Will a COVID Booster Vaccine for Lupus Patients Increase Response Rates?
We do not know, yet. However, the August 12, 2021 edition of the New England Journal of Medicine reported significant responses in immunosuppressed organ transplant patients. This provides hope that a COVID booster vaccine for lupus patients, and other autoimmune disease patients, who are immunosuppressed may also respond well.
The Problem: Early reports from COVID vaccine studies suggest that patients on immunosuppressants have lower response rates. The Johns Hopkins Hospital study has already suggested that patients on mycophenolate mofetil, rituximab, and steroids (when combined with another immunosuppressants) have high rates of nonresponse.
This leaves immunosuppressed patients, such as lupus patients, unsure of how well they responded to their COVID vaccines and they must remain vigilant with social distancing, mask wearing, etc. Unfortunately, the usual COVID antibody tests available to most doctors do not test for antibodies to the SARS-Cov-2 spike protein, which is essential to test for vaccine responses, so few patients know if they responded or not.
Anifrolumab FDA Approval to Treat Systemic Lupus Erythematosus (SLE)
AstraZeneca announced its anifrolumab FDA approval on 8/2/2021. In this blog, learn how anifrolumab works, how it is given, and its potential side effects. If you are a patient with lupus that is not in remission, this brings you hope for a potentially better treatment, read more below. If you are a healthcare provider searching for detailed information on the indications, dosing, and precautions, read more below.
The anifrolumab brand name is Saphnelo
History was made when the U.S. Food and Drug Administration (FDA) gave final approval to use anifrolumab (Saphnelo) as a safe and effective treatment for SLE. Note that anifrolumab is the generic drug name, and Saphnelo is the trade (brand) name. It is produced by AstraZeneca.Read more
What is the anti-SSA test?
Remember… Knowledge is Power!
So, let’s talk about anti-SSA (also called anti-Ro).
Do not automatically stop hydroxychloroquine if your eye doctor tells you your patient has HCQ-retinopathy!
Heed my practical advice below
The hydroxychloroquine eye tests, SD-OCT and VF 10-2, can have false positives.
PEARL: Don’t stop your lupus patient’s most important medicine without doing the following:
– It is a good idea to have your staff call retinologists around your area and find out if they have this capability or not
Rationale is below:
(note that this statement is made with help from retinologists Dr. Jonathan Lyons and Dr. Reshma Katira in Silver Spring, MD and Alexandria, VA respectively. They specialize in HCQ-retinopathy. This section will appear in the 2nd edition of “The Lupus Encyclopedia,” but it is important to make it known widely to help our patients)
Mistakes in the medical literature
We rheumatologists, and eye doctors who do not specialize in antimalarial retinopathy (AMR) need to be careful about the subtleties of making this diagnosis and the potential flaws of the screening tests. The 2014 Browning Clinical Ophthalmology article (so often cited for its sensitivities and specificities), and their reproduction in reports (such as the 2020 Aduriz-Lorenzo article in Lupus) aimed at rheumatologists, need to be mindful of the weaknesses of these methods. HCQ is such an essential therapy for our SLE patients that stopping it due to incorrect diagnoses of HCQ retinopathy should be avoided as much as possible. We have seen this in our own practice where patients have been told they have HCQ retinopathy (based on VF 10-2 or SD-OCT testing), yet have an AMR expert identify an unrelated eye problem (using mfERG testing) as the cause for the test abnormalities. These patients have continued their HCQ with close follow-up by the retinologist, using mfERG technology.
There is a differential diagnosis for SD-OCT and VF 10-2 changes that can look like HCQ damage
It is essential to keep in mind the differential diagnosis for AMR based on these screening tests. Common causes of false-positive tests on SD-OCT and visual field testing include vitreomacular traction, retinal detachment, and age-related macular degeneration in our patients. Some less common causes of abnormalities on these tests include retinitis pigmentosa, infectious retinitis (syphilis, rubella), autoimmune (paraneoplastic) retinopathy, inherited retinal dystrophies (Stargardt disease, Bardet Biedl syndrome, enhanced S-cone syndrome, isolated bulls-eye maculopathy), pigmented paravenous chorioretinal atrophy, and traumatic retinopathy. Visual field testing can have false positives due to dry eye, glaucoma ,and cataracts.
