Study: NovaTears helps symptoms, not signs, in oGvHD

NovaTears is an eye drop available in Europe.

The bottom line for GvHD patients on 4x daily NovaTears in this study:

No clinical, change, but a little over half of patients felt better. (Need I say, feeling better is good….) 1 out of 23 patients had an adverse reaction.

Semifluorinated Alkane Eye Drops in Chronic Ocular Graft-versus-Host Disease: A Prospective, Multicenter, Noninterventional Study. Eberwein et al, Ophthalmic Res. 2019 May 22:1-9

Abstract

PURPOSE:

Ocular graft-versus-host disease (oGvHD) following allogeneic hematopoietic stem cell transplantation develops as severe dry eye disease (DED) and is initially treated with lubricants, although no clinical trials are available using artificial tears in oGvHD. This trial was set up to test perfluorohexyloctane (NovaTears®) as nonpreserved layer-forming agent for the treatment of DED in oGvHD.

METHODS:

25 patients with severe DED due to oGvHD received 1 drop perfluorohexyloctane 4 times daily during a prospective, multicenter, observational 12-week study on top of established topical therapy. Clinical parameters included Schirmer test, tear film breakup time, corneal staining, meibum secretion and ocular surface disease index. Adverse events, visual acuity and intraocular pressure were key safety parameters.

RESULTS:

From 25 patients recruited, 23 presented for the second visit. Perfluorohexyloctane treatment did not lead to any changes in clinical or safety parameters but led to fast relief in symptoms in 57% of the patients. One adverse reaction occurred.

CONCLUSIONS:

This study showed no change in clinical signs in severe DED due to oGvHD, which was not unexpected due to the underlying pathomechanisms. However, the study showed improvement of symptoms in individual patients allowing application of perfluorohexyloctane as an additional symptomatic therapy in oGvHD.

Study: Measuring symptoms after DCR surgery... and ruminations on the meaning of safety and efficacy

Am J Rhinol Allergy. 2018 Jan 1;32(1):46-51. doi: 10.2500/ajra.2018.32.4494.
Comparison between endoscopic and external dacryocystorhinostomy by using the Lacrimal Symptom Questionnaire: A pilot study.
Wong WK, Dean S, Nair S.

Preface: What's a DCR and who among my readers would care?

Excess tears drain through ducts in the corners of your eyes through your canaliculus, lacrimal sac and nasolacrimal duct into your nasal passage. For some people these draining canals can get blocked and sometimes a surgery called a DCR is performed. A DCR is not about clearing the blockage per se, but rather creating a bypass. It can be done externally (incision through the nose!) or endoscopically.

The reason DCRs are sometimes relevant to the dry eye crowd is that dry eye patients are often treated with plugs, and permanent silicone or thermoplastic plugs (such as SmartPlugs) have a nasty way of traveling to places where they cannot be found, and then festering and causing problems. Once plugs "get inside" somewhere - anywhere - they cannot be seen with imaging, so sometimes the only way to solve that kind of problem is to basically cut it open and find it... hence the DCR. 

I've known an awful lot of people over the years who had plug complications. Oculoplastic surgeons tend to have a lot of horror stories to share about bits of plastic or silicone floating around in that lacrimal sac and re-appearing years later. I almost had to have a DCR myself a few years back due to a misbehaving SmartPlug that resurfaced (we believe) after more than a decade and rendered me miserable for about a year. I had a canaliculotomy first, and we didn't find the plug, but then the problem thankfully resolved itself before I went ahead with a DCR.

Safety vs efficacy, in endoscopic vs external DCR... and in medicine in general.

I remember vividly when I had to consider which type of DCR to get, at the time I was planning to go for it. It was a hard call. Usually they are compared in terms of "safety and efficacy", the standard measures of all things medical, from drugs to surgical interventions - that is, are there complications, and how well does it work according to the standard established.

Unfortunately the questions both of safety and of efficacy too often leave out how either of those things are measured by the patients themselves.

Safety standards may be acceptable to physicians because the side effects may be deemed to be so minor by the physicians... but minor to the physician does not always mean minor to the patient. Those of us with vision quality problems or dry eye symptoms after LASIK can readily attest to that, I'm sure. 

Likewise, efficacy may be assessed differently by doctors versus patients. It all depends on your point of view and which problem you're trying to solve. The problem the doctor's trying to solve, in this case, tear drainage, may not entirely overlap with the problem or problems the patient's trying to solve, which is why I appreciated this DCR study so much.

