Lupus tendinitis (lupus tendonitis), lupus tenosynovitis, and lupus enthesitis: What are they?
What is lupus tendinitis (also spelled lupus tendonitis)?
Lupus tendinitis (lupus tendonitis) and tenosynovitis are common in systemic lupus erythematosus (SLE). The tendons are sinewy, inelastic fibrous tissue that connects the muscles to the bones. When muscles contract to move parts of the body, these strong tendons enable the muscles to move the much stronger bones. The movement of these tendons in unison with the body’s muscles and joints allows us to move. To demonstrate tendons to yourself, place your left fingers on the front bend of your right elbow. Then, bend your right elbow. The muscle just above this is your biceps. The hard, long structures just below the biceps that connect to the bone below the bend are the biceps tendons. If these were to become inflamed and painful, this would be “biceps tendonitis.”
Just as lupus can cause inflammation of the joints, it can also cause inflammation of the tendons (lupus tendonitis or lupus tendonitis). Tendonitis usually causes pain around and between the joints of the body. The joint pains seen in SLE are commonly due to lupus tendonitis (lupus tendonitis) rather than arthritis. One Japanese study in 2017 showed that 94% of their SLE patients with joint pains had tendon involvement (tendonitis and tenosynovitis), while 80% had joint (arthritis) involvement. Many patients had a combination of both.
The photo above shows the hands of Dr. Thomas' patients with severe damage to her tendons from lupus tendinitis and lupus tenosynovitis. We call this "Jaccoud's arthropathy." Jaccoud's arthropathy was first seen in people affected by rheumatic fever. Today, SLE is the most common cause.
Make sure to read my "Lupus Secrets" to learn to take care of and prevent problems such as lupus tendinitis.
Benlysta (belimumab) is safe and effective for lupus
Benlysta is amazing. There are very good reasons why it has achieved 3 FDA approvals for lupus (SLE, pediatric lupus, and lupus nephritis) in the past 10 years. It is safe and effective.
How the target (BLyS) of Benlysta normally works in the immune system:
BLyS is B-cell fertilizer
There is an immune system chemical messenger (a cytokine) called BLyS (B Lymphocyte Stimulator) also called BAFF (B cell activating factor). B-cells that make antibodies require this BLyS (BAFF) to stay alive.
For Example: Suppose you get pneumonia from a bacteria called Pneumococcus pneumoniae (pneumococcus). B-cells are called upon to produce pneumococcal antibodies. The immune system makes a lot of BLyS to keep the pneumococcal antibody producing B-cells alive. When the infection is gone, the immune system stop making BLyS. The B-cells then retire and die because we don't need them any more. When cells of the body retire and die a natural death when not needed, it is called apoptosis. Think of BLyS as "B-cell fertilizer." Without BLyS, B-cells go through apoptosis, which is an important process of the body so that younger, newer cells can replace old, unneeded cells.
The tiny pink things floating around are cytokines (like BLyS) ready to attach to the purple white blood cell and tell it what to do (stay alive in the case of antibody producing B-cells) photo credit: Wikipedia and Scientific Animations at https://commons.wikimedia.org/wiki/File:Cytokine_release.jpg
Benlysta (belimumab) attaches to BLyS and takes it away so B-cells can die
Lupus patients constantly make too much BLyS, so those bad B-cells that make autoantibodies that attack your own body's cells (ANA, anti-dsDNA, etc) stay alive, and can even be immortal. Benlysta binds to BLyS and takes it away. The bad B-cells can then retire, die, and go away (go through apoptosis).
Yet, during infections, the immune system can still make lots of BLyS so that the important, needed B-cells can fight off the infection.
After studying Benlysta patients for over 20 years, we are not seeing any more infections in our Benlysta patients than we do in those taking placebo plus "standard of care" therapies.
Think of Benlysta as balancing out the immune system, achieving homeostasis, rather than suppressing it.
COMMENT above. Are you on Benlysta? How are you doing on it?
Don Thomas, MD, author of "The Lupus Encyclopedia" and "The Lupus Secrets"
Finally, the phase 3 data were published in the Lancet!
Lupkynis (voclosporin) impressively improves lupus nephritis compared to when patients get mycophenolate plus steroids alone.
