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Author: Stephen J. Klemawesch, MD

Damned if you do, Damned if you don’t 

Damned if you do, Damned if you don’t 

By; Sasha Klemawesch, MD 

Here’s a doozy of a “Would-You-Rather”: Would you prefer continuing to deal with chronic unremitting knee pain, or would you rather have several days of unrelenting hiccups? 

Those may seem totally unrelated, but actually, a little known (though not altogether uncommon) side effect of steroid injections is intractable hiccupping! 

This was news to me too, but one of my colleague’s fell victim to it recently and was absolutely miserable for days. His knee was great! To the point he was actually able to resume jogging! But he said in the future, he’d take the long-term arthritis over the short-term hiccups.  

Those two things seem so completely unrelated, I thought it couldn’t possibly be true that the knee injection caused his hiccups, but turns out there are myriad reports in the literature about this very phenomenon.  

“Singulata” (aka the medical term for hiccups) are caused by a reflex arc involving various nerve pathways, the diaphragm musculature, and multiple neurotransmitters including dopamine, serotonin, GABA, et al. Anything that may dysregulate any one of those components has the potential to trigger hiccupping. And steroids, particularly high-Dose steroids are a known potential risk to upset that fine balance.   

This unusual reaction is much better known in the fields of Neurosurgery and Rheumatology, both of which employ very high-dose/high-potency steroids more frequently in their day-to-day practice.  

Luckily the reaction is self-limiting, and there are various medications that can help curtail the length of the misery such as Reglan, Baclofen, and Thorazine, though often it takes several trial and errors to find an efficacious one for each individual. At this time, no literature exists regarding the percent success rate of the old “drink out of the topside of the cup” though. 

Dear Dr. K; 

Dear Dr. K; 

I heard on the news that there is a new nasal EpiPen, can it really work for anaphylaxis? 

The short, simple and sweet answer is “yes”.  But if you’ve read this newsletter previously you know how I like to elaborate on simple answers.    

The FDA did recently approve “Neffy” a single dose nasal spray containing epinephrine.  It can be used in adults and children who weigh 66 pounds or more.  There is a pediatric spray for smaller children that is also undergoing clinical trials.   

In addition to being “needle free” some additional advantages over the injectable forms (EpiPen and AuviQ) are its compact size, heat stability and ease of use.   

As you may know the mucus membranes in the mouth and nose provide a medium for almost instant absorption of medicines and recreational drugs.  Speaking of recreational drugs, far too many Americans die from opioid overdose.  In this regard the nasal spray Narcan has saved many lives.  Narcan (naloxone) is an opioid antagonist, and the spray is immediately absorbed and can prevent death from an overdose.   

In terms of medications Calcitonin nasal spray is an option for treating loss of bone density (osteopenia/osteoporosis).  It is a salmon derived bone building hormone that is absorbed intact through the nasal membrane.  If it were swallowed its breakdown in stomach would render it useless.   

Two commonly used “instant onset medications” that are absorbed in the mouth are nitroglycerine for angina/heart attacks and ondansetron for relief of nausea/vomiting.    

Currently 33 million Americans have a prescription for injectable epinephrine with this many people at potential risk for anaphylaxis it is not difficult to appreciate that unfortunately there have been some deaths due to fear of injection or due to inadvertent mishap while trying to inject the medicine.  The simple single dose nasal spray should prevent these issues.   

Because of its ease of use and safety it is also being studied for possible use to treat acute severe hives and acute severe asthma.  But the jury is still out in these applications.  However, if it is approved for these situations keep in mind that it is an urgent stop-gap, and as is true with its anaphylaxis application, immediate urgent care is still necessary.   

Protein Degraders 

Protein Degraders 

Inflammation is the causative common denominator for most of the allergic and autoimmune conditions that plague humans.  Inflammation is mediated at a cellular level by inflammatory proteins.  Many current therapies work by inhibiting the function of inflammatory proteins.  But a new evolving strategy is to develop protein degraders to remove these inflammatory proteins completely. 

Targeted protein degradation is a process using a new class of medicines that may revolutionize the treatment of inflammatory diseases.  These medicines are designed to selectively target and promote the degradation of disease-associated proteins.  By ramping up the body’s natural protein disposal system targeted protein degradation can remove the pathological proteins that are causing cellular inflammation.   