The superiority of mfERG for accurately diagnosing HCQ-retinopathy
The Browning article states that the specificities of VF 10-2 is 92.5%, SD-OCT is 98.1%, while mfERG is 86.9%. These findings are misleading. First, in the Browning research study, HCQ was stopped in patients based upon a clinical judgment for AMR diagnosis. Second, VF 10-2 testing included both red target and white target testing. Red target testing is not as reliable as white target VF 10-2 testing. Also, a 20% error rate was allowed for VF testing, which is too high to be reliable. Third, the mfERG criteria used is not the current standard. Therefore, VF 10-2 and SD-OCT should not be used individually for diagnosis. However, they have excellent sensitivities for screening tests.
The most recent research shows that mfERG testing has better sensitivity and specificity for AMR than either VF 10-2 or SD-OCT testing. Using mfERG and SD-OCT has 100% sensitivity for identifying ARM, while the currently accepted use of VF 10-2 and SD-OCT has only an 86% sensitivity. A British study recently showed a 95% specificity and sensitivity for mfERG in the diagnosis as a singular test (far superior to VF 10-2 and SD-OCT). Also, mfERG testing is useful for monitoring patients who have other retina problems.
The highest standard of care for this issue is to use SD-OCT and VF 10-2 (white target) testing as screening tests (per the 2016 AAO recommendations). If abnormalities are present that can be seen in AMR, a referral should be given for mfERG testing by a retinologist experienced in AMR. We realize that mfERG testing is not available in all locations, so many patients will not have this luxury. In these cases, referral to a retinologist who does not have mfEFG technology would be the next best step before assuming a diagnosis of AMR. In the future, hopefully, mfERG will be more commonly available to allow even earlier identification of ARM (used as a screening test with SD-OCT) as well as allowing a more accurate diagnosis.
Aduriz-Lorenzo PM, Aduriz-Llaneza P, Araiz-Iribarren J, Khamashta MA. Current opinion on hydroxychloroquine-related retinal toxicity screening: where do we stand now? Lupus. 2020;29(7):671-675. doi:10.1177/0961203320919499
K Broderick, MD, Harrison Ngo, BS, Reshma Katira, MD [abstract]. Evaluation of SD-OCT Results in Screening Patients in Early and Later Stages of HCQ Maculopathy. American Academy of Ophth. AAO 2020 Vision Virtual Meeting, NOV 13-15.
Browning, DJ, Lee, C. Relative sensitivity and specificity of 10-2 visual fields, multifocal electroretinography, and spectral domain optical coherence tomography in detecting hydroxychloroquine and chloroquine retinopathy. Clin Ophthalmol 2014; 8: 1389–1399.
Browning DJ, Lee C. Scotoma analysis of 10-2 visual field testing with a red target in screening for hydroxychloroquine retinopathy. Clin Ophthalmol. 2015;9:1499-1509. Published 2015 Aug 20. doi:10.2147/OPTH.S87850
Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol. 2007 May;143(5):801-809. doi: 10.1016/j.ajo.2006.12.042. Epub 2007 Mar 6. PMID: 17336914.
The American College of Rheumatology Provides Guidance for stopping drugs to enhance the COVID vaccine for immunocompromised patients
How should we deal with immunosuppressants and the COVID vaccine for immunocompromised patients? In February 2021, the American College of Rheumatology released recommendations on what to do with immunosuppressant drugs around the time of your COVID-19 vaccine. The reason for these recommendations is that some of our medicines can blunt the effects of the vaccine. Timing the drug to the vaccine to your medication can make a big difference.