We can now read the data ourselves, and it is impressive.
Here is where I break down the numbers into easier to understand language:
Here is a link to the article itself:
Treatments are getting better and better for lupus patients. Now, if only anifrolumab (Saphnelo) can get approved ASAP!
Prof Brad H Rovin, MD, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet May 07, 2021 Online; DOI:https://doi.org/10.1016/S0140-6736(21)00578-XDOI
Which is better for lupus nephritis?
Data below is from the phase III clinical trial (BLISS-LN) unless otherwise stated
- Flexible options. Given both by IV (intravenous) by a nurse, or at home by self injection (SQ form).
- Has been around and used for a long time (since March 2011), so there is a lot of experience with its safety and effectiveness
- Its safety in the lupus nephritis trials was similar to its safety in the phase III clinical trials for SLE.
- You don't have to fail other drugs 1st before using it for LN
- Most patients studied had class III or class IV nephritis
- Steroids had to be tapered to 10 mg a day or less of prednisone by week 24
- Complete renal response (CRR, remission or close to remission) at 104 weeks was 30% on Benlysta plus mycophenolate (MMF) or cyclophosphamide + steroids versus only 20% on standard of care alone (MMF or cyclophosphamide + steroids). Cautionary note: the definition for CRR was stricter in the Benlysta trial than the Lupkynis trial, so you cannot assume that Lupkynis did better for CRR. The Benlysta trial required better kidney function results than the Lupkynis trial did.
- The odds ratio for the CRR was 1.74 meaning that patients who received Benlysta plus standard of care had a 74% greater odds of achieving a CRR compared to patients treated with standard of care alone (ie placebo). Again, remember that the Benlysta trial had a stricter definition for CRR. You cannot compare the 1.74 for Benlysta to 2.7 for Lupkynis.
- Patients receiving Benlysta plus standard of care had a 58% increased likelihood at any time of achieving a CRR and remaining in a CRR until week 104. Note that this timing cannot be compared to Lupkynis' timing for decreased proteinuria. These are two different measurements.
- Black patients were more likely to achieve a CRR at 104 weeks on Benlysta plus standard of care compared to standard of care alone. However, these results were not calculated in the research paper.
- Benlysta plus standard of care resulted in a 49% lower likelihood of a "renal-related event or death" up to week 104 compared to placebo plus standard of care treatment.
- Benlysta was studied combined with both mycophenolate and cyclophosphamide. Lupkynis was only studied along with mycophenolate.
- Excellent patient assistance program at www.benlysta.com.
- Both the IV form and the self-injectable SQ forms can be used to treat lupus nephritis.
- Much easier dosing than Lupkynis. IV form is the same as that for SLE. The SQ form is 2 injections (400 mg) weekly for 4 doses followed by 1 injection weekly after that.
- The package insert does not recommend use in pregnancy (was not studied). However, the pregnancy registry conducted for more than 10 years has thus far shown no signals for fetal problems. Some rheumatologists have used it safely during pregnancy.
- There was a question of possible increased suicides, suicidal thoughts, and worsened depression in previous IV Benlysta studies. However, in this lupus nephritis study, there were actually more of these problems in the placebo group. However, this was most likely not statistically significant.
- Proven in multiple phase III clinical trials that it is safe and effective for systemic lupus problems other than kidney inflammation. This especially is true for arthritis, cutaneous (skin) lupus, and patients with high anti-dsDNA and low C3 and low C4 levels. Though the FDA would not allow a fatigue mention (due to not having a validated fatigue measure for SLE), there was improvements in energy (and I note this in my own patients). Of note, it is even FDA-approved to treat children with SLE as young as 5 years old!
- Both were studied for 104 weeks
- People who don't like injections may not like it
- Only around 14% of the patients were black (under-recruitment of black patients is a continuing problem)
- On the surface, the Lupkynis numbers are more impressive regarding how fast proteinuria is decreased and the number of patients who go into a complete renal response (CRR). However, definitions for these goals were different in the two studies, so direct comparisons cannot be made. From experience, we do know that other calcineurin inhibitors, such as tacrolimus, can have markedly fast and profound effects on proteinuria, so it would not be surprising if Lupkynis were to reduce proteinuria faster than Benlysta. SEE MY INDEPTH DISCUSSION ON THE CRR BELOW.
