstream” subspeciality, and fellows at many respected academic and private institutions are well trained in the use of systemic therapies. In addition, physicians tend to refer patients to uveitis specialists much earlier than in the past, which lowers patients’ exposure to systemic steroids and their associated side effects.

In and out of specialists’ practices, however, steroids are still the mainstay of treatment because rapid control of inflammation is essential to preserving vision.

For patients with NIU and a well-defined systemic autoimmune disease, systemic treatment is usually the best choice to control disease throughout the body. The question of systemic vs local treatment becomes more controversial if, after doing a head-to-toe work-up, the patient only manifests NIU and no other complaints. In such cases, it may make sense to treat systemically if the uveitis is bilateral, but perhaps locally if unilateral (but that ultimately depends on the specific diagnosis).

Local treatments for NIU are largely corticosteroids, though intraocular injection of agents such as sirolimus and methotrexate have been studied.

 Key considerations for local therapy include age and lens status, as well as individual or family history of glaucoma or steroid-induced ocular hypertension. A very young phakic patient, or one with numerous risk factors for glaucoma, may not be a good candidate for local corticosteroid therapy. On the other hand, patients who are pregnant or trying to conceive, or those who are immunocompromised, may be poor candidates for systemic therapy. Recently, even those with only a theoretical risk of compromised immunity (e.g., due to age or recent recovery from cancer) are often reluctant to undergo systemic immunosuppression because they fear the SARS-CoV-2 infection.

Current approved options for local therapy include topical steroids, shorter-acting intra- and periocular steroids, such as triamcinolone acetonide, and sustained-release intravitreal implants, including Ozurdex (dexamethasone intravitreal implant 0.7 mg, AbbVie) and YUTIQ (fluocinolone acetonide intravitreal implant 0.18 mg, EyePoint Pharmaceuticals). Ozurdex is typically effective for about 3 to 4 months when used to treat uveitis, while YUTIQ releases a consistent low dose of fluocinolone for 36 months. The surgically implanted Retisert (fluocinolone acetonide intravitreal implant 0.59 mg, Bausch + Lomb), which also lasts about 36 months, is generally reserved for more severe presentations in which a higher dose of steroid is warranted.

I usually bring patients on systemic immunosuppressive therapy back for follow-up every 2 to 3 months to examine the eyes for signs of recurrent inflammation and perform blood testing to ensure the efficacy and safety of the therapy. For patients who receive local, sustained-release steroid treatment such as YUTIQ and Retisert, I also follow them every 3 months to monitor intraocular pressure.

We can expect the future of immune-mediated uveitis to feature increasingly targeted and specific therapies, including more biologics and biologic response modifiers, both systemically and locally in the eye. In the immediate term, we can look forward to the suprachoroidal formulation of triamcinolone (Xipere, triamcinolone acetonide suprachoroidal injectable suspension, Bausch + Lomb)

, which may offer a more targeted impact on uveitic macular oedema with fewer adverse events of IOP elevation and cataract development than other intra- and periocular steroids. We may also see the approval of intravitreal sirolimus (Santen), which would offer a local, non-steroid option.

Case study: Preserving systemic immune function

I recently saw a 50-year-old man with metastatic melanoma, which was being successfully treated with immunotherapy. However, as a consequence of the immunotherapy, he had developed bilateral panuveitis, a side effect that has been reported with immune-checkpoint inhibitors.

 To avoid disrupting the patient’s systemic cancer care, we elected to treat the uveitis locally with YUTIQ following an incomplete response to topical steroid.

The patient experienced improvement in vision following YUTIQ injection and at about 18 months post-treatment, he remains 20/20 in both eyes. He did develop cataract, but is happy with his vision following surgery. Intraocular pressure (IOP) elevation, also secondary to YUTIQ, is well controlled on a single IOP-lowering drop.

In a 3-year, phase 3 clinical trial, patients who received YUTIQ experienced a statically significantly lower rate of uveitis recurrence compared to the sham/standard of care treatment arm (

 YUTIQ also resulted in greater resolution of macular oedema and greater improvement in visual acuity.

 IOP-lowering medications were used at similar rates, but more patients in the sham/standard of care group received IOP-lowering surgeries.

This case illustrates the important interaction between systemic immunity and ocular inflammation, and the value of long-term, local inflammation control.

Dr. Chang is Co-President and Partner at Massachusetts Eye Research & Surgery Institution (MERSI) in Waltham, MA. He specializes in ocular inflammatory disease and vitreoretinal surgery.

Caspi RR. Understanding autoimmune uveitis through animal models. The Friedenwald Lecture. 

Lee RW, Nicholson LB, Sen HN, et al. Autoimmune and autoinflammatory mechanisms in uveitis. 

Forrester JV, Kuffova L, Dick AD. Autoimmunity, Autoinflammation, and Infection in Uveitis.

Holland GN, Goldstein DA, Rosenbaum JT, Van Gelder RN. MD roundtable: the uveitis workup. 

https://www.aao.org/eyenet/article/md-roundtable-uveitis-workup

Knickelbein JE, Kim M, Argon E, Nussenblatt RB, Sen NH. Comparative efficacy of steroid-sparing therapies for non-infectious uveitis. 

Nguyen QD, Merrill PT, Sepah YJ, et al. Intravitreal sirolimus for the treatment of noninfectious uveitis: evolution through preclinical and clinical studies. 

Taylor SR, Banker A, Schlaen A, et al. Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis. 

