ICRS 2019 - Conference Calendar
8.1.1 - Scientist Perspective
IntroductionReliable joint preservation still eludes us. The biomechanical environment, the intra-articular milieu, the cells in the form of chondrocytes, mesenchymal stem cells and immune cells, and the regeneration of a durable cartilage matrix presents us with a formidable list of challenges.
ContentResults of techniques such as osteotomy and joint distraction aiming to decrease the dynamic load on a failing joint surface suggest that the biomechanical environment of the joint is critical. Outcomes of observational studies and clinical trials using these methods suggest that they may provide both symptomatic improvement and signs of joint cartilage regeneration. However, large, randomized, pivotal trials with low risk of bias and long follow-up are still lacking.
Chondrocyte implantation, using a variety of methods, has been practiced for many years. While there are success stories, there are also stories of failure, and we remain unable to a priori reliably predict responders and non-responders. Pivotal trials showing efficacy and cost-effectiveness are absent. The unregulated use of intra-articular injections of stem cells, platelets and other blood products continues to expand in the absence of clear evidence of benefit and lack of harm.
In spite of numerous drug candidates having been tested in phase III clinical trials, there is no drug approved by the regulatory authorities that has shown disease modification in osteoarthritis, i.e. an improvement in symptoms accompanied by preservation or improvement of joint structure. The FDA has recently recognized osteoarthritis as a serious disease, opening for novel trial designs and an accelerated approval path. Together with recognition of early stages of osteoarthritis, this may facilitate development of novel treatments for joint preservation.
8.1.2 - A Scientist’s Best & Worst Experiences Related to Cell Therapy for Joint Preservation
Worst Experience: How factors outside your apparent control can delay progress.
Mycoplasma is a genus of the smallest bacteria which, having no cell wall, are resistant to many commonly used antibiotics. Hence it often is present in laboratories and in cell cultures but remains occult. The concern with this is that when mycoplasma infects cells it can alter the metabolism, functioning and gene expression and indeed chromosomal structure of the native cell. Experimental results can then be erroneous leading to poor data (and also lack of reproducibility between centres etc). Other concerning properties are that they are particularly prevalent in cell lines and can remain viable and indeed transfer between samples in liquid nitrogen.
When first embarking on studies on allogenic sources of cells for cartilage repair (umbilical cord-derived mesenchymal stromal cells; UC-MSCs) our laboratory had a bad experience with mycoplasma infections. For a period of months in 2011-12, we were throwing away culture after culture, spending hours every week attempting to decontaminate incubators, flow hoods etc as well as doing several mycoplasma tests (via PCR) on many different cell populations. We appeared to make no headway in obliterating the infection so took advice from a professional mycoplasmology company whose sole function was to test for mycoplasma and offer advice in such situations! We never did get to the root cause of the infection but gradually we reduced the infections to zero. However, it was very costly in terms of manpower, reagents and samples but particularly in terms of staff morale. This was none more so than for an orthopaedic surgeon who was attempting to work fulltime as a surgeon AND do his PhD – which at that time was mainly on UC-MSCs. He would be coming in at 10pm to feed his cells and undertake his ‘research shift’, the fruits of which were more often than not at that stage was being thrown away further down the line. We now maintain regular mycoplasma testing (particularly whenever culturing a cell line) and use some additional precautions, eg a mycoplasma killing agent in waterbaths, greater use of Virkon. So far so good…….
Best Experience: Culmination of Research Efforts Impacting on Patient Care – and James B Richardson!
Thursday 5th October 2017 will forever be etched in the minds of attendees at the 11th Oswestry Cartilage Symposium. Professor James Richardson, who gave 20 years of his working life championing and battling to keep autologous chondrocyte implantation (ACI) going, reported at the meeting that the previous day the National Institute of Clinical Excellence (NICE) had announced their approval and evidence-based recommendations for using ACI to treat people with symptomatic articular cartilage defects of the knee (https://www.nice.org.uk/Guidance/TA477). It was a very emotive moment for all concerned, but particularly for James.
Some of the evidence that this decision was based on had come from patients treated by James and others, both in Oswestry and also elsewhere as part of the largest multicentre trial of ACI to date, ACTIVE (Autologous Chondrocyte Transplantation/Implantation Versus Existing treatment) which recruited 390 patients. The conclusion of the University of Warwick study for NICE was that survival analysis suggested that long-term results of cartilage repair are better with ACI than with microfracture (MF). In addition, and importantly, economic modelling suggested that ACI was cost-effective compared with MF across a range of scenarios. The cost-effectiveness analysis for the ACTIVE trial uses EQ-5D-3L (EuroQol-5 Dimensions, three-level version) and at the time of presenting evidence to NICE, data was based on up to 8 years of follow-up. It assumed a cost for cells of £4125, based on in house production costs. The data showed little difference between ACI and MF for the first 4 years but, after that, EQ-5D results were better in the ACI group, with a cost per QALY for ACI compared with MF of around £6000.
There remains a long way to go to make cell therapy more cost-effective (which can be achieved by decreasing cell production costs, eg with an allogeneic cell product, or simplifying the application procedure to an intra-articular injection), and indeed steps are being made along that route. But to know that research and audit of patients treated in our centre has contributed to the approval of ACI by NICE and retain the ability for this treatment to be available on the NHS in the UK is heart-warming for those concerned. Thank goodness Professor Richardson lived to see that day.
