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 Another option for our patients who may be unable to wean down glucocorticoids or continue to have active inflammatory symptoms despite being on steroid-sparing or DMARD [disease-modifying antirheumatic drug] agents, such as mycophenolate, methotrexate, or azathioprine, there’s the option of repository corticotropin, also known as Acthar. Acthar comes in a gel formulation that can be administered subcutaneously or intramuscularly. Typically, these patients have tried and failed or continue to have active symptoms on corticosteroids. The intent of using a repository corticotropin option is to minimize some of the sequelae and long-term adverse effects that chronic steroid use can cause. It’s intended to help decrease disease activity and help maintain a steady state with the patient.

The suggested mechanism of action of repository corticotropin involves the adrenal cortex and the melanocortin system; it shares many features with corticosteroids. However, the majority of its mechanism of action is seen outside the adrenal gland. Thus, it’s suggested to have more of an immunomodulatory effect. Typically, you will see a response as corticosteroids wean off after cessation. Some trials in rheumatoid arthritis demonstrated enhanced or continued activity despite the withdrawal of corticotropin up to 12 weeks after therapy. So, it’s more than a traditional corticosteroid.

I’d prefer to use the subcutaneous route of administration in patients who have good dexterity and have disease activity that requires them to self-administer the treatment. For the intramuscular route, I would reserve that for my patients who might not be as well-versed and may not be able to handle the administration on their own, and thus require a potential caregiver to administer it for them. Alternatively, these are the patients who would come into the office and have it administered by a medical professional.

Patients who are on these medications are on long-term treatment, and we need to monitor them for any adverse effects. Steroids can be used in combination with these medications when patients develop either flare-ups or have severe organ involvement. The selection of these medications is related to what comorbidities or any adverse effects the patients may have had in the past, because they require frequent lab monitoring, such as liver functions, white blood cells, hemoglobin, and platelets. Patients who are on these medications are at increased risk of infections as well, and that needs to be taken into consideration when selecting such agents.

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An expert in rheumatic diseases considers therapeutic options for the treatment of SARDS including subcutaneous and intramuscular formulations of Repository Corticotropin Injection as well as immunosuppressive agents. 

Inflammation

Repository Corticotropin and Immunotherapy for SARDS 

It’s been a revolution of the things we have that we can treat our patients to prevent cardiovascular events. We talked some about the diabetic therapies, but there are certainly antiplatelet and antithrombotic therapies that work. Just to remind everyone that, the coagulation cascade has both an extrinsic and an intrinsic pathway. I often tell my patients, imagine that I’ve got a camera and I’m looking down any 1 of your blood vessels. There’s probably some cobblestone, which are the cells sitting on the line. As plaque builds up, it can build up. When plaque ruptures or a little disruption happens, the circulating platelets start to clot on the plaque. Additionally, you start clotting cascade with some tissue factor or other things being demonstrated to the cells. One of the strongest clotting-function factions happens along with some fibrin, thrombin leads to clotting at that cell level. 

The first action on the platelet side is that platelets come and aggregate. The antiplatelet agents aspirin, which works at the thromboxane level or, clopidogrel, ticagrelor, or prasugrel. They are P2RY12 inhibitors—a receptor on the platelets associated with aggregation. These oral agents work to inhibit platelet aggregation. We know that patients with diabetes have extra activated platelets…. They’ve been inflamed. They’ve been putting out fires all over the vascular bed for a while. They’re much more likely to aggregate than other patients. That’s partly how these agents work.

One of the most contentious places of care, in taking care of our patients, is how long do you use antiplatelet therapy on our patients with coronary artery disease and patients with diabetes? The most recent guidelines are from 2016, but there’s certainly a variety of data that have come out subsequently. In general, my general sense is, once somebody has had an acute coronary syndrome [ACS] in that first year after they’ve had a heart attack or an acute coronary syndrome, there’s broad agreement that dual antiplatelet therapy [DAPT] has been shown through several trials to be beneficial for up to a year. However, some of the more recent trials after the guidelines, such as TWILIGHT and other trials in which the aspirin was dropped after some period of time, have showed similar efficacy and less bleeding.

There’s some ongoing investigation to see in the acute coronary syndrome scenario if can we shorten the duration of dual antiplatelet therapy. Many have asked me, “What about after 1 year and the ACS? What about people chronically with coronary artery disease? After 1 year of an acute coronary syndrome, or after 1 year of an angioplasty PCI [percutaneous coronary intervention] event, we’ve had some other evidence: the dual antiplatelet trial, or the DAPT trial, and certainly trials associated with ticagrelor. In PEGASUS we studied patients with prolonged dual antiplatelet ticagrelor.