Yeh S, Khurana RN, Shah M, et al. PEACHTREE Study Investigators. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial. 

Shahzad O, Thompson N, Clare G, et al. Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm. 

Sharma S. Best corrected visual acuity at 36 months in a study of fluocinolone acetonide intravitreal (FAi) insert for non-infectious uveitis affecting the posterior segment of the eye (NIU-PS). Presented at the ASRS annual meeting, Chicago, IL; July 26-30, 2019.

Hariprasad SM, Patel K. Course of macular edema through 36 months with fluocinolone acetonide intravitreal insert for noninfectious uveitis affecting the posterior segment. Presented at the American Society of Retina Specialists 38th annual scientific meeting. July 24-26, 2020 (virtual).

Singer MA, Krambeer C, Paggiarino D. IOP elevation in patients treated with fluocinolone acetonide insert for chronic noninfectious uveitis affecting the posterior segment. 

Ophthalmic Surgery, Lasers and Imaging Retina

Articles

Underlying autoimmune disease alters uveitis therapy.

Current approaches to treatment of uveitis with autoimmune disease

Anti-VEGF therapies have been highly beneficial for patients with macular degenerations, but these patients require frequent treatment to maintain visual acuity, underscoring the need for sustained-release products, according to Dr Lejla Vajzovic, an associate professor of ophthalmology at Duke University Eye Center in Durham, North Carolina.

Dr Vajzovic discussed the 2 surgical options that facilitate increased durability for patients with retinal degenerations for exudative age-related macular degeneration (AMD).

The Port Delivery System (PDS) (Susvimo; Genentech), a recently FDA-approved drug delivery system, is a permanent refillable intraocular implant that is positioned at the pars plana. The device contains a customized formulation of ranibizumab (Lucentis; Genentech) that can be refilled in the office.

The Phase 3 ARCHWAY study of patients with wet AMD showed a favourable benefit-risk profile for the PDS. The change in best-corrected visual acuity at weeks 36 and 40 was comparable to that achieved with monthly ranibizumab injections. This approach was able to maintain the visual acuity with a reduced treatment burden.

Dr Vajzovic emphasized the importance of strict adherence to the surgical steps during PDS implantation: peritomy, implant preparation, scleral dissection, pars plana laser ablation and incision, implant insertion, and conjunctival and Tenon’s capsule closure.

“Control of haemostasis is critical at all steps to ensure optimal visualization and minimize the risk of postoperative vitreous haemorrhage,” she said.

Precise handling of the conjunctiva and Tenon’s capsule and anchoring both to the limbus during closure are crucial to optical outcomes, Dr Vajzovic pointed out. Proper handling ultimately results in decreased risks of exposure and infection. Scleral dissection followed by laser ablation of the pars plana reduces the chances of intraocular bleeding.

The office refill procedure necessitates precise perpendicular targeting using a needle that both injects new drug and excretes the fluid that fills the implant.

Dr Vajzovic provided 4 key points about PDS insertion:

The sclera is incised layer by layer to expose the pars plana, followed by pars plana laser ablation incision. The incision size is maintained at 3.5 mm to ensure the secure fit of the implant and pars plana haemostasis.

The conjunctiva and Tenon’s capsule are manipulated with care and anchored to the limbal sclera using a slight overapproximation, which is critical for the implant to stay covered.

Control of haemostasis is critical at all stages of the implantation to minimize vitreous haemorrhages.

During the refill/exchange procedure, the surgeon stands on the contralateral side of the study eye, using a perpendicular approach and precise targeting.

The ranibizumab PDS implant received FDA approval in October 2021 following positive Phase 3 results.

RGX-314 is a novel adeno-associated virus vector used to deliver an anti-VEGF drug that has shown favourable results in Phase 1/2a neovascular AMD studies. The study tested 5 doses administered to patients who previously required frequent injections. The subretinal dosing to date has been completed in 42 subjects in dose-escalating cohorts. The patients were followed up to 2 years.

This procedure involves a vitrectomy followed by subretinal injection of the device with subsequent bleb formation. The patients generally required only a subconjunctival steroid injection.

Dr Vajzovic related the case of an 86-year-old patient randomized to the highest tested dose who did not require further injections after the injection and experienced a small, stable visual improvement.

The interim conclusions drawn from the results were that RGX-314 was well tolerated by all patients and that the treatment provided a long-term, durable treatment effect seen with the 3 highest doses. The patients in the 2 highest-dose cohorts have been followed for more than 1.5 years with stable to improved vision and reductions in the treatment burden. Those in cohort 3 who were followed for more than 3 years had the same results. The pivotal trial, ATMOSPHERE, is now enrolling patients.

RGX-314 is also being evaluated for suprachoroidal use in a Phase 2 neovascular AMD study, and the interim data are expected to be released the third quarter of 2021. A Phase 2 trial, ALTITUDE, for treatment of diabetic retinopathy is now enrolling patients, and the initial data release is expected this year.

This article is adapted from Dr Vajzovic’s presentation at the Women in Ophthalmology 2021 Summer Symposium. Dr Vajzovic is a consultant to RegenXBio Inc and Roche/Genentech.

Surgical options facilitate increased durability for patients with retinal degeneration.

PDS and RGX-314: Two new surgical procedures for the treatment of wet AMD

The port delivery system is an ocular delivery system that is surgically inserted via the pars plana area in the superotemporal quadrant of the eye. It provides continuous delivery of ranibizumab to the posterior segment. It has a reservoir chamber where a higher concentration of ranibizumab is held, and there is slow release into the vitreous cavity. It has been approved for use in patients with neovascular AMD [age-related macular degeneration], although other indications, including diabetic macular edema, are also being investigated.