– Do not do any of these without asking your rheumatologist first (let them know that you did read these up to date recommendations here)
– I also recommend these to my patients who get any vaccine, IF they are in remission or at low risk of flaring when they get the vaccine (again, do not do this without talking to your rheumatologist first)
The link to the full recommendations is below at the bottom of the post.
Drug recommendations summary:
What I am doing in my practice regarding immunosuppressants and vaccines to include COVID vaccines in immunocompromised patients :
Other important recommendations from the ACR:
– Lab testing is NOT required after vaccines to assess response to the vaccine
– Ask all household members, friends and loved-ones to get vaccinated to protect you (the cocoon effect)
– If you don’t believe in the vaccine, get vaccinated at least to protect those you love (Dr. Thomas’ addition)
– Get vaccinated even if your disease is active
REFERENCE: ACR, COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and Musculoskeletal Diseases. Developed by the ACR COVID-19 Vaccine Clinical Guidance Task Force.
This draft summary was approved by the ACR Board of Directors on February 8, 2021.. A full manuscript is pending journal peer review.
Lupus and COVID vaccine: Dr. Thomas recommends not waiting to his patients, read below…
“I’ll tell you what I tell my patients, “PLEASE, get your COVID-19 vaccine as soon as it is your turn! However, make sure to ask your doctor first” Why? People are dying left and right. People who did not ever think they would get it – get it. Just this week, I have had 3 patients tell me the horrible, sad story of a loved one or friend who recently died. One was on a ventilator 12 weeks…. 12 weeks! Guess how many similar stories I’ve heard about the COVID-19 vaccine… none.
The COVID-19 vaccines are the most studied vaccines EVER. No vaccine comes close. Over 70,000 people were in the clinical trials for Pfizer and Moderna. And now… millions have been given out with no bad safety signals. Sure, you will have a very sore arm for a week. Sure, you may have achiness, headache, and low-grade fever for a few days. There is always the chance for an allergic reaction (true for any medicine or vaccine … I took my EpiPen with me, just in case.) I’ll take these mild side effects any day over being in the ICU on a ventilator where I could die alone, only able to see my loved ones on FaceTime.
True, patients with autoimmune diseases were excluded from the clinical trials. True, immunosuppressed patients were as well. However, that goes with all vaccine phase I-III clinical trials. If you want to wait for research on lupus patients. You will wait a very long time.
Lupus and live vaccines are a bad combination if you take strong immunosuppressants. They are OK to take with weak immunosuppressants.
Caveats … there is always the possibility you may not have as strong of a response. However, thus far, lupus patients respond very well to other vaccines.
Bottom line: Fear COVID-19 … don’t fear the vaccine.
“Fear COVID-19; Embrace the vaccine!”
Lupus and vaccines are an important combination in preventing dangerous and deadly infections.
Protect yourself from medical mistakes.
Lupus Question of the day …
It is not uncommon to ask, “can you have lupus with a negative ANA?”
Dr. T responds to the question of “can you have lupus with a negative ANA?”:
1. I hope you kept personal records at home to give to your new doctor. One of my “Lupus Secrets” is to keep copies of your labs, biopsies, and doctor notes, especially those that first made the diagnosis of systemic lupus. The purpose is exactly for situations like this. I had two patients in the past end up having severe flares of their systemic lupus after their drugs were stopped by a new rheumatologist, due to this exact scenario (one had moved, the other changed insurance plans). Having all the records can make a huge difference and prevent this mistake.
2. Around 20% of SLE patients will have their ANA become negative on successful treatment. These are typically patients who go into remission or “low disease activity.” Recent studies also show that they end up having fewer flares than other patients. In the past, we always taught that the ANA never needs repeating once positive the first time in SLE patients because it is not reliable in following disease activity on treatment. However, now, we know that it helps give our patients information about prognosis. If it becomes negative, we can tell our patients, “this is great news! You have a lower likelihood of flaring compared to patients whose ANA stays positive, as long as you keep taking your medications.”