On top of aspirin, 2 different doses of ticagrelor were compared with aspirin. The DAPT trial showed us that prolonged dual antiplatelet therapy did not reduce mortality but did reduce EMI [electromagnetic interference], not always at the state level but other places. That came at the risk of an increase in bleeding. In fact, there’s a DAPT calculator for patients. And we make individualized decisions based on the patient’s risk of some of those thrombotic complications vs some of those bleeding complications. In fact, that’s what the guidelines do. The guidelines speak to determining the patient’s thrombotic risk vs their bleeding risk for prolonged dual antiplatelet therapy. But most recommend 1 year after ACS. After an angioplasty without ACS, based on some of the drug-coded data and others, the recommendations are in the 3- to 6-month time period.

 Recently the results of the THEMIS trial were reported. They were originally reported at the European Society of Cardiology Congress, and there was a publication in the New England Journal of Medicine. This was a very large diabetes trial. Of patients with type 2 diabetes, 19,000 or so had coronary disease. There were patients who had a prior revascularization, but none of them had had a prior myocardial infarction. These were patients with stable chronic coronary disease and diabetes. And we saw that these patients were at very high risk of a myocardial infarction, stroke, and cardiovascular death and that the addition of a P2RY12 inhibitor, 1 called ticagrelor to aspirin vs aspirin alone reduced that risk. There was also an increase in bleeding. In the overall population, there was uncertain benefit, but in 1 of the analyses that was shown, there was a particular benefit with patients who had a prior history of coronary revascularization. From that trial we’ve learned that patients with diabetes and atherosclerotic cardiovascular disease [ASCVD] and coronary disease are at heightened risk of major adverse cardiovascular events and that a more potent antithrombotic therapy reduces that risk but increases bleeding. For P2RY12 inhibitors, the most benefited appears to be in those with coronary intervention.

When we think about dual antiplatelet therapy—the combination of aspirin and P2RY12 inhibitor—we think of it in the context of a procedure, most often a coronary procedure, like coronary stent. It’s often also used in peripheral artery stenting. It’s generally time limited with the notion that it provides some stent protection for a period of time, 1 month to several months. And then it’s stopped. There are a group of patients—for example, those with prior myocardial infarction or acute coronary syndrome, who may benefit from longer durations of dual antiplatelet therapy. For patients who don’t warrant long-term dual antiplatelet therapy, once their duration ends, once it’s safe to stop it from a stent protection perspective, those patients remain at heightened risk of atherothrombosis. In fact, we know patients with peripheral artery disease, polyvascular disease and coronary disease, particularly those with risk factors like comorbid diabetes, patients who have polyvascular disease or chronic kidney disease, are at long-term heightened risk of major adverse cardiovascular events. Even though their duration of DAPT has stopped, their risk remains and even increases over time. There’s significant residual risk of atherothrombosis in patients with ASCVD, particularly those with comorbid diabetes.

When we consider dual antiplatelet therapy, there are some contraindications. Certainly if a patient were to have an allergy to 1 or both of the agents, we wouldn’t use it, but primarily we worry about bleeding risk. For patients who are at very high risk of bleeding, patients who are on therapeutic anticoagulation, we may choose to use a single antiplatelet or even drop antiplatelet therapy after a period of time. For patients who had intracranial hemorrhage or prior stroke, we’d generally be more cautious about long-term dual antiplatelet therapy.

Recommendations for treating patients with coronary artery disease and type 2 diabetes with dual antiplatelet therapy based on data revealed by the THEMIS trial. 

Diabetes

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Dual Antiplatelet Therapy for CV Risk Reduction 

 The topic of gene therapy and gene editing in sickle cell disease in and of itself is a misnomer. What has to be acknowledged is that the terminology should probably be referred to as myeloablative gene therapy and myeloablative gene editing. Why is that important? It’s important because as a former oncologist, I know that when you treat someone with myeloablative therapy, in this case, busulfan for both gene editing and gene therapy, you may cause unwanted effects 5 years down the road. The key is to recognize that when you provide myeloablative therapy to a 10-year-old, you would want to follow them for the next 50 years to know what the effects are. We know from late health effects of chemotherapy, specifically hematopoietic stem cell transplant, that there is no plateau for cardiovascular risk and other complications associated with curing a child with hematopoietic stem cell transplant. That’s the first challenge that I think we need to address. Also, families need to understand that it’s not just gene therapy and gene editing; it’s myeloablative gene therapy and gene editing. Furthermore, the field is moving forward so that 5 years from now, maybe 10 years from now, we may have nonmyeloablative gene therapy and gene editing, which we hope would decrease the sequelae associated with myeloablative therapy. 