- It is expensive. But not as expensive as Lupkynis. The ICER (Institute for Clinical and Economic Review) estimates a yearly price of $43,000 for patients who stay on Benlysta.
Data below is from the phase III clinical trial (AURORA trial) unless otherwise stated
- Oral capsule form. Not an injection.
- It is brand new with no long term data. However, it is in a class of drugs called calcineurin inhibitors (CNI) which have been around for a long time.
- It is a new and improved 3rd generation CNI. It is more potent than cyclosporine (another CNI) and is less likely to cause cholesterol problems than cyclosporine. It is much less likely to cause diabetes compared to the CNI called tacrolimus. It results in such a stable, predictable drug level that blood drug levels are not needed.
- You don't have to fail other drugs 1st before using it for LN
- Most patients studied had class IV nephritis (the type with the worst prognosis)
- Amazing steroid taper! Only 500 mg IV SoluMEDROL for 2 days (many docs use 1000 mg for 3 days) followed by 25 mg a day prednisone tapered to 5 mg a day by 2 months and 2.5 mg a day by 4 months. Many, to most docs, use 40 mg to 60 mg a day after the IV steroids. So, starting with just 25 mg is phenomenal!
- Complete renal response (CRR, remission or close to remission) at 52 weeks was 41% on Lupkynis plus mycophenolate (MMF) + steroids versus only 23% on standard of care alone (MMF + steroids).
- The odds ratio for the CRR was 2.7 meaning that patients who received Lupkynis plus standard of care had a 170% greater odds of achieving a CRR compared to patients treated with standard of care alone (ie placebo).
- Lupkynis plus standard of care resulted in low urine protein levels (urine protein to creatinine ratio of 0.5 mg/mg or less) twice as fast compared to standard of care. The median time to this goal was 172 days for Lupkynis and 372 days for standard of care! "Time is kidney," we want our treatments to work as fast as possible, so this is amazing.
- 46% of black patients on Lupkynis had a CRR by 1 year compared to 16% on standard of care. In other words, three times as many black patients achieved a CRR on Lupkynis compared to standard of care! Our black patients are harder to treat and get their disease under control, so this is promising.
- Likewise, 39% of Hispanic patients on Lupkynis had a CRR at 1 year compared to 19% on standard of care (again, they typically are harder to treat, so this is promising).
- When looking at the type of LN, the worst type, class IV diffuse proliferative-- 47% of patients had a CRR at 1 year on Lupkynis, while 25% of those did on standard of care.
- It has 2 modes of action. In addition to the immunosuppressive effects, it also stabilizes podocytes, which are essential kidney cells that ensure the kidney filters (nephrons, glomeruli) are working properly and not allowing large proteins to escape from the blood into the urine.
- Excellent patient assistance program, Aurinia Alliance. They will get medication in the patient's hands within 5 days if there is any delay in getting it while they help work on the prior authorization process: support@AuriniaAlliance.com and 833-287-4642
- It is not FDA-approved to treat SLE problems other than lupus nephritis. However, in both the phase 2 and phase 3 clinical trials, there were some numerical improvements in a lupus disease measurement called the SELENA-SLEDAI score. The lupus nephritis trials were not designed to answers this question. I hope Aurinia pharmaceuticals considers doing an SLE study.
- Although the phase III clinical trial was only 52 weeks, a press release in May 2021 stated that low urine protein levels along with stabilization of kidney function was seen through week 104 in the long term extension trial.
- Lots of pills to take daily. Most commonly 3 capsules twice daily
- Only around 9% of the patients were black (under-recruitment of black patients is a continuing problem)
- As expected for a calcineurin inhibitor, decreased kidney function and high blood pressure were the most common side effects
- However, at week 24 and week 52, there was no difference in blood pressure between patients on Lupkynis and those on placebo plus standard of care
- In those with decreased kidney function, the dose of Lupkynis was decreased as recommended in the package insert. Most patients rebounded well to normal or to their target kidney function goal. In the end, there was "no clinically meaningful differences in mean eGFR vs placebo plus standard of care."