All of our human cells have a garbage disposal system for removing unwanted or senescent proteins.  It is a good system but of limited capacity.  When cells are overwhelmed with a myriad of inflammatory proteins the disposal system simply can’t keep up, think sanitation strike scenario.  The system works in large part by tagging unwanted proteins with a molecule called ubiquitin.  (In my adopted home state of Alabama, we’d pronounce that as “you-be-quitin”  as in “you’re out of here”).   

So, protein degrader medicines work by dramatically enhancing the ubiquitin targeting process, thus speeding removal.  Keep in mind it is only the unwanted proteins that are specifically targeted.  One benefit of this approach over protein inhibitors is the complete removal of the bad proteins, not just inhibiting them.  In the latter case a log-jam can occur where there is such a large buildup of the bad proteins not all of them can be inhibited and hence inflammation continues.  Another benefit of degraders over inhibitors is that inhibitors can also block important cellular processes thereby suppressing desirable immune function (i.e. they can suppress the immune system leading to a greater chance for infections).   

Early research trials with a degrader IRAK4 have shown it to be effective in treating two skin diseases:  atopic dermatitis and hidradenitis suppurativa (a chronic condition of boils/cysts in the armpits).  As in all new research there is a lot more study to be done, but the outlook is very promising.   

Lucky 13 

Lucky 13 

13% of Americans have not been infected with Covid-19.  Roughly the same number is true in other developed countries where epidemiologic studies have been done.  Is it simply good luck or is some other force at work?   

As it turns out a recent bit of research published in the journal Nature points toward genetics.  Scientists in the UK placed infecting doses of Corona virus in the nostrils of study volunteers.  The small minority who did not become ill had high levels of gene HLA-DQAZ a gene that controls the production of interferon (an immune protein that does what the name implies:  interferes with viral replication).  The study participants who became ill produced modest amounts of interferon, but not enough to stop the virus from reaching the critical mass necessary to cause infection.  

TIL:  Tumor Infiltrating Lymphocyte Therapy 

TIL:  Tumor Infiltrating Lymphocyte Therapy 

TIL is a recently FDA approved therapy for treating certain types of metastatic cancer.  It has been referred to as a “living drug” as it is made up of the individual patients T lymphocytes.  It does so by taking cancer-targeting T cells from the patient’s own tumor and then growing them into billions more of the same cells in the lab and then re-infusing them into the patient.   This massive influx of warrior T cells can destroy the tumor whereas the previous small number of T cells were just holding it at bay.  

The initial FDA approval is for metastatic melanoma but it’s used for other solid tumors such as breast, pancreas and colon cancers.   

TIL is not the first use of immune cells to fight cancer.  CAR T-Cell therapy is another FDA approved method to fight certain “liquid” cancers, primarily leukemia, lymphoma, and multiple myeloma.  So far it has not proven effective for solid cancers.  CAR T-Cell therapy is so named because it involves making a chimeric antigen receptor (CAR) on T-cells.  It uses genetic engineering to modify the patient’s own T-cells so they can recognize (and then destroy) a specific cancer cell signal (antigen).  CAR-T therapy has helped and cured thousands of patients but one drawback of its use is that it is tricky to find a molecular signal (antigen) that is totally unique to the cancer.  Since healthy cells may also share this molecular signal, they can sometimes be damaged by the chimeric T-cells.  TIL on the other hand doesn’t modify the innate targeting system of the T-cells it simply uses a normal immune cytokine IL-2 (interleukin-2) to boost cell growth.  As it turns out one “target” that the TIL cells seem to pick out is the mutated protein that would otherwise control healthy cell growth.  Once this protein undergoes a Jekyll-Hyde transformation it allows uncontrolled cell growth otherwise known as cancer.   

HANE (HAE) 

HANE (HAE) 

A recent New England Journal of Medicine had three articles and an editorial about hereditary angioedema previously called hereditary angioneurotic edema.   

By way of reminder, HAE causes recurrent episodes of swelling that can affect various parts of the body:  face, tongue, throat, abdomen, extremities.  It is caused by a gene mutation in SERPING 1 which controls the production of C1-inhibitor.  In type 1 HAE there is a deficiency of the inhibitor, in type 2 the inhibitor protein is present but non-functional.  Lack of C1-inhibitor leads to excess levels of bradykinin which causes the tissue swelling.   

Current treatment of HAE is two pronged:  prevention and rescue.   This strategy is very similar to the approach to chronic asthma; that is, using a daily controller medicine but also having a rescue inhaler.  There are several preventative therapies available.  There are two types (one IV and one injected sub-Q) of purified C-1 inhibitor.  There are drugs that inhibit the procession of brady kinin kallikrein.  (An injectable monoclonal antibody and also an oral kallikrein inhibitor).     There are injectable kallikrein inhibitors and injectable brady kinin receptor blockers.  These medications can be used for both prevention and for rescue from acute attacks.   