The second point is that these therapies are experimental. They are the newest approaches to curative therapy in children and adults with sickle cell disease. They were developed because the donor pool was small for individuals who wanted to be cured from sickle cell disease. Specifically, for the gold standard approach, which is myeloablative, matched related donor transplant, which has been in existence for over 25 years in sickle cell disease, you had to have an instantly matched sibling donor. Unfortunately, less than 15% of individuals had donors who met the criteria of being a matched related donor. Thus, there had to be a strategy to increase the donor pool, and gene therapy was the original alternative 25 years ago. There are people who’ve worked in this field for over 2 decades because they recognized that you needed to expand the donor pool. Potentially the best donor would be the patient’s own cells. That’s No. 1. But then No. 2 is this challenge of myeloablative chemotherapy. Apparently, gene therapy and gene editing require myeloablation. As a result, many adults with comorbid conditions of heart, lung, or kidney disease could not undergo curative therapy.

What’s happened in the last decade is that there’s been what we refer to as haploidentical transplant with post-transplant cyclophosphamide. Why is that important? First, this therapy does not require myeloablation. You use a nonmyeloablative preparative regimen, which is much more amenable for adults who have chronic heart, lung, and kidney disease, which many of our adults with sickle cell disease have. Second, the donor can be a half match. Thus, in systematic studies that have been done, not only in the United States but in other areas of the world, the donor pool for patients with sickle cell disease is about 90%. In other words, 90% of individuals who want to have curative therapy, have the availability as a result of having a half match, and that’s typically a parent or it could be a sibling. Or it could be a child of the individual who wants to be cured. Consequently, there’s a much more expansive pool.

Now, when an individual with sickle cell disease comes in, and says, “I want to be cured of my disease,” there’s no longer just a single approach. If you don’t have a matched related donor, you still have these alternative strategies. You have the myeloablative approach, you have a nonmyeloablative approach for a matched related donor. Then, you have the nonmyeloablative haploidentical transplant protocol. I would consider all of these therapies that I just mentioned to be experimental. They should be done in a clinical trial setting with a data and safety monitoring board to address safety and utility of the clinical outcome. I would discourage single center trials as a strategy unless there are high levels of oversight and the benefits clearly outweigh the risks compared to the existing trials available at clinicaltrials.gov.

An expert in hematology/oncology discusses the emerging role of gene therapy to treat sickle cell disease. 

Sickle Cell

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Investigating Strategies to Treat SCD Using Gene Therapy 

The goal of therapy is to achieve the lowest disease activity, prevent organ damage, minimize drug toxicity, and improve quality of life.

For joint pain and stiffness, NSAIDs are the initial treatment options. Typically, the joint symptoms would manifest as morning stiffness with some associated swelling. Presentation tends to be polyarticular and symmetrical. After that, we may move on to corticosteroids or DMARDs [disease-modifying antirheumatic drugs], such as hydroxychloroquine. 

In lupus, hydroxychloroquine is the cornerstone of treatment and is also used in other autoimmune rheumatic conditions, including rheumatoid arthritis. It’s intended to improve the constitutional and musculoskeletal manifestations, including joint pain and stiffness. It may improve or reduce the rate of flares in patients with lupus, as well as thrombotic effects, organ damage, and mortality. 

Oral corticosteroids are used when there’s organ involvement that’s typically nonthreatening. Constitutional musculoskeletal cutaneous manifestation and hematologic manifestations may include the use of short-term corticosteroids. Occasionally steroid-sparing immunosuppressive agents such as azathioprine or methotrexate can often be used to help control symptoms as well. Similarly, in myositis, glucocorticoids are the mainstay of treatment. Typically, they’re used in conjunction with a glucocorticoid-sparing agents, such as methotrexate, mycophenolate, azathioprine, and rituximab and IVIG [intravenous immunoglobulin].

A key opinion leader in rheumatology discusses the goals of therapy for SARDs and provides an overview of current approaches to treatment including the use of NSAIDs, corticosteroids, and immunosuppressive agents. 

Goals of Therapy and Treatment Approaches for SARDs 

Besides gene therapy, we hopped over some other potentially very useful, valuable, and promising intravitreal biologic injections, going back to anti-VEGF–like approach of injecting in the office. Can you tell me, Diana, a bit about what else is out there on the horizon?


Sure. There are some exciting new agents also in late stage development. One of them is KSI-301, which is an intravitreal anti-VEGF agent built on a novel ABC platform. ABC stands for antibody biopolymer conjugate, and this medicine is designed for enhanced durability with up to 6 months of VEGF suppression via a single injection. That is also in phase 3 clinical trials right now in wet macular degeneration, diabetic macular edema, and retinal vein occlusion, and the early data have been very promising, with robust visual acuity gains, long duration of VEGF suppression with the need for very few repeat injections, and fortunately no safety signals. I think that’s a very promising program in late stage development. Carl, you’ve had some experience with that. What are your thoughts on KSI-301?