With the approval of Lucentis [ranibizumab] for the indications of neovascular AMD, the treatments for neovascular AMD were revolutionized. However, there still is a significant treatment burden for many of our patients who require frequent, often monthly, injections. The treatment burden for both the patients and the family can be quite high. In addition, although we’re delivering a nice bolus of anti-VEGF treatment, there is a waning of the amount of medication in the vitreous cavity. Therefore, a more sustained, endurable treatment modality was needed. Like most devices, the port delivery system was started in the preclinical stages, where it was developed and then tested in nonhuman subjects. Once its safety was verified, it went on to trials to verify safety in human patients, and then to look at the efficacy.

In the phase 2 LADDER study, the technique that was done in human patients initially showed an increased risk for vitreous hemorrhages. The technique for implantation was modified to include laser cautery of the corneal bed]. After this, the incidence of vitreous hemorrhages dropped precipitously. Prior to the amendment, there were 6 out of 10 cases of vitreous hemorrhage. After the amendment, there were no cases of vitreous hemorrhage out of 48 patients within the first month, which is generally considered the postoperative period. At 2 months, there was 1 patient who did have a vitreous hemorrhage.

Although the procedure is generally well tolerated, since it is surgical procedure, there are some potential complications that surgeons and patients should be aware of. Initially, in the LADDER study, there was a higher rate of vitreous hemorrhages. A modification of the procedure has since reduced those rates tremendously. Any surgery has a risk of infection, and with respect to the implant itself, if the conjunctiva is not closed properly or not covering the implant adequately, there is a possibility of the implant being exposed. Also, if the conjunctiva is very thin, there is a possibility of erosion. Therefore, presurgical evaluation and meticulous care to close the conjunctiva are very important.

When evaluating a patient preoperatively, you want to take note of a few things. Particularly, you want to take note of the conjunctiva to see if it’s very thin, and if there’s good mobility of the conjunctiva, so that you can adequately access the subconjunctival and sub-Tenon space. In addition, you also want to note any areas of potential scleral thinning, so that when you’re making your wound you’re aware, and so you don’t start making your wound too deep. In addition, you may also want to avoid those areas, so that there isn’t a risk of dehiscence or any other potential issues with the wound.

Videos

Expert insight on the history of the port delivery system in neovascular AMD and how it has impacted patient experience and outcomes.

The Development and Safety of Port Delivery System in Retinal Diseases 

Michelle Senchyna, PhD, spoke with Modern Retina at the American Academy of Ophthalmology 2021 annual meeting about the phase 2b study results of AR-15512 for the treatment of dry eye. The TRPM8 antagonist stimulates the production of tears and creates a cooling sensation across the ocular surface to treat both signs and symptoms of dry eye. Two concentrations were tested in the trial; both formulations were found to be safe and well-tolerated.

 Hello everyone, my name is Michelle Senchyna. I am the vice president of both clinical development and medical affairs at Aerie Pharmaceuticals, and I'm at AAO and pleased to talk to you. We just presented the results from our phase 2b study on our asset AR-15512, which is a TRPM8agonist.

TRPM8 is a neat little receptor. It causes, when stimulated, the production of tears as well as a cooling sensation across the ocular surface. And so because of those mechanisms, we think it will be a fantastic asset to treat the signs and symptoms of dry eye.

In our relatively large phase 2b study, a total of 369 patients that were randomized between two different concentrations of 512 as well as vehicle, we saw very statistically significant increases in tear production with both concentrations of 512. It was actually the high dose, 0.003%, that demonstrated the most robust efficacy, upwards of 20 mm of wetting on an uninitialized Schirmer.

When we looked at the data a different way based on a responder analysis, where a responder is someone that has an increase of at least 10 mm of wetting, between 82–86% of the population in the high dose were responders. It's just a phenomenal response.

Now, symptom-wise was even more exciting. We saw statistically significant improvements with the high dose of 512, first based on a SANDE questionnaire as early as day 14. And then the magnitude of that improvement actually got better at day 28 and 84, relative to vehicle. We also saw statistically significant improvements in ocular discomfort and eye dryness both at day 84.

And then lastly, we showed some really unique data, and that is, signs and symptoms are something that really resonates to the clinician. But at the end of the day, we know quality of life is what matters to patients. And so we saw with again, the high dose of 512, very statistically significant improvements in a number of different measures of quality of life, things like driving or reading or watching TV. And that was just very exciting—again, as early as day 14. So these folks are definitely getting better, and consistent with the sign and symptom improvement.

From a safety perspective, all formulations were safe and well-tolerated. The number of ocular adverse events that we had was normal, and 95% of those were reported as mild by the subjects.

So in sum, we are just really very excited about the data. We showed multiple sign and symptom improvements quality of life improvements. We have selected the high dose of 512 to go into phase 3 development. We are going to be starting those studies early next year, and I am really looking forward to being able to share more data with you in the near future. So thank you very much.

The American Academy of Ophthalmology (AAO) annual meeting was held November 12 to 15 at the Ernest N. Morial Convention Centre in New Orleans, Louisiana. The event included Subspecialty Days and a virtual component for remote participation.

At AAO 2021, Aerie Pharmaceuticals presented the results of their phase 2b clinical trial of AR-15512, a TRPM8 antagonist, for the treatment of dry eye.