One of the new medicines discussed in the journal is donidalorsen (an antisense oligonucleotide) that inhibits the messenger RNA that would otherwise stimulate excess kallikrein production.  Donidalorsen is an injected medication but unlike other kallikrein drugs that require more frequent injection, it can be given every two months.   

The other new drug that was discussed in the journal is sebetralstat an oral kallikrein inhibitor designed to treat acute attacks.  Currently the only rescue medicines for acute attacks are all either IV or injected.  Being IV or injected leads to barriers to compliance:  effort needed to transport, store and prepare the medication and reluctance to self-injection or infusion.  Also, if the swelling involves the hands the patient is incapable of self-administration.  These issues are especially problematic in teenagers and have led to withholding of treatment and subsequent hospitalization or death.  This makes an oral rescue medication a welcome option.   

For the sake of completeness there is a third type of HAE with normal C-1 inhibitor but excess brady kinin that can occur due to other protein abnormalities.  This group is very rare.   

Chronic Pruritis 

Chronic Pruritis 

A recent issue of JAMA the Journal of the American Medical Association had a review article of this condition.    Chronic pruritis is defined as an itch that lasts 6 weeks or longer.  It occurs in 22% of people during their lifetime and it accounts for 1% of doctor visits in the US.  Chronic pruritis can be classified as either inflammatory or neuropathic.   

The inflammatory causes are myriad.  Believe it or not a very common cause of inflammatory itch is dry skin.  Dry skin can occur due to overzealous use of soap and due to aging.  When the skin is dry it releases an inflammatory molecule (cytokine) called interleukin 33.  In eczema other interleukins (IL-4, IL-13 and IL-31) are the inflammatory cytokines.   These various interleukins activate another mediator of inflammation:  Janus Kinase (JAK).   

In people with hives, it is the tissue release of histamine that is the main cause of pruritis.  Contact dermatitis (poison ivy, nickel allergy) and insect bites are also inflammatory causes of itching.  Neuropathic causes for itch are also myriad.  Two very specific examples are due to nerve impingement:  notalgia paresthetica which is a chronic itch on the shoulder blade and brachioradial pruritis which is a chronic itch on one arm.  Chronic itch can also occur due to nerve injury from a previous case of shingles.  The patient will have itching only in the area where he/she had shingles.   

Some neuropathic itch conditions are due to amplification of the itch/scratch cycle.  Scalp pruritis and scrotal pruritis (watch out baseball players) are common examples.  The seminal event that led to initial scratching is often lost to memory but repetitive scratching strengthens the neural circuit to produce a greater sense of itch and therefore more scratching.  An especially problematic condition in this genre is prurigo nodularis.  In this condition the itch/scratch cycle is so severe that patients develop calloused nodules from the repetitive scratching.  The nodules themselves strongly stimulate the cutaneous nerves leading to a greater sensation of itch.   

Sometimes the nerve irritation is generalized.  In its most severe form it causes formication, a sensation that bugs (formic refers to ants) are crawling under the skin.  Diabetic neuropathy can do this.  Narcotic medications are another common cause.  And amphetamine-based stimulants including medications used to treat ADHD are known causes.   

Sometimes chronic itch is due to serious underlying health conditions including hepatitis, renal failure, lymphoma or other cancers, hyper-thyroidism and polycythemia (too many red blood cells).   

Obviously, the treatment needs to be directed at the cause.  Moisturizing the skin is always a good first step.  There are a variety of anti-inflammatory therapies starting with OTC hydrocortisone on up to prescription drugs that target the interleukins or Janus Kinase.  For neuro pathic issues therapies that break the itch/scratch cycle are important and include topical anesthetics, capsaicin, menthol, nerve blocks, acupuncture and neuroleptics.  Neuroleptics are medications that reduce aberrant nerve transmission (for example gabapentin and SSRI’s).   

Dear Dr. K; 

Dear Dr. K; 

I’ve modified my diet to include lots of anti-oxidants and I take vitamin E, vitamin A and beta carotene supplements.  Now I’ve recently heard they don’t reduce inflammation.  What’s the truth and, oh by the way, why can’t scientists get things straight? 

