406 - Knee DJD Treatment, CGM Prescribing, CRISPR-Cas9 Intro
Take 3 – Practical Practice Pointers©
From the Literature
1) Physical Therapy vs. Steroid Injections for Knee Osteoarthritis
The very common problem of osteoarthritis of the knee causes no small amount of exasperation for both patients and clinicians in primary care. Guidelines and reviews conflict about the respective roles of physical therapy (PT) and glucocorticoid injection for this condition. We also know that plenty of NSAIDs and opioids are used for this problem – often to the detriment of blood pressures, stomach linings, kidney function and addiction risk.
A lovely and simple randomized controlled trial of PT vs. steroid injection was undertaken in the Army healthcare system in 2020. One hundred fifty-six patients were documented to have osteoarthritis clinically and radiologically, then each randomized to one of the interventions (in an open fashion – there were no placebo injections or sham PT interventions). PT was described as “manual techniques” followed by reinforcing supervised exercises for an average of eight sessions over 4-6 weeks. The steroid injections were performed by orthopedists or rheumatologists using 40 mg triamcinolone and 7 cc of lidocaine. Patients could have up to three injections per year. The patients underwent carefully blinded assessments using validated scales of pain, physical function, and stiffness – primarily the Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC) scale.
The PT group patients had statistically and clinically significantly greater improvement in their WOMAC scores after 1 year compared to the steroid injection group. All other measures showed this consistent benefit to PT. These effects were robust to multiple sensitivity analyses. Measures of self-improvement and physical task completion also favored the PT group. Total healthcare costs were similar in both groups, but this was not formally tested. There were no significant harms in either group aside from one fainting episode in the steroid injection group.
There were some study limitations. The authors state that patients in the PT group had more interactions with health care providers than those in the steroid injection group, and, of course, the trial was not blinded, both of which may have biased toward PT. There was also some contamination of the groups – 18% of the steroid group got PT, and 9% of the PT group got steroid injections – but this would have had the effect of biasing the study against PT. Similarly, there was more severe arthritis in the PT group than in the steroid injection group.
I wish we could get past the multiple barriers to physical therapy for our patients – their motivation, the time required, the specialty level copays, and most of all, the unwarranted belief that it doesn’t work. We should encourage a solid course of physical therapy for our patients with knee osteoarthritis. We should also advocate for a change in the coverage of this benefit for our patients.
Deyle GD et al. Physical Therapy versus Glucocorticoid Injection for Osteoarthritis of the Knee. New England Journal of Medicine. 2020 Apr 9;382(15):1420–9. Link
A Question From a Colleague
2) Prescribing Instructions for Continuous Glucose Monitors (CGM)
“Thank you for the recent Pointer regarding continuous glucose monitors ( Link ). How do we go about ordering these in our practice?”
We reached out to one of our residency faculty PharmDs, Randy Earls, who is also a certified diabetic educator, for her input. Randi provided the following information:
FreeStyle Libre Systems
Freestyle Libre 2: no app available, alarms available
Freestyle Libre 14 day: app available, alarms not available
Commercially Insured Patients:
- FreeStyle Libre systems Rx should include:
- Freestyle Libre Reader: Quantity: 1, Refills: 0
- Freestyle Libre Sensor: Quantity 2 sensors/month, refills prn or 12
- Patients can fill their Rx at any major retail pharmacy
- If patients are asked to pay >$75 for 2 sensors or have questions about coverage and costs, please have patients call Abbott at: 1-844-330-5535
Dexcom G6 System
Commercially Insured Patients:
- Dexcom G6 system Rx should include:
- Dexcom G6 Receiver: Quantity 1, refill yearly
- Dexcom G6 Transmitter: Quantity 1, refill every 3 months
- Dexcom G6 Sensor: Quantity 3/box, refill prn or 12 annually
Other Insurance (for both systems, will vary by insurance)
Medicare Eligible Patients:
- Patient must be on at least 3 insulin injections per day and provider notes should reflect this. Should also document that frequent adjustments to insulin regimen are needed or patient is experiencing hypo/hyperglycemia
- Per Medicare Criteria orders must be placed through DME
- Solara Medical Supply, Total Medical Supply, Home Care Delivered are DMEs that help most patients in VA.