Phase 2b study results of AR-15512 for the treatment of dry eye

Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

As cases of diabetes increase worldwide, the disease is accompanied by a precipitous increase in its most common complication, diabetic retinopathy (DR). At the same time, the aging population is growing, which is significant considering that the risk of developing DR increases the longer individuals live with diabetes and that the consequences of DR are unique in older patients.

In a recently published article, Dr Ashay D. Bhatwadekar and colleagues reviewed these issues to increase awareness and identify the best strategies for patient care.

“Understanding age-related retinal changes that increase vulnerability to DR in older individuals and age-related therapeutic challenges is essential for optimizing treatment of DR within the senior population,” said Dr Bhatwadekar, an associate professor of ophthalmology at the Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, in Indianapolis.

“Proper treatment of DR in [senior patients] could reduce the overall burden of diabetes.”

The authors pointed out that the retinal structure is altered with age in several ways. Macular blood flow decreases by 20% on average and the retina becomes thinner, with the change in thickness especially affecting the inner nuclear layer. In addition, the response of the microglia to injury slows, Müller cells become more susceptible to oxidative stress and the extent of lipofuscin accumulation in retinal pigment epithelial cells increases.

“The changes in blood flow that occur with aging may worsen ocular perfusion abnormalities in diabetes, and proliferation of microglia in the outer retina can contribute to proinflammatory responses,” Dr Bhatwadekar said.

There are also age-related metabolic changes affecting the retina that are relevant for the development of DR. Disease-specific pathophysiologic mechanisms, such as accumulation of advanced glycation end products and the polyol pathway that contribute to oxidative stress, take advantage of the aging retina’s vulnerability that is associated with a defunct antioxidant defence system.

In addition, the effects of the VEGF pathway, which promotes angiogenesis, vascular permeability, and inflammation, could be augmented in the eyes of elderly individuals by the presence of a decreased retinal blood flow, Dr Bhatwadekar explained.

Other DR pathogenic pathways that may be exacerbated by aging-related alterations relate to protein kinase C activation and hexosamine.

Clinical studies of DR in aging individuals highlight the heightened concerns in senior patients. Not only does the prevalence of DR increase with age, but available evidence points to associations with depression and cognitive decline.

The article reviews current treatments for DR and diabetic macular oedema, including a discussion of their mechanisms and role in clinical care. In addition, summary information is presented about emerging treatments that are being investigated in both preclinical and clinical trials. These include aldose reductase inhibitors that work by inhibiting the polyol pathway, a treatment that increases expression of sirtuin 1, protein kinase C inhibition and gene therapy to introduce VEGF genes. In addition, there is interest in sodium-glucose cotransporter 2 inhibition and angiopoietin-2 inhibition.

Highlighting the therapy-related challenges occurring in the senior population, the article discusses problems with medication adherence and age-related changes in drug pharmacokinetics and pharmacodynamics.

Anatomic and physiologic changes that occur with aging and the effects of medications that are commonly used by elderly individuals can lead to decreased absorption of orally administered drugs with the potential for reduced efficacy. Thus, the need may arise to consider modifications in the dosing regimen or delivery method.

As noted in the article, an increase in proteases within the vitreous that has been noted with aging suggests there may be age-related pharmacokinetic differences in drugs administered by intravitreal injection. Changes in drug distribution within the eye also may occur, and the potential for age-related differences in systemic distribution, drug metabolism and elimination also needs to be considered when investigating medications administered via an extraocular route.

Older individuals are more prone to medication nonadherence, which should be considered in their use of oral medications and in maintaining follow-up when receiving in-office treatments for diabetic eye disease.

“In the future, it is necessary to consider all of the above factors [when] treating senior patients with DR,” Dr Bhatwadekar said. “Special programs directed toward tailoring and monitoring therapy may provide a better therapeutic outcome for [elderly patients].”

Dr Bhatwadekar is an ad hoc pharmacist at PCA Pharmacy. He reports no other relevant conflicts of interest.

Leley SP, Ciulla TA, Bhatwadekar AD. Diabetic retinopathy in the aging population: A perspective of pathogenesis and treatment. 

. 2021;16:1367-1378. doi:10.2147/CIA.S297494

Confronting issues unique to aging may lead to better outcomes.

Managing senior-specific complications of diabetic eye disease

Dr LaHood is an ophthalmologist specialising in refractive cataract and laser surgery in Adelaide, Australia. His research and teaching focus on the management of astigmatism. He is a consultant to Alcon and Zeiss.

, published in the last month’s edition of 

, looked at patient selection and optimising biometry. In Part 2 of this three-part series, I will provide tips on calculating toric IOL sphere and cylinder power, which can be a great concern to surgeons who use these lenses. I will attempt to simplify the process and explain away certain myths that exist.

There are many toric IOLs on the market. One of the most common questions I am asked is: “What is your go-to lens?” My answer is that all the major brands have good-quality toric lenses that will give you favourable results if you follow the steps I outline.

One of the key considerations is hydrophilic versus hydrophobic designs. Hydrophilic lenses go through a much smaller incision than hydrophobic lenses (1.8 mm) which we know is astigmatically neutral. However, an incision this size requires more specialised equipment, and the hassle-to-benefit ratio favours it being a hassle, in my view.

I advise new surgeons to make their incision size as small as they comfortably can. There is no longer a reason to use a 2.75-mm or even 2.4-mm incision. The sweet spot of incision sizes is 2.2 mm. It provides for a multitude of choices, including hydrophobic lenses.