In this study: Compare results by SYMPTOMS and quality of life

These are the things that always make me sit up and read more carefully - when I see studies focusing on the outcome as measured by the patients themselves. 

In this study, they employed a Lacrimal Symptom Questionnaire before and after surgery, comparing the two surgical approaches. The questionnaire has just a few questions to gauge (1) social and lifestyle impact of the tear duct problem and (2) a scorecard for the type and extent of problems experienced with each eye, from watering to pain to stickiness to swelling. Both types of surgery showed significant improvements, though it looks like the endonasal group won. I'm not a subscriber to the journal so I haven't seen the complete results to be able to report back on nuances that might be important - I just liked that someone is focusing on quality of life impact from the surgery afterwards.

BACKGROUND:
Epiphora has a significant impact on the patient's quality of life and is commonly caused by nasolacrimal duct obstruction. Dacryocystorhinostomy (DCR) has traditionally been performed via an external approach, which involves a skin incision. With the advent of endoscopes, the endonasal approach to DCR has gained significant popularity.
METHOD:
To prospectively compare the quality of life of adult patients who underwent either an endonasal or an external DCR for acquired nasolacrimal duct obstruction, the Lacrimal Symptom Questionnaire (Lac-Q) was administered before and after surgery. The treatment group assignment was nonrandom and performed based on patient preference. The Lac-Q is a validated questionnaire that assesses the subjective perception of one's well-being from an eye-specific symptom and social impact standpoint. Total scores range from 0 (no concerns) to 33 (maximal degree of ocular symptoms and social impact).
RESULTS:
Sixty patients (22 in the endonasal group, 38 in the external group) were recruited between January 1, 2014, and January 1, 2016. Postoperative assessment was performed at 3 and 6 months. Patients who underwent external DCR reported a median 7.0-point improvement (interquartile range [IQR], 3.0-11.0) in total Lac-Q scores. A 12.0-point improvement (IQR, 10.0-18.5) was seen in the endonasal group (p = 0.005). The median change in the social impact score was 3.0 and 4.0 in the external group and the endoscopic group, respectively (p = 0.029). Changes in the median lacrimal symptom score were 4.0 in the external group and 8.0 in the endoscopic group (p = 0.014). The anatomic patency rate was lower in the external group (60.0%) when compared with the endonasal group (90.4%). Patients in the external DCR group were significantly older (median age, 51 versus 41 years).
CONCLUSION:
Our study indicated that both endonasal and external DCR can lead to improvement in quality of life by using a validated questionnaire. Although there are differences in age and anatomic success rates between the two groups, subgroup analyses indicated that the differences in the Lac-Q scores persisted when age and anatomic patency were removed as potential confounding factors. Further larger, randomized studies would be helpful.

Study: The age factor in dry eye

Ahhhh one of my favorite journals - I love when a new issue of IOVS comes out with lots of dry eye goodies. 

This is quite interesting, because most, but not all, of the dry eye related lab testing in this study correlated with increased age, BUT the OSDI (i.e. symptom scores) did not.

Those of you who worry about "My eyes are so bad now, and it's only worse from here as I age, right?"... bear in mind, it's nowhere near that simple. At the end of the day, symptoms rule, and even if dry eye testing looks worse, it's never a foregone conclusion that you will actually feel worse.

Invest Ophthalmol Vis Sci. 2018 Apr 1;59(5):2024-2031. doi: 10.1167/iovs.17-23358.
Age-Related Changes to Human Tear Composition.
Micera, Di Zazzo, Esposito, Longo, Foulsham, Sacco, Sgrulletta, Bonini S

Abstract
PURPOSE:
We characterize age-associated alterations in the expression of inflammatory mediators and tissue remodeling factors in human tears.

METHODS:
A total of 75 consecutive volunteers (32 male/44 female; 19-93 years) underwent clinical assessment of ocular surface status, ocular surface disease index (OSDI) grading and tear sampling. The volunteers were categorized into three groups: young (18-40 years), middle-aged (41-60 years), and old (>60 years). Total protein profiles and chip-based protein array evaluations were conducted to investigate the expression of 60 potential candidates, including pro-/anti-inflammatory mediators and tissue remodeling factors. Appropriate validations were performed using conventional assays. Multiple comparisons for regression between potential candidates and age were performed, as well as statistical analyses among the three age groups. Nonpooled samples were used for quantifications.