We are grateful to Versus Arthritis (grant numbers 18480, 19429 and 21156) and the Medical Research Council, UK (grant numbers MR/L0104531/1 and MR/N02706X/1) for funding contributions.
8.1.3 - Scientist Perspective
8.1.4 - Clinician Perspective
8.1.5 - Clinician Perspective
My Best & Worst Experiences in Joint Preservation
Joint preservation requires a combined approach from all members of the team integrating many disciplines. Someone said that regarding knee replacement that someone in the room needs to be over 50 before doing a knee replacement - and that is a reflection that experience counts.
We learn from experience and experience makes learning, no doubt about that. Cases presented reflect on the experience of listening, reading and trying, plus reflection and trying again.
TruFit plugs work in the end but not on an acceptable timescale. Meniscus Transplant works in most but when it goes bad it goes bad. Some patients don’t listen and break the rules creating new rules, if we don’t listen to them we don’t learn.
This presentation reflects on these messages, but not in print
8.1.6 - Clinician Perspective - “Experience is the Hardest Teacher, it gives you the Test First and the Lesson After” - Oscar Wilde
IntroductionIn 1989, as a young orthopaedic intern, I witnessed my first cartilage repair procedure: an osteochondral allograft in a 28-year-old man with osteonecrosis of the femoral head. I was fascinated by the elegance of replacing diseased tissue with healthy tissue- like for like- versus the metal and plastic joint replacements I was routinely exposed to as a trainee. I was also lucky in a way. Training in San Diego, where fresh allograft transplantation surgery was being pioneered, afforded the opportunity to learn from pioneers and become interested from the beginning of our joint preservation specialty. Eight years later, when I returned to San Diego as a young faculty member, I remember the day that Lars Peterson and Matts Brittberg ACI study was published in the New England Journal of Medicine, which effectively launched the era of cartilage repair as we know it today. It has been a pleasure and a privilege to participate in this field.
ContentWhat are my best experiences? Certainly, it is the friendships and collegiality I have experienced worldwide. It is not many who can say they are privileged to have friends around the world! It is also the trust and gratitude of patients that I have helped when they were told nothing more can be done (and now seeing them thrive 20 years later).
What are my worst experiences? Doing an operation that does not help the patient and seeing their hope fade. And, after 30 years in joint preservation and arthritis care, knowing I (and we) have made little progress in solving the ultimate puzzle of the arthritic joint. I have learned a lot of ways to tell patients they have an incurable disease! Let’s agree that cartilage repair and joint restoration is hard work. I have a special day of the week to take care of these patients- usually Fridays so there can be a “happy hour” after clinic. Most of my allograft surgeries take place at night, after the regular day of work is done. Bad experience?
Aside from philosophy, there is a practicality to experience that informs us about how we did and how we can be better. We often know this intuitively, but science demands data. We have collected, prospectively, data on every single joint preservation procedure we have performed in the last three decades. The size and quality of this database has become a powerful tool in our understanding “best and worst”. I don't remember the source but I am fond of the saying “those that have data need not shout”
At this meeting we will report predictors of failure of fresh osteochondral allografts along with outcomes in “ideal patients”, literally the two ends of the spectrum. We all know that young patients (under 30 years) with healthy joints and focal traumatic cartilage lesions or OCD have predictably good outcomes and thus fall into my “best experience” category. Ironically, I have also learned that isolated trochlea lesions have great outcomes (think of how rare this is, most bad patellofemoral joints start with patella lesions). I can confidently tell them (and their parents) we have over 90% chance of success and I know from my data these knees are functioning normally. Ironically the very worst patella cartilage disease often is a good allograft experience. Patients seem to be genuinely happy with a knee you or I might not like but one that is infinitely better than the disaster they lived with. Less obvious is the other best case for me: usually lateral, but sometimes medial, degenerative lesions with malalignment and some amount of meniscal deficiency. I have learned to love the distal femoral osteotomy, like the high tibial osteotomy and am ambivalent about meniscal transplantation. It’s what the data and my patients tell me
What does the data tell me is the worst? Trying to be heroic and treat multicompartment knee arthritis. After 20 years I haven’t figured that out and I don't think anyone else has. I just don't do it, particularly in middle aged people. My data says that if you are over 40, have OA or degenerative chondral lesions and have grafts in more than one compartment, your chance of “success” long term is no more than 40%. The same holds true for the patellofemoral joint with bipolar disease and the typical dysplasia/ malalignment. To me this often goes beyond a disease of the organ (the synovial joint) and becomes a disease of the organism. How can cartilage repair restore a whole limb that is dysfunctional? As an arthroplasty surgeon I am much more confident in success with metal and plastic implants in this group. I’ll still try joint preservation in young people under 30 but it has to be a special case.
One thing that I have observed in the world of joint preservation, is that most of us have come to similar conclusions in our own “experience. I find that remarkable, but it is probably predictable as well. Experience is teaching us every day. Outcome data is getting incrementally better with every passing year. One day I hope we all can talk about how we solved the “worst experience” phenomenon in joint preservation