Hydrophilic lenses have had bad press in the past few years because of fears of opacification, especially if they are exposed to gases inside the eye. In my experience of reviewing these IOLs over many years, I have not seen a single opaque lens, but I accept it does occur on rare occasions.

I think the risks of hydrophilic lens use have been overstated. I avoid them in patients who may undergo procedures with gas in the future, such as an endothelial transplant, but in a standard eye it would not sway my decision.

Certain hydrophilic lenses also have an advantage in terms of ease of rotation. For example, the haptic design of the AT TORBI Toric IOL (Carl Zeiss) is bidirectional and bi-toric, so it can be implanted upside down. This benefits those who are learning because there is no need to worry about the direction of rotation to the targeted axis.

With the standard C-loop haptic design of many toric lenses, if you go slightly past where you intended to place it then you have to bring it back around 180° to get closer to where you want it. Some people call this “the lap of shame” and some call it “the lap of honour.” Either way it can be a frustrating process.

The extra time involved should not be a concern, though. Keep in mind that you are working hard to place it in the right spot for the rest of the patient’s life, so it does not matter if it takes an extra 5 minutes. This is better than having to schedule a second surgery to rotate a misplaced toric IOL.

Another consideration is the cylinder steps that each manufacturer produces. For example, the AcrySOf IQ Toric IOL or Clareon Toric IOL (Alcon) and the Tecnis Toric II (Johnson & Johnson) have 0.75-D steps between most of the cylinder powers, whereas the AT TORBI Toric IOL has a consistent 0.5-D cylinder step.

My colleagues and I recently completed a study evaluating whether the step magnitude made any difference in around 1,000 implanted eyes with two surgeons using 0.5-D steps and two surgeons using 0.75-D steps. We audited our results and found no significant difference between the two in terms of residual refractive error (unpublished data).

This might seem counterintuitive because you would think that smaller steps yield better results. The key is to keep in mind that regardless of whether you are using 0.75-D or 0.5-D steps, you are doing a good job and do not need to change your approach, so do not base your toric choice on the cylinder step magnitude.

In the end, IOL selection will likely come down to familiarity with the platform. There are no features of the major toric IOLs that make me feel that any one is significantly superior to the others.

Whether you are used to a plate haptic or a C-loop haptic, stick with that selection for your early cases and then feel free to experiment once you have some experience. Eventually you will choose based on the predictability of refractive results but, until that time, I urge you to try all the options and see what suits you best.

There are a lot of third-party and manufacturer toric IOL calculators online. With very basic maths, anyone can calculate what spherical power an eye needs by simply knowing the shape of the front and the length of the eye.

Calculating a toric lens means calculating two lenses – one for each axis. This is still rather simple but people have put a lot of time and effort into refining the process by taking into account the expected lens position, anticipated tilt, posterior corneal astigmatism, etc., so it makes sense to rely on robust, tested calculators. Each of the main lens manufacturers has a calculator, and those such as the Barrett Toric Calculator are also available.

For beginners, I recommend starting out with your lens manufacturer’s calculator. When people are implanting a spherical lens, they will usually look at multiple formulas and decide on which formula suits the eye. With a toric calculator, you do not have this option unless you want to look at multiple calculators.

I have used the Z CALC Online IOL Calculator (Carl Zeiss) website in conjunction with the Goggin nomogram adjusted anterior keratometry (GNAK) when implanting Zeiss toric IOLs and the Barrett Toric Calculator when implanting Alcon toric IOLs and been very happy with both sets of results.

Historically, toric calculators would use the anterior keratometry values and tell you which toric lens would suit a particular eye to give the best refractive outcome. However, we then rediscovered that posterior corneal astigmatism has an impact on the precision of that calculation.

Therefore, different ideas arose for how to incorporate the posterior cornea into the toric IOL calculation. One of these was the Baylor nomogram by Dr Douglas Koch, which makes an adjustment to the cylinder power of the toric IOL. He reported that, depending on the orientation of the anterior corneal astigmatism, you can adjust the cylinder power for that eye up or down.

The other nomogram was from Dr Michael G. Goggin: he adjusted the input instead of the output. He adjusted the keratometry values themselves, and his nomogram is available online at goggintoric.com. I use this calculator because it is the only toric calculator that has prospective published data proving that it is effective.1

Third-party calculators, such as the Alcon Toric IOL Calculator, the Johnson & Johnson Toric Calculator and the Barrett Toric Calculator, incorporate a posterior corneal adjustment that means that nomogram adjustments are not necessary. If you used one of those calculators and also added the Baylor or the GNAK, in principle you would over-adjust for the posterior cornea because you would adjust for it twice. Now, you can simply use one of those calculators mentioned.

What you will find is, when an adjustment is made for the posterior cornea in the calculation of the toric IOL, there is an adjustment made to the power of the cylinder that you are putting in, and you will also notice an adjustment to the axis of implantation. This means that when you take the posterior cornea into consideration as well as the anterior cornea, you are playing with the total corneal power. It is simple vector mathematics that makes sense.

Notably, the steep axis of the total cornea may be quite different from what you have measured on the anterior surface. This will have the biggest impact for a toric lens to treat low-powered oblique astigmatism. A recent study revealed that when you are dealing with an eye with oblique anterior corneal astigmatism, there is no need to adjust the axis of toric IOL implantation from the steep axis of the anterior cornea.2

It can be quite disconcerting to go against the recommendation of online calculators, so I recommend starting with simple with-the-rule or against-the-rule eyes. In some instances, toric IOL calculators can provide various powers with different options.

