Mary Strek, MD of the University of Chicago discusses the diagnosis of Scleroderma-ILD, the emerging role of exposures, and treatments.
It’s a pleasure night in cheetahs my co-chair again mary straight from the university of chicago where she has been many contributions i think tara care and understanding of patients with a variety of interstitial diseases and she’s going to give us an update in advances in the therapy force lehrer dharma thank you so i’m going to talk about a different autoimmune
Disease the autoimmune disease scleroderma or systemic sclerosis these are my conflicts of interests so interstitial lung disease insular adharma is common and likely under recognized it’s important to note that the lung disease may not track with the rheumatologic features which makes it a bit more challenging in terms of diagnosis and it’s clear to those of us
Who take care of patients with scleroderma that the interstitial lung disease is indeed a cause of great morbidity and some mortality as i mentioned it may masquerade as idiopathic disease and as i’d like to talk about today there’s increasing evidence that we have robust information about effective treatment for patients with scleroderma ild today i’m going to
Talk about new understanding and the guidelines updated guidelines on diagnosis the emerging role of exposures and then as i said finish up by talking about a couple new trials of treatment so the american and european rheumatology associations published in 2013 new criteria for the diagnosis of scleroderma these criteria are easily searchable actually i think
Quite easily usable in the clinic and what i think is most impressive is that the rheumatologists have recognized the importance of the contribution of the lung and included both pulmonary hypertension and interstitial lung disease within their diagnostic category which has not been done for the other connective tissue diseases in addition they included a robust
Validation cohort within their diagnostic criteria with sensitivity and specificity over 90% scleroderma ild is noted in the majority of patients with scleroderma fortunately it seems to be progressive in a minority although we need more information on the exact figure of of that it is associated with the scleroderma antibody and lower lung function is associated
With worse outcome i show you here a series of ct scans from a patient that i’ve cared for now for 20 years who presented in the late 90s with systemic sclerosis the main finding really was the interstitial lung disease but he had near normal lung function and has not been on treatment in 2003 that seemed like a wise decision but over the course of the last few
Years i think you’ll see that his ct now shows some honeycomb fibrosis now if he were in his 80s that might not be a big deal but he originally presented in his 40s and so now he’s a very otherwise very healthy man in his early 60s with some significant fibrotic interstitial lung disease i also want to talk a little bit about our understanding of the ct pattern on
In patients with interstitial lung disease from scleroderma the majority of patients have nsip nonspecific interstitial pneumonia but this comes in two flavors and many of the patients with systemic sclerosis and ild have the fibrotic flavor and so while the prognosis is much better than with usual interstitial pneumonia it is as you saw on the patient i showed
You previously it can be a fibrotic process if that can progress we have published on patients with uip in the setting of connective tissue disease and have shown in a nice paper by dr. cheung that there are certain findings on the ct including the straight edge sign which you see on the coronal view so unlike the honeycomb fibrosis that hugs the periphery an ipf
In patients with connective tissue ild including scleroderma there is more of a straight edge or pancake sign and then the exuberant honeycombing that i’ve shown here is also much more characteristic of uip from a connective tissue disease in addition a process in the lung that has been thought to be rare but i think i certainly am seeing increasingly commonly
Pleural prank omo fibro alas ptosis where there’s upper lobe fibrotic sickening along with sub adjacent parenchymal fibrosis this upper lobe process can coexist with lower lobe nsip or uip and has been shown to be due to recurrent infections and exposures but i’ve as i’ve noted in patients in my clinic and is when noted in this publication can also be seen in
Scleroderma and so i suggest if you see this pattern in a patient in your clinic you undertake a thorough evaluation for systemic sclerosis and other autoimmune diseases i want to spend just a minute talking about some data that i think is probably not widely recognized for the role of occupational exposures i in the connective tissue diseases and in particular in
Systemic sclerosis a french study looked at 200 subjects with systemic sclerosis and compared them to 300 age sex and cigarette match controls and what they saw that there was a significant increased risk of systemic sclerosis in patients who had exposure to silica other paint thinner and other solvents and welding fumes as you can see by the occupations listed the
Exposures actually did significantly differ by gender in a another study this one i in an italian center looking at patients who presented now with a formal pneumoconiosis pulmonary silicosis patients all had advanced interstitial lung disease and pulmonary fibrosis and were being evaluated for lung transplant of those 40 cases nine patients at autoimmune disease
Which is seven fold increase over the general population six of nine had mediastinal adenopathy and three of those patients had scleroderma with this showing the digital ischemia and infarcts that we sometimes see in patients with systemic sclerosis and was seen in a male patient in this study the cdc of course has been very busy helping us understand the vaping
Acute lung injury there also has been work from them and from a group in australia looking at the stone fabrication and its role in causing significant progressive interstitial lung disease with some patients also having autoimmune disease and so this stone fabrication results in a high level of toxic exposure to respirable silica and in some patients scleroderma
Rheumatoid arthritis and other autoimmune diseases much more commonly seen in men and many patients but not all have classic silicosis others have upper lobe fibrosis and mediastinal adenopathy unfortunately it is progressive sometimes even years later hence sometimes i think the dissociation between recognizing the occupational exposure and is sometimes fatal and
It is likely that this is preventable with appropriate wetting of the stone during the fabrication process and perhaps with mass and so the conclusion by turner at all was that patients presenting with connective tissue disease should have a full occupational history taken and so i would conclude this part of my talk by suggesting like in patients with idiopathic
