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JAK Inhibitors

A promising new drug class

Charles E. Crutchfield III, MD and Pallavi Kannan, MS

If you’ve graduated from medical or nursing school, this paragraph should make complete sense to you and might even mimic medical encounters you’ve witnessed at some point in your careers. Unfortunately, if you’re a patient, these brief sentences are full of enough medical jargon to be rendered completely nonsensical. When patients don’t understand their plans of care, they are not truly being included in shared medical decision-making. 

As research continues, the JAK protein family has grown and there are now four main family members. Greater understanding of how they work and can be manipulated has led to 8 different pharmaceuticals FDA-approved for their dermatological applications, with strong potential for more, including the ability to treat certain cancers.

Patients have found that JAK inhibitors can reduce the number of medications they had been taking.

Current Status

Presently, the numerous products available have proven especially successful in treating several common chronic conditions, many which relate to dermatological, inflammatory, and autoimmune conditions, such as rheumatoid arthritis, psoriatic arthritis, alopecia, atopic dermatitis, and plaque psoriasis. FDA-approved products come from a wide range of pharmaceutical manufacturers including, Pfizer, Eli Lilly, Bristol Meyers Squib, AbbVie, and many others.

Beyond improved outcomes for many fairly common conditions, many patients have found that JAK inhibitors can reduce the number of medications they had been taking while achieving superior outcomes. Examples of some conditions that responded to this new class of drugs with improved outcomes, and how they have most commonly been treated include:

• Atopic Dermatitis: conventionally treated using topical corticosteroids (e.g., clobetasol, hydrocortisone, triamcinolone), phototherapy, hydrotherapy, topical non-steroidal medications (e.g., pimecrolimus, tacrolimus), calcipotriene and Dupixent® (dupilumab delivered via injection)
• Alopecia: often treated using topical corticosteroids, phototherapy, minoxidil (topical, oral), oral immunomodulators (e.g., methotrexate, cyclosporine), and 5-alpha-reductase inhibitors (e.g., finasteride, dutasteride)
• Psoriasis: commonly treated with topical corticosteroids (e.g., clobetasol, triamcinolone, betamethasone), topical non-steroidal medications, phototherapy, coal tar, and oral immunomodulators
  

Another benefit to patients is that JAK inhibitors can be taken orally, and in the case of Opzelura (ruxolitinib), applied topically. In some cases of extreme Rheumatoid Arthritis, treatment involves injections, which some patients do not tolerate well. It is never desirable when a patient has to wonder which is worse—the disease or the treatment.

All in this new class of drugs come with the usual extensive list of Black Box warnings. When they were first introduced, there were some initial negative reactions which might be the most salient features some patients or physicians recall about the medications. Ten years later, they have proven to be very safe, but it is always important to review the warnings with the patient before prescribing. Even if the patient has no specific concerns or worries a review of the warnings is always helpful.

Contraindications

As with any medication there some conditions that preclude use and JAK inhibitors are no exception. Some conditions that are important to check for before prescribing include:

Pregnancy: JAK inhibitors are contraindicated in pregnancy. Female patients of child-bearing potential should be tested for pregnancy. Patients should also be provided contraception counseling and be informed that contraception will need to be used for a duration even after discontinuing the medication.

Lactation: Breastfeeding is not advisable during treatment and in the post-treatment wash-out period.

Serious infections, active tuberculosis, viral hepatitis, and herpes virus: JAK inhibitors are contraindicated in patients with active tuberculosis and active viral infections. Patients should be evaluated (and treated for) latent and active tuberculosis (TB), viral hepatitis, and herpes virus infections prior to initiating therapy. Patients should also be routinely monitored for signs and symptoms of serious infections and viral reactivation. Therapy should be interrupted if any of these conditions develop and should only resume once the condition has been successfully treated.

JAK inhibitors are a game changer for many patients.

Live vaccines: Live vaccines (immediately before, during, and after) are also contraindicated. Update patient on immunizations before initiating treatment.

Major cardiovascular events and thrombosis (monitor sreatine phosphokinase): The use of JAK inhibitors increases the risk of major adverse cardiovascular events (includes cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) and thrombosis (includes deep vein thrombosis, pulmonary embolism, and arterial thrombosis). Patients with a history of such events, with cardiovascular risk factors, and current or former smokers are at an increased risk, and therefore should be monitored closely. Patients who experience thrombotic and/or major cardiovascular events during treatment with a JAK inhibitor should discontinue its use.

Renal and hepatic impairment: Depending on the specific JAK inhibitor, patients with renal impairment may require dose adjustments and routine monitoring. Furthermore, depending on the severity of renal impairment, the use of specific JAK inhibitors may be contraindicated as their use in such populations has not been studied. Depending on the specific JAK inhibitor, monitor in patients with known or suspected liver disease. Some JAK inhibitors have not been studied in patients with severe hepatic impairment and therefore may not be indicated for use in these populations.