Some of those options are going to ‘flip the axis’. For example, one cylinder power option will suggest leaving the eye with 0.5 D of astigmatism in the pre-existing axis. Essentially, you underpower the treatment. This could be reasonable, or you could put in the next cylinder magnitude step up and flip the axis of astigmatism but leave that person with only 0.1 D of residual astigmatism.

With glasses, we know that you should not flip the axis, but inside the eye, minimal residual astigmatism regardless of axis is beneficial in terms of visual quality. My advice is to aim for the smallest predicted residual astigmatic error and not to worry at all about flipping the axis of astigmatism.

The other consideration that often arises with targeting minimal residual astigmatism is whether patients should be left with some with-the-rule astigmatism so that they are happy as they age and their cornea changes shape. We know that at a population level, there is more against-the-rule corneal astigmatism in older age and more with-the-rule astigmatism in younger patients. However, we cannot currently predict at an individual level whether an eye will change with time.

I do not personally subscribe to the philosophy of leaving someone with residual with-the-rule astigmatism to ‘future-proof’ their vision. I instead prefer to aim for the best possible unaided visual acuity initially and to deal with any change in the future. This comes down to personal preference.

The final myth that I would like to address when it comes to calculating an appropriate toric IOL cylinder power is that you can ‘depower’ a toric IOL cylinder power by leaving it a few degrees off axis. The idea for this comes from our knowledge that if a toric IOL is not aligned correctly to the steep corneal axis, then it has less optical effect to neutralise astigmatism at that axis. However, the cylinder power does not magically disappear; it is still inside the eye.

The best optical result you can achieve is when the cylinder of the toric IOL is aligned with the steep axis of the cornea. Rotating it away from this location to depower it and precisely treat the astigmatism on the steep axis will only add residual astigmatism at another axis. This can be proven mathematically and graphically but the technique is still commonly discussed.

My advice is to calculate a toric IOL with the best cylinder power to treat the astigmatism in the eye and to aim to leave it on that steep corneal axis. It may slightly under- or over-treat the corneal astigmatism but it will ultimately give the best achievable refractive outcome with that IOL.

When inputting your data and plans into toric calculators, you will be asked for a surgically induced astigmatism (SIA) prediction. What you are basically doing is telling the calculator, when it is doing the vector maths and taking into consideration the anterior and posterior corneal astigmatism as well as that of the toric IOL, to add a vector of a certain magnitude acting at the axis of your planned incision. This should seem straightforward enough.

If you were to plot the SIA figures from multiple eyes onto a double-angle vector diagram or a centroid plot, you would obtain roughly 0.1 D. Many surgeons would say that is what you should put into the calculator, a 0.1-D flattening effect at your incision. This estimate does work but the problem is that we do not know where that surgically induced astigmatism is going to act in an individual eye.

When we make a cut into a cornea, we simply do not know enough about corneal biomechanics to be able to predict how it will respond. Classical teaching was that if you make a cut at 180°, you will get flattening on that axis and steepening at 90°. If only life were that simple!

Certainly, this is the case for very large incisions, however, for smaller phaco incisions the orientation of the average flattening effect is extremely unpredictable. The centroid value is reasonable since, when you add the vectors of all the SIA values and average them, a 0.1D flattening effect occurs at the axis of the incision; however, if we are going to guess where this effect occurs for an individual eye, I personally would rather estimate zero. This way, even if the flattening effect occurs at 90° to what I had expected, my outcome is no worse off.

I realise that the difference between zero and 0.1 D is tiny but if you understand that this is an estimate for an individual eye based on an extremely variable axis, then I would hope you would also see that zero makes more sense in terms of eliminating unnecessary variables.

So, we have chosen a patient, taken biometry and calculated a toric IOL. The next step is to perform surgery. In the third and final part of this series on getting started with toric IOLs I will discuss what I consider the key points of the surgical and postoperative periods to achieving successful outcomes and how to deal with problems.

1. LaHood BR, Goggin M, Esterman A. Assessing the likely effect of posterior corneal curvature on toric IOL calculation for IOLs of 2.50 D or greater cylinder power. 

2. Ophir SS, LaHood B, Goggin M. Refractive outcome of toric intraocular lens calculation in cases of oblique anterior corneal astigmatism.

This three-part feature discusses tips for success when getting started with toric IOLs. Part 2 tackles calculating toric IOL sphere and cylinder power; though it can seem daunting when treating astigmatism, the process can be simplified with a few key considerations.

Toric IOLs for beginners: Advice on selecting and calculating toric IOL sphere and cylinder power

At the American Academy of Ophthalmology annual meeting, Marc Berger, COO of Verana Health, discussed the VeraQ quality measures dashboard for the IRIS registry report. It is anticipated to launch in 2022.

VeraQ is AI-enhanced health data engine that utilizes the Axon, AQUA and IRIS registries to report on unfiltered healthcare data. Additionally, it enables compliance with Merit-based Incentive Payment System (MIPS), meeting care quality measurements required by the Centres for Medicare and Medicaid Services (CMS). It also helps to identify patients who qualify for a clinical trial.

 Very excited to be here with everyone. In terms of the IRIS registry, I think this is the first year where Verana actually has been ingesting and curating data directly from participating practices.

So we are working end-to-end processing of EHR data, where we're partnering with practices and our technology on our platform, the VeraQ platform, brings in the data, and then organizes in a way which which more effectively processes the data and gives us a better sense of for analysing this information. And in turn, we're able to then provide better insights, more accurate calculations for MIPS specifically, but then they're also use cases that are going to be developed on top of that.