RESULTS:
Pearson analysis of chip-arrays identified 9 of 60 potential candidates. Specifically, IL-8, IL-6, and regulated on activation, normal T cell expressed and secreted (RANTES; P < 0.0083) protein as well as matrix metalloproteinase (MMP)-1, IL-3, and TNF-α (P < 0.05) correlated positively with aging. MIP-3β showed an opposite tendency. Western blot and ELISA analysis corroborated the array data. OSDI grading did not correlate with aging.

CONCLUSIONS:
Dynamic changes to tear protein profiles occur with aging. Our study identifies the expression of IL-8, IL-6, RANTES, MMP-1, and MIP-3β as increasing with age. These select inflammatory and matrix remodeling factors may be relevant to the development of novel diagnostic tools and therapeutics in the context of age-related ocular surface disease.

Numbers matter: Why and how to track your dry eye symptoms

Dry eye disease involves two parallel realities that can be hard to reconcile:

1) Our eye doctor's findings.

2) Our own experiences, i.e. how our eyes feel and how we see.

When these two things are too far apart, frustration is inevitable. Is there anyone who hasn't experienced that at some point in their dry eye journey? For some of you, perhaps it's been more the rule than the exception: where you're trying to express how uncomfortable you are and describe the impact of dry eye on your life, but it seems so far out of alignment with what your doctor thinks during the examination. The bottom line is that, so often, we just don't feel heard or understood. 

It's the classic sign vs. symptom clash.

It doesn't have to be this way.

What if BOTH parties were equally equipped with ways to measure and communicate the relevant facts?

Doctors get to measure clinical signs of dry eye, e.g. tear break-up time, tear volume, tear film osmolarity, and so on. Measuring these regularly is helpful in many ways, from creating a treatment plan to evaluating progress along the way.

But patients also have important data that needs to be assessed and reported: symptoms, e.g. burning, foreign body sensation, blurred vision, pain, light sensitivity, itching and so on. 

Did you know that our symptoms can and should be evaluated regularly, using scientifically validated surveys? This type of symptom data is critically important because it seeks to capture how your eyes actually feel and how they are affecting your vision function and even quality of life, but in a reliable and measurable way. (This type of data is used in FDA clinical trials of dry eye drugs, by the way, and medicine in general is, at last, slowly trending towards considering the patient's experience and priorities more.)

Imagine having numbers to give your doctor, as opposed to "My eyes are killing me!" "My eyes hurt so much at the end of the day." "This dry eye thing is running my life!" etc. No matter how true it all is, it may also just be too difficult for doctors to take on board, particularly if the severity of clinical measurements doesn't seem to explain what you're describing. Push come to shove, your subjective descriptions will be sidelined in favor of their objective numbers. So, be objective and get numbers. The right numbers speak for themselves, and they help you talk your eye doctor's language. I'm talking about symptom data collected methodically and scientifically.

Think about it. The FDA requires drug companies to show improvement to symptoms, not just clinical signs of dry eye, in order to approve dry eye drugs. Several things then stand to reason, including: (1) Reliable ways to measure symptoms really do exist, and (2) your doctor ought to find symptom data of that kind at least as interesting as the FDA does.

So: Get into the numbers game!

Some dry eye doctors ask their patients to complete a survey of their symptoms before each appointment. They might be using one of the well known and validated surveys, or they might be using something they created themselves which they feel works as well or better. Either way, that's great! Consider getting a copy, and complete it weekly or monthly in between appointments, not just at appointments. If your doctor does not use any type of survey to gather symptom data, take the initiative. Get a questionnaire (see below for a simple place to start), complete it and print it before every appointment, and ask your doctor to put it in your medical record. Complete it at regular intervals in between appointments as well. In addition to everything your doctor will learn, you may even find yourself surprised at the results. Patterns may emerge that you might not be aware of.

Where do I get a dry eye questionnaire?

For starters, try OSDI (Ocular Surface Disease Index (copyrighted by Allergan) It is far from perfect, for sure! However, I've tended to recommend this one because:

• It's easy to find.

• It's very well known and broadly accepted (including in clinical trials).

• There's a smartphone app. (So far as I know, this is the only one of its kind, but if I'm wrong, please enlighten me!)

For those who care to dig further, TFOS DEWS II's Epidemiology Report (published July 2017) contains a review of all the dry eye patient questionnaires that have been used in studies, including 12 that have been validated. 

What is dry eye like?

I recently invited members of our Facebook DryEyeTalk group to respond to the following: "Describe (a) how your eyes feel, and (b) how that impacts your quality of life." The following is a collection of the responses:

They are irritated, hurt and feel dry almost all the time. This lessens the quality of my life because wind, sun and everything else make them feel worse. The dramatic redness these problems cause makes me self-conscious and depressed.