Disclaimer: This is for medical information only and is not for individual medical advice.
Causes of, reasons, and solutions (if needed) when the ANA is negative and one wonders “can you have lupus with a negative ANA?”:
“Can you have lupus with a negative ANA?” Yes… for many reasons as noted below
– When you have systemic lupus erythematosus (SLE) that is under good control on treatment (as in this patient)
PROS = this is great, you are less likely to flare!
CONS = a new doctor could question the diagnosis. Keep all your old records and labs!
– Laboratory error during the workup of SLE, especially when done by the ELISA or multiarray method
SOLUTION = ask for your ANA to be done by 2 different methods, especially by immunofluorescence
or ask for the AVISE Lupus test
– Have SLE plus a different autoantibody, especially anti-SSA antibody and ribosomal-P antibody
SOLUTION = check anti-SSA and anti-ribosomal-P if someone has SLE symptoms
or ask for the AVISE Lupus test
– Someone has very early SLE with fluctuating low level ANA levels
SOLUTION = repeat ANA test using two different methods, especially by immunofluorescence
or ask for the AVISE Lupus test
– If have severe hypogammaglobulinemia (immunodeficiency) and have SLE
SOLUTION = ask your doctor to order the AVISE Lupus test
– Childhood SLE
Especially younger children have a much higher chance for ANA negativity
However, they usually become ANA positive as they get older and their lupus worsens
– Cutaneous (skin) lupus
Most patients are ANA negative when it is confined to the skin
Antimalarial drugs can treat autoimmune diseases, such as lupus, Sjogren’s, and rheumatoid arthritis…
Here’s how! (described in easy to understand language)
Antimalarial drugs, such as hydroxychloroquine (Plaquenil), chloroquine, and quinacrine, are some of the most common medicines used to treat autoimmune disorders, especially lupus (SLE) and Sjogren’s.
To answer this question, you need to understand how the immune system works. One of the key things in the immune system is antigen presentation (figure 30.1A). Antigens are proteins that cause the immune system to make antibodies directed toward those specific antigens for protection. For example, let us say you are infected with parvovirus, which can cause a cold-like illness and sometimes even rash, joint pain, and even a lupus-like illness. The immune system “sees” the proteins (which act as antigens) on this virus, recognizes that they do not belong to the body, and launches an all-out war against the virus. It does this by making antibodies that can attach to the parvovirus antigens, which in turn identifies the virus invaders as the “bad guys.” Subsequently, this alerts other white blood cells of the immune system to attack the virus. The immune system has now learned that parvovirus is a “bad guy.” It is now able to produce these antibodies that recognize parvovirus for the rest of your life. Suppose you are infected by parvovirus ever again. Your immune system’s white blood cells can attack the virus so that you do not get sick from it ever again.
So now, let us go a little deeper into how the body makes these antibodies in the first place, focusing on a concept called antigen processing (figure 30.1A). This is a very technical discussion that can be skipped by many people reading this book. However, it can be interesting for the person who wants to know more about how anti-malarial medicines work. Macrophages are white blood cells that are responsible for identifying foreign antigens for the immune system. You can think of them as the frontline soldiers that come into contact first with any unusual antigen proteins such as viruses and bacteria invading the body.
Macrophages are often also called “antigen-presenting cells” in immunology. In lupus, where the immune system starts to attack parts of the body itself, the antigens it thinks are foreign are actually antigen proteins naturally occurring in the body. When the macrophages see these antigens (such as proteins from skin cells), they engulf them into little bubbles called vacuoles (follow along in figure 30.1A). The vacuoles break down (or digest) these antigen proteins into numerous smaller components and reassemble them into structures that are then attached to the outside of the macrophage cell surface. The macrophages then show these antigens (antigen presentation) to other white blood cells of the immune system (especially T-cells) so that they can recognize them as being “bad” proteins. This causes other white blood cells (called B-cells) to start making antibodies directed against these antigen proteins. However, in lupus, these antigen proteins that end up being attacked belong to the person’s own body. The antibodies produced to attack the body’s own antigens are called “auto-antibodies.”