Medicaid Eligible Patients
- Generally, patients should be on at least 3 insulin injections per day and provider notes should reflect this. Should also document that frequent adjustments to insulin regimen are needed or patient is experiencing hypo/hyperglycemia
- For most Medicaid plans orders must be placed through DME with exceptions (in Virginia - VA Premiere, CCCP Magellan, CCCP Anthem)
- Send orders as per commercially insured patients
- Patients can fill their Rx at any major retail pharmacy
- GoodRx Freestyle Libre copay for 2 sensors ~$60; copay for 1 reader ~$75
- GoodRx Dexcom G6 copay: Not covered
One challenge with prescribing these is the coverage is very plan specific. Getting to know what the plans in your state cover will be useful as more of our patients seek access to this technology. Refer to the previous Take 3 ( Link ) for additional information about the guidelines regarding CGMs.
From the Cutting Edge of Genetic Technology
3) Introduction to CRISPR-Cas9 Gene Editing
In October of 2020, in the midst of the COVID pandemic, scientists Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel Prize in Chemistry for discovering and modifying the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease genetic editing process.
The CRISPR technique provides the ability to precisely edit genomes – enabling specific genes or DNA sequences to be accurately targeted and snipped out or replaced. It has been likened to genetic scissors with the letter-by-letter editing capabilities of word-processing software. The original process evolved in bacteria as a protective mechanism against viruses. Since the introduction of the technology in 2012, it has profoundly changed the science and technologies of gene editing. (see video in references for an intro).
In the last 6 months, 2 papers have been published in the New England Journal of Medicine that speak to the clinical potential of this technology. In the first, two patients, one with transfusion-dependent β-thalassemia (TDT) and one with sever sickle cell disease (SCD), had transplantation of CD34+ hematopoietic stem and progenitor healthy donor cells which had undergone a process called electroporation with CRISPR/Cas9 targeting the BCL11A erythroid-specific enhancer.cells. This resulted in long-term engraftment with the potential of lifelong production of red cells with high levels of fetal hemoglobin. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vasoocclusive episodes. This result has provided a proof of principle of the emerging clinical potential for gene-editing treatments.
In the 2nd paper, six patients with transthyretin amyloidosis (also called ATTR amyloidosis), a life-threatening disease characterized by accumulation in tissues of amyloid fibrils and resulting in progressive cardiomyopathy and polyneuropathy, received a single intravenous dose of NTLA-2001. This is a new CRISPR-Cas9–based in vivo gene-editing therapy that is intended to edit TTR in hepatocytes, leading to a decrease in the production of both wild-type and mutant TTR amyloid after a single administration. Over the 28-day study, all patients experienced a significant reduction in TTR levels, which will be continued to be followed over time. These data provide an additional clinical proof of concept for in vivo CRISPR-Cas9–mediated gene editing as a therapeutic strategy.
The potential for this powerful technology which can make precise changes to the human genome is mind-blowing. Yet it also comes with some significant and difficult ethical issues and social concerns that have only begun to be explored/addressed. Should genome engineering be restricted to the avoidance of genetic disease, or might it be justified for genetic enhancement? What would such uses mean for the status of people with existing genetic diseases or impairments, if these are “edited out” of future generations? Can we hope to ensure equitable access to these powerful techniques, or would they widen the divide between haves and have-nots? Should we use CRISPR on the human germline, so that modifications are inherited by future generations?
The role we who work in primary care will have in helping to answer these questions is yet to be determined, but our awareness of this technology is vital. Indeed, just yesterday I received an advertisement from the company Applied StemCell where for a reduced price of $13,000 I could “leverage our extensive expertise in both stem cell and CRISPR/Cas9 gene editing technologies to generate genetically modified induced pluripotent stem cells (iPSCs).” It’s an entirely new language and a whole new world (… don’t you dare close your eyes … ;>)
- Jansen, K. How CRISPR-Cas9 works (Video). C&EN 9 October 2020. VIDEO
- Frangoul H, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 21 January 2021; 384:252-260. Link
- Gillmore J, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. Published ahead of print. 26 June 2021. Link
Mark and John
Carilion Clinic Department of Family and Community Medicine
Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.