- The next most common side effects, as expected, were gastrointestinal issues, infections, and headaches.
- Long term side effects for infections and cancer is unknown.
- Lupkynis is more expensive. The ICER estimates a yearly price of $92,000 for patients who stay on it.
- Complicated dosing. The dose should be reduced if the kidney function decreases too much, or if there is cirrhosis of the liver, or if used with drugs that affect metabolism (CYP3A4 inducers, inhibitors, and P-gp substrates)
- Numerous potential drug interactions (such as listed above). It is important to use a drug interaction program such as UpToDate.
- Blood pressure and kidney function need checked before treatment, then every 2 weeks the first month. Kidney function should be checked monthly on treatment after month 1.
- Use during pregnancy and breastfeeding not recommended.
- Benlysta was studied combined with both mycophenolate and cyclophosphamide. Lupkynis was only studied along with mycophenolate.
- More difficult to prescribe than Benlysta. Only one specialty pharmacy handles it. Must contact Aurinia Alliance for assistance 1-833-287-4642
Why is a complete renal response (CRR) so important? Our goal in treating lupus nephritis is to get it into remission. Patients who reach remission are much less likely to go into kidney failure, have less organ damage, and live significantly longer than patients who have a partial response to therapy. CRR is not called "remission" because you truly do not know if the patient is in remission unless you do a kidney biopsy, but it is the closest we have without the biopsy.
First, what did they have in common? - Both did not allow any significant increase in steroids, change in doses of ACEi's or ARBs (blood pressure medicines that lower urine protein), addition of an antimalarial if not on one already, and no addition of any other immunosuppressant drug.
The other is they both had a similar urine protein to creatinine ratio (UPCR) goal (with one slight, nonsignificant difference). Lupkynis patients had to reach a UPCR of 0.5 mg/mg or less; Benlysta patients had to be below 0.5 mg/mg.
The big difference for complete renal response was in the kidney function stabilization criteria:
Benlysta required a eGFR of 90 ml/min or higher (or within 10% of the baseline if less than 90).
Lupkynis patients could have a eGFR of 60 ml/min or more (or within 20% of the baseline if less than 60).
It is much more difficult to have an eGFR of 90 ml/min or higher when you have severe lupus nephritis. So, this was an impressive requirement.
However, this is balanced out by Lupkynis using the CRR as its primary endpoint, while Benlysta used it as a secondary endpoint. Having it as the primary endpoint is wonderful as that is truly our goal. We don't just want a "renal response," with a treatment, we want remission (CRR or close to a CRR).
INTERESTING FACT ABOUT LUPKYNIS AND PREGNANCY:
Other calcineurin inhibitors (such as tacrolimus) are safe to use in pregnancy.
Why is it recommended not to use Lupkynis in pregnancy?
Each capsule of Lupkynis contains 21 mg of alcohol.
Putting it into perspective, 5 oz of red wine contains around 4000 mg of alcohol.
However, the Centers for Disease Control states, " There is no known safe amount of alcohol use during pregnancy or while trying to get pregnant."
Neither is definitely any better or worse than the other!
They are both game changers in the treatment for lupus nephritis, and they both have their place
What would I do if I had severe lupus nephritis?
Whenever I treat a patient, I always put myself in their shoes and ask myself, "what would I want if I were the patient, knowing everything that I know?" Or, what would I recommend to my family member if they were the patient.
The problem with the treatments for lupus nephritis prior to Benlysta and Lupkynis is that most patients do NOT go into remission.
Previous therapies (called ""standard of care" in the research studies) take too long to work. While we wait for them to work, permanent damage to the kidneys occurs. Once you lose each nephron (filter) due to lupus inflammation, it is gone forever.
We end up having to use too much steroids which cause side effects in everyone when used at high doses for lupus nephritis. These high doses of steroids also cause organ damage themselves. We always want to get away from treatments that also cause damage to our bodies!
So here we have two drugs that have proven themselves to increase remission, work faster, and decrease the need for steroids.
Plus, they had excellent safety in the studies. In my opinion, they are markedly safer than steroids.
If I had lupus nephritis, I would absolutely want Benlysta or Lupkynis plus mycophenolate plus hydroxychloroquine plus an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker plus vitamin D plus religious sunscreen usage immediately as my treatment.