A well-known example in systemic lupus erythematosus (SLE) is when ultraviolet (UV) light can damage skin cells. These can then release their inner contents, such as the nucleus and its own DNA, into the surrounding tissues and bloodstream. The lupus immune system can then make anti-DNA autoantibodies that attach to the person’s own DNA from the skin cells (thinking that the DNA is a foreign attacker). This combination of the DNA protein antigen bound to the anti-DNA antibody is called an “immune complex.” These immune complexes can then travel throughout the body, depositing in other tissues where the lupus immune system can cause inflammation and damage. An important example of this is the kidneys. These immune complexes can contribute to kidney inflammation (lupus nephritis). This illustrates how UV light exposure can cause a lupus rash in the area of exposure and in distant parts of the body, like the kidneys.
For this antigen presentation to occur, the macrophages’ vacuoles must have a low pH level (in other words, they must be acidic). Otherwise, the enzymes of the vacuoles that are responsible for processing the antigens will not work. The anti-malarial medicines (such as hydroxychloroquine, Plaquenil) enter the macrophages and subsequently concentrate inside these vacuoles. The anti-malarials have a higher pH level and cause the vacuoles to develop a higher pH level (figure 30.1B). The vacuole enzymes only work under precise pH conditions. This higher pH level in the vacuoles prevents the macrophages’ digesting enzymes from breaking down the antigens to present the T-cells. Therefore, the T-cells cannot “see” these antigens and do not signal the B-cells to make the lupus autoantibodies. Therefore, the anti-malarial medicine calms down the immune system of the person who has lupus. Interestingly, though, it does not actually cause overt immunosuppression. In other words, the immune system can still function normally in different areas and still protects the person from infections and cancer.
Why hydroxychloroquine is not a cure for autoimmune diseases-
After reading the above, one may think it sounds like a cure! It stops autoantibody formation; therefore, it should control lupus completely!
We wish it were that easy. This is just one little tiny part of the immune system. There are many other sections of the immune system that are functioning abnormally in SLE. Also, hydroxychloroquine doesn’t completely stop antigen processing and antibody formation. It is a weak medication. Think of it as “calming down” the process, not eliminating it entirely. And, thank goodness it doesn’t! We need antigen processing to keep working so that our immune system still fights off infections, cancers, etc. The immune system continues to function well with antimalarial drugs. In fact, SLE patients who take hydroxychloroquine are less apt to get infections and cancers compared to patients who do not take it.
Also, this is not the only way that antimalarials work on the immune system. They also work in other ways. For example, we think that inhibiting part of the immune system called toll-like receptors probably plays a more critical role in how antimalarials help in treating lupus. However, delving deeper is beyond the scope of this post.
That would have to be the subject of a different (long) post. The purpose of this article was to just give one part of the story on why a medicine used to treat an infection would work for an autoimmune disease. The immune system is indeed fascinating!
A similar thing occurs in malaria. Malaria is an infection due to single-celled parasites called Plasmodium that get into humans from mosquito bites. The malaria organisms get into the red blood cells, where they ingest iron-rich hemoglobin. The malaria parasite needs to digest this hemoglobin inside vacuoles within their own bodies (similar to the macrophages of the immune system ingesting antigen proteins inside their vacuoles). The malaria organisms digest the proteins of the hemoglobin to use for food and reproduce. Just as our macrophage vacuoles need an acidic environment to digest antigen proteins, the malaria organisms also require an acidic environment to digest the hemoglobin and dispose of the waste product (the iron-rich heme portion of the hemoglobin). The anti-malarial medicine dissolves into the vacuoles of the malaria organisms and raises their pH levels. The malaria organisms are unable to digest the hemoglobin and to get rid of the heme. The heme molecules combine with the anti-malarial medicine molecules and build up inside the malaria organisms, trapped within their vacuoles. This is toxic to the malaria organisms, and they stop reproducing and hopefully die.