My eyes feel like rocks- dry, gritty, and hard. They burn and make my head ache. I am a prisoner inside my house wishing I could enjoy the sunshine and cool breeze.

I am blessed to not have daily pain, as many describe.... My life has changed. Clear vision and vigilance on sclorel lenses/fluids dictate everything I do. Safety glasses outdoors in slightest breeze, monitoring humidity indoors, how long I'm in a store atmosphere.... too many things to list. 

Eyes are sore and ache all the time. Also so dry I can no longer enjoy simple pleasures such as going out on a windy day, a cup of coffee, a glass of wine. Can no longer read. Quality of life has drastically decreased. Also suffer from headaches now due to dry eye.

My dry eyes began 12 years ago & have worsened since then. My left eye, the far more miserable one, burns & feels parched, more so as the day goes on. I find I am avoiding evening plans since my eyes fatigue me so much & increase my chronic headaches. I wish I could cry but no tears come.

My dry eye has resulted in an ulcer on my cornea.My vision is gone in that eye and there is only 1 Dr. In U.S. that could possibly help. He happens to be over 1000 miles away and does not accept insurance. I really can't afford to go.Ive turned into a semi recluse because of my eyes.

My dry eyes began at age 20 and for the last 32 years have become worse and worse. I feel my eyeballs all the time, gritty, sticky, bad vision, and now the pain has become central, meaning it's triggered the trigeminal nerve to produce pain in my face and ear and eye (the latter feeling like pins sticking in there). I'm on 3 different medications to calm the eye/face pain down.

My eyes burn almost constantly. My vision is blurred from lack of tears. Bright lights actually hurt my eyes and trigger very bad headaches. I am seeing a specialist who is making me somewhat more comfortable but will not cure me with the technologies we have at this time. This is a very time consuming and expensive condition. We are ripped off by insurance co's not covering our expenses.

My eyes burn and feel gritty, and when they get bad my life becomes "smaller." I stop enjoying time with friends and family, and I don't try new activities, because my confidence level drops. I become a hermit. BUT, I am fortunate that attentive people have stepped up to show me how to navigate many of these problems.

Burn burn lots of days Sensitive to light. Can't read or do phone when they r that way. Eyes aren't clear. Glassy looking. Red too. Sunglasses evening too DED has destroyed my career ambitions and hopes for having children, interfered with relationships, and robbed me of the ability to enjoy even small things in life. It is hell on earth.

My eyes get so dry when I'm sleeping (even with ointment and drops) that my eye lids stick to my eyes. I wake up numerous times per night and need to carefully add drops to free my eye lids. If I happen to quickly open my eyes or if the sticking is really bad, I will get nasty abrasions on my eyes that cause severe pain, eye lid swelling (I look like I've been punched), watering, light sensitivity, etc. The abrasions, when they happen, will hamper my activities that day and I am not able to have optimal rest each night.

On my worse days it feels like I have glass in my eye or someone scratched my eye, on my best days I have only slight pain. They have affected my life by turning me into a homebody that stays in a dark room without heat on because that is most comfortable. I no longer do activities I used to do because the movement of my body creates air that dries my eyes out. I drive only short distances and travel is out of the question due to the fear of a pain flare up.

Feels like I have dried out contacts in my eyes, blurry like I don't have my glasses on and dull pressure. It's made worse by computers and other cellular devices. Affects driving any time of day and working in the afternoon. Night driving is very painful- even if I could drive at night.

My eyes feel like foreign objects in my head. They burn, sting, ache, scratch, itch, and cause crushing headaches, earaches, and sinus pain. 

My eyes are dry due to a lack of tears, which causes blurry vision that oftentimes is near debilitating. Its hard to do anything when you can't see and it is depressing as glasses can't fix it.

Dry eye has caused me to withdraw from life. It has affected my relationships with friends and family. I dread waking up in the morning and start watching the clock at 9PM looking forward to closing my eyes. My quality of life has been compromised and I dwell in a state of depression.

My eyes used to be my best feature. Now they look diminished and vacant. I can't wear any eye makeup so I just keep the sunglasses on. It just looks better.

Sore, dry, gritty, extreme discomfort with even the slightest breeze. Sometimes I just have to keep my eyes closed because it hurts too much to keep them open. Many activities are off limits. Forget doing anything outside unless I can wear goggles. I don’t go anywhere in the evening. I stay home much more than I would like.