So our use cases are developing particularly around the MIPS calculations and our quality measures. So participating practice will have better and more accurate information, accurate data, be able to run their practices more effectively, and ultimately treat patients with better care.

And that's really the, the keystone of what we're accomplishing over these past two years in our partnership with the AAO. The quality measures database is now being powered by our VeraQ platform. And this platform, like we discussed is more effective from a technological perspective. We've got proprietary algorithms using the data that's provided by participating practices. We're able to provide more accurate and more effective data sets which can then lead to better calculations for MIPS and better-quality reporting, just giving doctors and the administrators as part of these practices, better information within their practices.

Verana Health showcases the VeraQ quality measures dashboard for the IRIS registry report at AAO 2021.

Verana Health's new quality measures dashboard unveiled at AAO 2021

The LADDER trial was a phase 2 trial that showed overall good safety and efficacy for the port delivery system [PDS] for the treatment of neovascular AMD [age-related macular degeneration]. It looked at varying doses of ranibizumab in the PDS implant. Patients were dosed at 10-mg, 40-mg, and 100-mg concentrations. Interestingly, and this is different than the ARCHWAY study which we’ll talk about shortly, patients were only given a refill of ranibizumab if they met criteria of worsening fluid, vision, or new submacular hemorrhage. The 100-mg concentration, which is what is approved, showed that about 80% of patients were able to go 6 months or longer before needing a refill; the median time for needing the first refill in the 100-mg group was nearly 16 months.

Overall, the port delivery system procedure was very well tolerated. As mentioned before, after the modification of the technique, patients did not have any vitreous hemorrhage within the first month. The refill procedure was also very well tolerated, and was able to be done in an in-office setting.

Coming from very good results from the LADDER trial, ARCHWAY was the phase 3 trial, which was a 2-year study comparing monthly ranibizumab to the PDS implant with 100 mg ranibizumab and refills [every] 6 months. The patients enrolled in this study were patients who had wet AMD, were diagnosed within 9 months of screening, and who were responding to anti-VEGF treatment. The ARCHWAY trial showed that 98% of patients were able to go without any additional treatment in the PDS group. The PORTAL trial is an extension study that will be looking at how patients do beyond 2 years. The safety and tolerability of the procedure were also consistent with the LADDER study, particularly with respect to very low incidence of vitreous hemorrhage, as well as the procedure being very well tolerated.

The patients who were included in the ARCHWAY study were recently diagnosed with neovascular AMD. All the patients had to be diagnosed within 9 months of their screening visit, and they all had to show a good response to anti-VEGF therapy.

The ARCHWAY study so far shows that patients are tolerating the port delivery system very well, even in a long-term manner. We’re also showing that patients have good, consistent visual recovery, as well as good stability of their macular thickness. We also analyzed patients with fluid fluctuations, and showed that patients with the port delivery system have good minimization of fluid fluctuations, similar to having monthly ranibizumab injections. I’m also excited about learning what longer-term data are going to show in the PORTAL study. The PORTAL study is looking at patients well beyond 2 years, as well as multiple refills beyond 2 years.

Chirag Jhaveri, MD, reviews the trial design and results of the LADDER and ARCHWAY studies, which tested the port delivery system in neovascular AMD. 

PDS in Retinal Diseases: Interpreting the LADDER and ARCHWAY Studies

Ophthalmologists have seen a progression in cyclophotocoagulation (CPC), with each generation of the technology becoming more doctor- and patient-friendly. Dr Shan Lin, a glaucoma specialist at the Glaucoma Center of San Francisco in California, United States, recently described some of the recent advancements in the treatment.

Transscleral cyclophotocoagulation (TCPC) was developed first, but it has its limitations. In some cases, the treatment is unable to reach the targeted tissue because the tissue is not visible.

In addition, the surrounding structures can potentially be damaged. Excessive treatment using TCPC can also occur and cause an audible popping and explosion of the ciliary processes and pars plana, which can result in inflammation such as cystoid macular oedema (CMO).

The G-Probe Illuminate Delivery Device (Iridex) has helped to address these problems. This technology uses a diode laser to treat the ciliary processes through the sclera and reduces the intraocular pressure (IOP) by decreasing aqueous production.

“This latest generation of the technology allows identification of the ciliary process locations either before or at the time of treatment,” Dr Lin said. He explained that the locations of the ciliary processes can vary among the different ocular quadrants and among different patients with glaucoma. He cited a study

 reporting that they can range from 2–5 mm behind the limbus.

Endoscopic CPC is a newer technology that facilitates direct visualisation of the ciliary processes as they are being treated. Probes with different gauge sizes (18, 19, 20 and 23 gauge) are available for this intraoperative procedure. In addition, the availability of curved probes allows the treatment of a larger area within the same incision, according to Dr Lin.

A typical procedure, as he described, is one performed in a pseudophakic patient through a limbal approach. “The goal is to cause shrinkage and whitening of the ciliary processes,” he said.

A study of endoscopic CPC in 68 patients, which included a range of glaucoma types, found that the IOP decreased from approximately 27 mm Hg preoperatively to 17 mm Hg postoperatively. In addition, the numbers of medications needed decreased from approximately three to two.

 The complications associated with endoscopic CPC included fibrin exudate (24%), hyphaema (12%), CMO (10%), vision loss (6%)—due to CMO in most cases—and choroidal detachment (4%).