The bottom line is that anti-malarials appear to work by increasing the vacuoles’ pH inside malaria organisms and macrophages. These vacuoles usually ingest hemoglobin (in the case of malaria organisms) or antigen proteins (in the case of macrophages in people with lupus). When the pH is increased, these vacuoles are unable to process these components. In the case of malaria, the malaria organisms die due to the buildup of toxic waste products. In the case of lupus, the macrophages cannot process antigens properly to present them to T-cells. Therefore the immune system is calmed down so that it does not attack the body (such as the skin, joints, or kidneys) as much.
Anti-malarial drugs have other effects on the immune system. However, we will only discuss the above effect as it is simple to illustrate.
Please get 2 yearly eye exams (SD-OCT and a VF 10-2) if you take Plaquenil or chloroquine.
Get 3 tests if you are Asian (add on a VF 24-2 or a VF 30-2)
The above excerpt and figure comes from “The Lupus Encyclopedia” by Johns Hopkins University Press. The language has been altered for better readability.
Source of electron microscope malaria parasite food vacuole: Jani D, et al. HDP-a novel heme detoxification protein from the malaria parasite. PLoS Pathog. 2008 Apr 25;4(4):e1000053. doi: 10.1371/journal.ppat.1000053. PMID: 18437218; PMCID: PMC2291572.
Torigoe M, Sakata K, Ishii A, Iwata S, Nakayamada S, Tanaka Y. Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via Toll-like receptor 9 inhibition. Clin Immunol. 2018 Oct;195:1-7. doi: 10.1016/j.clim.2018.07.003. Epub 2018 Jul 4. PMID: 29981383.
Wang F, Muller S. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. Front Immunol. 2015;6:252. Published 2015 May 19. doi:10.3389/fimmu.2015.00252
Lupus Question of The Day: Is Benlysta for mild lupus nephritis?
Question of the Day:
Dr. T’s Answer:
Types of mild lupus nephritis-
“It all depends upon what your definition is of “mild nephritis.” I would consider ISN/RPS classes 1 (minimal mesangial) and 2 (mesangial proliferative) as mild. They do not need treatment at all (except for Plaquenil/hydroxychloroquine plus often an angiotensin receptor blocker, such as losartan, or an angiotensin converting enzyme inhibitor, such as lisinopril, medicine to lower protein in the urine).
In addition, lupus podocytopathy could also be considered a “mild” type of lupus nephritis. Usually, lupus podocytopathy goes into remission quickly with Plaquenil plus steroids, with a rapid steroid taper. Therefore, for my definitions of “mild” lupus nephritis, Benlysta is not needed.
Benlysta was used in cases of severe lupus nephritis in the BLISS-LN study-
The Benlysta lupus nephritis clinical trial (called BLISS-LN) showed that when Benlysta was added on top of standard of care (Plaquenil, steroids and either mycophenolate or cyclophosphamide) there were significantly more people who improved on Benlysta plus standard of care compared to those who were treated with standard of care alone. More patients had partial or complete responses (including remissions) compared to standard of care (i.e. how we treat lupus nephritis before Benlysta). Plus… there were no significant differences in side effects, which is amazing. Also, more patients who got placebo plus standard of care died or went into complete kidney failure compared to the Benlysta group.
This is all great news. The lupus community is excited about this landmark event: Benlysta being the first FDA-approved drug for lupus nephritis ever. “
UPDATE September 2021: Lupkynis became the second FDA-approved drug for the treatment of lupus nephritis in January 2021.
Donald Thomas, MD, author of “The Lupus Encyclopedia” and “The Lupus Secrets”
Note that this post is for informational purposes only, and is not meant to be specific medical advice. Always seek the advice of your healthcare provider with any questions regarding your own medical situation.