Laboratory abnormalities: Patients should be routinely monitored for elevations in triglyceride levels. Providers should manage hyperlipidemia according to clinical guidelines.

Concomitant use of certain other drugs: Concomitant use with other immunosuppressants or with other JAK inhibitors is not recommended.

Cancer: Use of JAK inhibitors may increase the risk of non-melanoma skin cancers and secondary malignancies.

Data on off-label use is growing, with potential benefits covering a widening range of conditions including Alopecia Areata, Dermatomyositis, Graft-Versus-Host Disease, Granuloma Annulare, Hidradenitis Suppurativa, Lichen Planus, Necrobiosis Lipoidica, Psoriasis, Pyoderma Gangrenosum, Sarcoidosis, Systemic and Cutaneous, Lupus, Morphea/Systemic Sclerosis, and Vitiligo.

Barriers to Widespread Adoption

There are many reasons why JAK inhibitors are not more widely prescribed. Some of these involve the “first to fail” syndrome whereby physicians fear using their patients as trial participants. Until a new medication shows up on a formulary list there may be little motivation to learn about something new.

Additionally, although the pharmaceutical industry spends extensively on direct-to-consumer messaging, no advertisements mention “JAK inhibitors” directly and almost all include the call to action “ask your doctor”. Furthermore, primary care providers will refer the most extreme cases to a specialist, who may have more experience with the superior JAK inhibitor outcomes. However, considering the number of existing medications to treat those conditions, many patients may not get access.

Another important element of this involves cost. JAK inhibitors cost more than existing products that treat the same conditions. Even though outcomes are clearly superior, quality of life considerations rarely register in the decision-making process of creating health plan formularies. Obtaining coverage for patients often includes the prior authorization process, which has been terribly detrimental with respect to patient care and a bane to the existence of many medical practices. Authorizations are extremely time-consuming and there’s no way for medical practices to recover the cost invested in obtaining them. On average, physicians spend ten hours a week dealing with prior authorization concerns. 

It is fair to ask, if most of the medications we prescribe have similar costs, why do we have prior authorizations? It’s clear that the purpose of many prior authorizations is not necessarily to improve quality of care, but merely to reduce costs for the insurance companies. In fact, one insurance representative claimed that a guaranteed percentage of prior authorization requests will not seek appeal upon receiving denial of coverage. Even more damning is the reality that denied prescriptions are often funneled to medications for which the health insurance company receives a more significant rebate. It may be argued that prior authorizations are simply a cost-reduction strategy for insurance companies. Clearly, better legislation is needed (some of which is being currently debated) to better regulate prior authorizations and minimize their negative impact on health care delivery.

There is another problem. Most medications cost so much in the United States because the vast majority of people cannot afford brand name products on a long-term basis, especially for treating chronic medical conditions. Many of these medications can cost $10,000 per month and upward. Because the JAK inhibitors are a new class of medications, without generic alternatives, insurance companies are not quite sure how to deal with them. Fortunately, like coverage for all new medications, the more prescriptions are written the more likely the insurance companies are to eventually develop a policy to enable payment for them. Additionally, pharmaceutical companies will have patient assistance programs to help the medication break into the market. Many times, for the first several months to a year, patients can get their medicines at an extraordinarily reduced cost. I always tell patients that if their insurance is not covering a prescription to check with the pharmaceutical company, as there may be pharmaceutical assistance programs for that medication. 

Conclusions

JAK inhibitors are a game changer for many patients. They are a prime example of the value of investing in scientific research and the more widespread their use, the lower their costs will become.  

Since their initial development, there has been rapid expansion of JAK inhibitors and their applications, with numerous new drugs in the pipeline as well as repurposing of FDA-approved drugs for other dermatological conditions. These include: Cibinqo (abrocitinib) for prurigo nodularis and pruritus; Jakafi (ruxolitinib) for hidradenitis suppurativa and alopecia areata; Corectim (delgocitinib) for chronic hand eczema and atopic dermatitis; and Sotyktu (deucravacitinib) for alopecia areata, psoriatic arthritis, and psoriasis. If you have patients who may benefit from this new class of drug, there is ongoing new research and outcomes data that is well worth some exploration. The insurance industry will continue to push back on spending; however, enough requests will help justify more patient-centric policies.

Charles E. Crutchfield III, MD, is a clinical professor of dermatology at the University of Minnesota Medical School and Benedict Distinguished Visiting Professor of Biology Carleton College. He is also medical director at Crutchfield Dermatology.

Pallavi Kannan, MS, is a clinical researcher at Crutchfield Dermatology with a background in pharmacology.