I agree. KSI is looking very promising in that category of second-generation anti-VEGF therapy with greater durability. It seems to work as well; it seems to be as safe, although that experience is still quite limited, but nonetheless looking good. Durability, boy that looks to be at least as good as faricimab. We have about 60% of patients going 6 months in the maintenance phase. That’s quite good, after the load. This ABC platform effectively doubles or more the half-life of the drug. It’s a nice way to keep it in the vitreous longer, and that’s looking like its mechanism to get that greater degree of durability. I also put that in the next-generation or second-generation anti-VEGF category.

There is another drug that is interesting. It’s not a VEGF-A blocker, but it blocks VEGF-C and VEGF-D, and is called OPT-302. That’s a fusion protein that blocks C and D. This is an add-on; it’s not a standalone drug. In phase 2 it was added to VEGF-A blocker ranibizumab and did show enhanced vision benefit. It’s aiming at getting maybe better visual acuity outcomes, not necessarily greater durability, because it has to be injected pretty frequently, either every month or every other month, that’s been tested now in phase 3. That’s the only thing on the horizon that might actually get us better acuity. We mentioned limited durability and hoping to get more durable drugs as our big unmet need, and it is. But getting some better vision outcomes of course would be welcome, and that’s working by this combo approach, VEGF-A blockade like we’ve been doing and is still coming, and then adding in a VEGF-C and VEGF-D blocker. Again, an intravitreal injection, fusion protein, and it’s combination therapy, so it’s got to show superiority in vision to what we’re using now.

Then there is this class of tyrosine kinase inhibitor [TKI] molecules, small molecules that have to be packaged in a sustained-release platform, all of which are being injected intravitreally. It’s not a surgery, and there are 4 programs. Three are intravitreal injections, either suspension of microparticles with given TKI, or maybe a biodegradable implant injected intravitreally. There is even a suspension of TKI suprachoroidal injection. They are all aiming to get an anti-VEGF–like effect over about 6 or more months, but that has yet to be demonstrated adequately. What are your thoughts about what you’re hearing about these TKIs?



I think it’s terrific to see all of this innovation continue to push the field forward for patients. It’s wonderful to think out of the box. Certainly, there is room for improvement because not all patients have an optimal response to VEGF inhibitors, and angiogenesis is complicated. There are lots of different cytokines and molecules in play. I think exploring these different inhibitors is a terrific way to try to improve the outcome for all patients. I’ll be excited to see more data as they emerge.



 In the TKI category, there are few things they have to prove. They have to prove they work as well as our anti-VEGF biologics, have to be as safe, and truly give us the durability factor, give us 6 months or more, not just 3 or 4 months, because the other medicines we’ve been talking about like faricimab and KSI are probably going to achieve that 3 or 4 or more benchmark and durability. They’ve got a hurdle there to try to stack up to what’s on the near horizon with biologics, again KSI-301, faricimab, and then we’ve got the port [Port Delivery System], all in the very near future. A lot is going to be in our hands. There will be a lot of choice for our patients, and that’s all good in terms of decreasing treatment burden with greater durability and hopefully getting better vision outcomes in practice.

Thank you for watching this 

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Carl Regillo, MD and Diana Do, MD react to newer therapies being explored for wet AMD and discuss their place in future therapeutic algorithms. 

Ophthalmology

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Innovative Therapies on the Horizon to Treat AMD 

Strategies used to help determine patients’ risk for cardiovascular disease and the role of lifestyle management in helping reduce the risk for events in patients with type 2 diabetes. 

CV Risk Reduction in Patients with Type 2 Diabetes 

Considerations for using HSCT (hematopoietic stem cell transplantation) in patients with sickle cell disease. 

Stem Cell Transplant: Management of Sickle Cell Disease 

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Suspected suicide attempts have increased more among females.

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Suicide Attempts Up Among Adolescents During COVID-19

Investigators study loci and the hereditary nature of the disease, which was categorized as a global health priority by the WHO 3 years ago.

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Rheumatic Heart Disease Risk Genetically Linked to African Patients

Hematopoietic stem cell transplant is generally associated with increased C difficile infection risk.

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Baseline eGFR and increasing age were good predictors of eGFR.

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DAA Treatment Reduces Risk of Death for Hepatitis C Patients

The rate of major thromboembolism within 90 days was 1.2% for placebo and 1.0% for dalteparin. 

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No Signficant Benefit to Dalteparin Bridging in Prevention of Arterial Thromboembolism 

A new Polish study calls for greater focus on asthma and the link to delirium in older patients, who may face greater mortality risk.

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