Well, first of all, scientists are people and therefore fallible.  But, science itself can be thought of as a ratchet to the truth moving forward one cog at a time.  And the complete truth/understanding may not become apparent early in the process.  Such is the case with free radicals and antioxidants.   

There has been intensive global research on inflammation and aging.  Early on it was discovered that reactive oxygen species and free radicals cause inflammation and speed up aging.  It was only later on that it was realized that amount matters.  This is based on a phenomenon called hormesis, which means small amounts are beneficial and large amounts are harmful.  Or as Friedrich Nietzsche said “what doesn’t kill you makes you stronger”. 

As it turns out small levels of reactive oxygen and free radicals stimulate the production of detoxifying enzymes and repair proteins for our individual cells and most importantly our mitochondria.  Whereas large levels have the opposite effect.   

Inflammation and aging encompass a spectrum of physiologies but mitochondrial function seems to be a lynch pin factor.  By way of reminder mitochondria are our “cellular batteries” providing life and energy for all of our cells through the production of ATP.  It’s hard to conceptualize but every 24 hours our mitochondria produce an amount of ATP equivalent to our body weight.  So, any perturbation of this system can have significant ramifications.  Because our mitochondria are so active they do break down and fall into disrepair.  That is why the detoxifying enzymes and repair proteins generated by low level free radicals are critical to mitochondrial wellness.    

Having too many broken or fragmented mitochondria not only reduces the numerical workforce but also disrupts cell function by another mechanism dubbed “inflammaging”.  Inflammaging owes its existence to our mitochondria‘s ancient bacterial origins (yes, our mitochondria are due to cells co-opting bacteria internally).  As the mitochondria spill their “bacterial origins” our immune systems mistake these fragments for actual bacterial invaders and attack the cells.  This is why low levels of reactive oxygen are critical to stimulate repair of mitochondria before this occurs.   

Thus, the “Goldilocks” niche of allowing some reactive oxygen for its goodness (all your supplements can interfere with this) but not having too much reactive oxygen (which can be accomplished through healthy diet and exercise).   

Immune Memory Cells 

Immune Memory Cells 

Scientists at McMaster University in Canada and at Mount Sanai in the US have co-discovered the cells that remember an allergy.  The Canadians call it MBC2 while the Americans call it a type 2 Memory B cell.   

B cell refers to a type of lymphocyte critical to immune function.  B cells are the factory for producing immune proteins called immunoglobulins (Ig’s).  Ig’s have a finite life span, but the B cells are much longer lived.  This is important in terms of providing for long-term immunity.  It’s our memory B cells that keep producing Ig’s (AKA antibodies) for all the illnesses we have caught and for all the vaccines we have received.  IgG is especially important in its role of providing durable immunity.   

IgE is the immune protein that causes allergy.  When B cells switch from making IgG (the protective antibody) to making IgE (the allergic antibody) it’s called an isotype switch.  You might ask why in the world would our B cells change from helping to harming?  As it turns out, other than causing allergy, IgE attacks parasites.  Our distant human ancestors all had one or another parasite in their GI tracts.  So, we evolved as a species to have a protective mechanism for this problem.  Fast forward to proper sanitation, safe drinking water and universal footwear and the worms are gone.  So now the IgE is segued to causing allergy.   

Although many people find that their allergies improve over time, many do not.  Peanut allergy is particularly known to be a persistent allergy.  So, the researchers used peanut allergic individuals to find these new memory B cells that weren’t found in non-allergic people.   

It is known that RNA (ribonucleic acid) instructs the B cells to switch from IgG production to IgE.  It does this through a protein called JAK (Janus Kinase).  So, new research is targeting this JAK signaling to see if the long-term memory can be switched off. 

Islet Cell Transplant 

Islet Cell Transplant 

The FDA has recently approved the first pancreatic islet cell transplant for some type I diabetics.  By way of clarification, type I diabetes is due to loss of the pancreatic islet cells and therefore a lack of insulin.  Whereas; type II diabetes is due to insulin resistance because the islet cells are over producing insulin due to obesity.   

Most type I diabetics can be treated with insulin, either by injection or continuous infusion.  But in a small minority safe control cannot be established with insulin.  It is this group of fragile diabetics where the transplant has value.   

The islet cells are obtained from a single deceased donor pancreas and infused into the portal vein of the liver.  Since they are from an unrelated donor, immunosuppressant drugs are required as in other organ transplants.  So far, the procedure has had long term (>5 years) success in only 1/3 of recipients.  But the concept is a novel one and improvements are likely to occur.