MicroPulse is the newest of the technologies. It controls the thermal effect by “chopping” a continuous wave of the energy beam into repetitive short pulses interrupted by relaxation times, which makes for less thermal damage to the targeted area. Dr Lin explained that the technology is also thought to stimulate biological factors, such as cytokines and growth factors, at the treatment area.

The Cyclo G6 Glaucoma Laser with the MicroPulse P3 probe (Iridex) is a transscleral procedure designed to deliver laser energy in a pulse pattern to avoid excessive damage to the tissues. It also differs from the G-Probe in that the treatment is aimed at the pars plana rather than the ciliary processes and involves a slow sweeping motion along the superior and inferior limbuses rather than the discrete spot placement of the G-Probe.

An advantage of this new technology is that it can be performed either in an ophthalmologist’s surgery or in the operating theatre. Dr Lin said that he prefers performing the procedure in the operating theatre, for increased control and patient comfort.

In addition, there are no pops involved with the treatment. However, Dr Lin noted that the sweeping motion should avoid the 3 and 9 o’clock positions. “Having slower sweeps with the MicroPulse facilitates better uptake of the laser and efficacy,” he explained.

A study with follow-up of almost 7 years reported the long-term efficacy and durability of this treatment. The authors reported a 43% reduction of IOP at 78 months in 14 patients and a concomitant reduction in medications from 1.8 to 1.1. A number of treatments were needed, with an approximate average of 4.5, to achieve IOP lowering.

Dr Lin also presented results of MicroPulse technology in a retrospective analysis of 54 patients with a baseline IOP of 24 mm Hg, 75% of whom had primary open-angle glaucoma. Postoperatively, the average IOP was 17 mm Hg (

Success in this study was defined as IOP lowering of 20% or more with or without medications; this criterion was met in 68% of patients. Seven of the eyes required re-treatment. The potential complications of the technology include rare, unexplained visual loss; hypotony; ocular inflammation; and CMO.

In anatomical assessments using ultrasound biomicroscopy, there were no observable changes comparing before and after treatment. Iridex recently introduced a new Rev-2 probe with a footplate that helps with limbal alignment, improves tissue coupling for better laser delivery, makes the technique easier to perform and potentially has fewer complications.

“Diode TCPC with the G-Probe is usually reserved for blind, painful eyes and is now available with transillumination. Endoscopic CPC can be useful in some cases; however, there are risks associated with penetrating surgery,” Dr Lin concluded.

“Micropulse TCPC is useful for patients with refractory glaucoma, with less inflammation and possibly less risk than with diode laser. In addition, the new REV-2 probe is now available.”

This article is adapted from Dr Lin’s presentation at the Glaucoma Research Foundation’s 25th Annual Glaucoma Symposium. Dr Lin is a consultant to Iridex.

1. Agarwal P, Martin KR. Ciliary body position variability in glaucoma patients assessed by scleral transillumination. 

2. Chen J, Cohn RA, Lin SC, et al. Endoscopic photocoagulation of the ciliary body for treatment of refractory glaucomas. 

3. Aquino MC, Chew P. Long-term efficacy of micropulse diode transscleral cyclophotocoagulation in the treatment of refractory glaucoma. Meeting abstract. Presented at the European Glaucoma Society (EGS) Meeting,Prague, Czech Republic, June 19-22, 2016.

Benefits include better visualisation of ciliary processes and avoidance of tissue damage.

Newer CPC laser technologies are improving glaucoma outcomes

Genetic investigations have garnered a wealth of information about glaucoma. The findings have pinpointed specific genes involved in early-onset familial disease with autosomal dominant or recessive inheritance, as well as genetic risk factors for common glaucoma types with complex inheritance patterns.

Speaking at a recent ophthalmology conference, Dr Janey Wiggs, the Paul Austin Chandler Professor of Ophthalmology, Harvard Medical School, Massachusetts, United States, defined the major goals of genetic research as being to identify at-risk individuals and to use knowledge about disease-causing genes to develop novel therapies.

She reported how current studies have set out to evaluate the risk and clinical outcomes in primary open-angle glaucoma (POAG) based on development of a polygenic risk score (PRS) applied to data in genome-wide association studies (GWASs).

The contribution of any single genetic variant to POAG is only small; multiple gene variants are needed to increase both the risk of disease and adverse outcomes. According to Dr Wiggs, to assess the risk, multiple variants must be tested simultaneously using a tool such as the recently developed PRS.

The PRS score determines the total number of genetic risk variants for each person, and individuals in a population are scored according to the number of DNA risk variants they have. Those with the highest number of variants have the highest genetic burden, which is likely to have the greatest impact on the risk of developing POAG and the outcome.

In analyses, the outcomes of individuals with the highest PRS (highest percentile) are often compared with the overall population distribution or with individuals who have the lowest genetic burden. Dr Wiggs said that to develop this valuable tool, two requirements must be met: a GWAS that is large enough to facilitate identifying all potential variants to be included in the PRS, and use of computational methods that can manage large data sets and create the score.

The International Glaucoma Genetics Consortium (IGGC), which comprises investigators from around the world, was formed to complete the GWASs to identify all genetic risk variants for POAG. Each research group contributed their clinical and genetic data from POAG cases and controls.

Polygenic risk score allows multiple variants to be tested simultaneously.

PDS in Retinal Diseases: Interpreting the LADDER and ARCHWAY Studies

Newer CPC laser technologies are improving glaucoma outcomes

Identifying individuals at risk of glaucoma via genetics studies