Pulmonary fibrosis in patients with autoimmune ald there is a balance between injury and repair and that the clinical presentation may indeed as dr. rosa says said involves some common genetic pathways but then a exposure risk um that we’re just beginning to appreciate along with a behrendt immune response so now i’d like to turn our attention to some of the new
Treatment options in patients with scleroderma ild and i’m going to talk about mycophenolate ma fatale rituximab and nint an annette so most of you probably are familiar with the scleroderma to lung study which looked at cyclophosphamide versus mycophenolate patients had to have less than 7 years of systemic sclerosis they could have they had to have restriction
On p of t’s although some patients as you can see by the fe c of 85 upper limit of 85 percent had rather mild disease the ct had to show ground-glass opacity and the primary endpoint was change in vital capacity as a percent predicted which i’m going to show you on the next slide this looks at the survival probability and while this was a secondary outcome and
Was not officially positive i think all of us would rather be in the group at the top that received mycophenolate both because the outcome sure looks better and the side effects were much less as you see here on the the bottom of that graph also there was a three percent two to three percent improvement in the percent predicted vital capacity in both groups but i
Think most of us would agree that mycophenolate moffitt l is a much much better and less toxic agent so sometimes patients have progressive interstitial lung disease with connective tissue disease and there’s now an emerging understanding that for some of these patients iv therapy with rituximab is a very effective salvage therapy and so this is another prospective
Randomized but here open label study number of subjects is rather small patients all had diffuse scleroderma along with skin involvement and were randomized to iv cyclophosphamide versus rituximab with the primary outcome percent predicted fec at six months there was an improvement in the primary endpoint in the rituximab group while unlike in scleroderma to the
Cyclophosphamide group actually declined although really if you look at the data they essentially stayed the same but there certainly was a difference in the efficacy of these two agents the skin score also fell in the rituximab group it was unchanged in this like taxon group although prior studies the scleroderma one have suggested that cyclophosphamide has some
Efficacy for the skin disease in scleroderma and as we all recognize there are serious adverse events that in this study were definitely more common with cyclophosphamide and so the conclusion was that rituximab was more efficacious and better tolerated so i’m going to turn and finish with a discussion of the census trial which was just recently reported and published
Again nicely done rigorous trial looking at the anti fibrotic an antenna nib versus placebo over the course of a year patients with systemic sclerosis were allowed to be on background mycophenolate therapy and again patients had to have relatively early scleroderma the h rct had to show at least 10% fibrosis patients could have normal lung function vital capacity
Requirement was only that it be greater than 40 percent and the primary endpoint was the annual rate and decline in vital capacity over 52 weeks and as you see here this is a graph that’s becoming very familiar to us when we look at the efficacy of anti fibrotic s– in a variety now of fibrotic interstitial lung diseases and you can see that the the patients who
Got in in tentative had a much slower decline than the patients who received placebo and the other thing i note on in all of the studies is that the divergence occurs rather early and so patients really seem to be getting benefit from the anti fibrotic therapies after weeks of therapy which i think is very interesting to note here you see the number of patients
The extent of fibrosis had to be less than 10% but the mean was 36% in both groups fvc percent predicted 72% so again a rather mild population and then the difference in the annual rate of decline in vital capacity there was no effect on skin score or unfortunately on patient reported outcomes or quality of life adverse events as you might expect were a little
We’re not over all different but gastrointestinal toxicity was higher in terms of diarrhea nausea and vomiting in the patients who received an antenna nib with those of us who used mycophenolate moffitt ill knowing that some of those gi toxicities are actually seen with that drug as well although it the i think the impression was that most patients tolerated both
Therapies in this trial so now that we have some treatments that seem to have some efficacy we are going to need to have more rigorous robust data to help us decide whom we need to treat and right now that really is at the level of expert opinion and so i think the expert opinion right now is that if you have more than mild in quotes quote unquote smiled ild on
Hrc t not entirely clear what that definition is progressive aisle d symptomatic ld it is likely that therapy should be offered this is a recent but but small and not really very robust retrospective study that maybe gives us a little bit of insight patients had mild systemic sclerosis fe c greater than 85% and so many of us would probably in the old days not be
Treating those patients of those 294 patients they chose to treat of those pay of the 294 patients 116 excuse me had mild disease and of those 116 13 were exposed to cyclophosphamide or mycophenolate at baseline and those who had immunosuppressive therapy at baseline had a higher fec than those that were unexposed with no progression versus 24% progression in
The unexposed so not a robust study but a little bit of a sense that early treatment may be a benefit although i think many of us would argue cyclophosphamide would not be most of us would argue not be the drug that we would want to use in a patient with mild disease and so in summary i think there have been some significant advances in the field of scleroderma
Ild with refinement in the diagnostic criteria i really think these criteria are a roadmap that could be followed for other guidelines in terms of their inclusion of a validation cohort within the guidelines expanded h rct patterns that should lead us to think about systemic sclerosis i think more and more there may be a recognition of exposures contributing to
Autoimmunity and certainly to systemic sclerosis and rheumatoid arthritis ild and that there is now some evidence based on which to decide on therapy and then as we have really all benefited from our interactions with patients i add a quote from a patient who emailed me after i spoke at the pump at this scleroderma foundation a few months ago diane had talked a
Little bit about exposures and her email was i wanted to add my story to the research of the connection between slurred erm and silica i worked with fiberglass and had silica exposure from age 23 to 30 8 and then she finished and nobody ever asked me about my occupation or exposures so thank you very much
Transcribed from video
Advances in Scleroderma-ILD | Mary Strek, MD By Pulmonary Fibrosis Foundation