If my nephritis were severe, I'd only want 250 mg to 500 mg IV pulse SoluMEDROL for only 2 days followed by just 20 mg to 25 mg a day of prednisone daily with a rapid taper. I want as little of steroids as possible.
I would also see if my insurance would allow me to use both Benlysta plus Lupkynis at the same time! They work in 2 different directions and if they could get me into remission faster and get me off steroids faster, why not?
What should you do if you have lupus nephritis?
- Learn as much as you can. Knowledge is Power!
- Mentally accept the fact that you will need to take numerous medications to treat the nephritis. Take all the medicines religiously. When you get tired of taking your medicine, tell yourself, "I want to do everything possible to stay off dialysis and prevent needing a kidney transplant." Each treatment has its reason behind using it. Your goal is to let the other meds (Hydroxychloroquine, vitamin D, sunscreen, mycophenolate or cyclophosphamide, Benlysta, Lupkynis, ACEi or ARB) do their magic so you can get under control faster and get down and off of those steroids! Just for example, I recently started taking care of this very nice gentleman with severe lupus nephritis who had numerous, painful, broken bones in his spine from steroids (his treatment did not include all the things I mention above). I wish I could have taken care of him from day #1. I'm confident I could have helped prevent that from happening. Don't let that be you.
- If you want an easy to take medicine that has proven long term safety, and is less of a hassle to take, then Benlysta may be a good choice for you.
- If you think that Lupkynis may work faster and better (we do not know this 100%, however), then Lupkynis may be a good choice if you don't mind taking 6 capsules daily and getting frequent blood pressure and blood work done.
- If you want to give it everything possible (like I would) ask your doctor about taking both.
PLEASE COMMENT above. Would you add any other pros or cons? What are your questions about lupus nephritis, Benlysta, and Lupkynis?
Package inserts for both Benlysta and Lupkynis
Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, Amoura Z, Yu X, Mok CC, Santiago MB, Saxena A, Green Y, Ji B, Kleoudis C, Burriss SW, Barnett C, Roth DA. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020 Sep 17;383(12):1117-1128. doi: 10.1056/NEJMoa2001180. PMID: 32937045.
Kuglstatter A, Mueller F, Kusznir E, et al. Structural basis for the cyclophilin A binding affinity
and immunosuppressive potency of E‐ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr.
Bîrsan T, Dambrin C, Freitag DG, et al. The novel calcineurin inhibitor ISA247: a more potent
immunosuppressant than cyclosporine in vitro. Transpl Int. 2005;17(12):767‐771.
Mayo PR, Huizinga RB, Ling SY, et al. Voclosporin food effect and single oral ascending dose
pharmacokinetic and pharmacodynamic studies in healthy human subjects. J Clin Pharmacol.
Gibson K, Parikh S, Saxena A, et al; AURORA Study Group. AURORA phase 3 study
demonstrates voclosporin statistical superiority over standard of care in lupus nephritis.
Presented at: National Kidney Foundation virtual 2020 Spring Clinical Meetings; March 26‐29,
Arriens C, Polyakova S, Adzerikho I, et al; AURORA Study Group. AURORA phase 3 study
demonstrates voclosporin statistical superiority over standard of care in lupus nephritis.
Presented at: EULAR European E‐Congress of Rheumatology 2020; June 3‐Sept 1, 2020
Askanase A, Randhawa S, Lisk L, et al. Efficacy of voclosporin across lupus nephritis
biopsy classes: pooled data from the AURORA 1 and AURA‐LV trials. Presented at:
National Kidney Foundation virtual 2021 Spring Clinical Meetings; April 6‐10, 2021.
Rovin BH, Parikh SW, Huizinga RB, et al; AURORA Study Group. Management of lupus nephritis with voclosporin: an
update from a pooled analysis of 534 patients. Presented at: American Society of Nephrology Kidney Week 2020
Reimagined; Oct 19‐25, 2020
Caster DJ, Solomons N, Randhawa S, et al; AURORA Study Group. AURORA phase 3 study demonstrates voclosporin
statistical superiority over standard of care in lupus nephritis. Presented at: ERA‐EDTA Virtual Congress; June 6‐9, 2020
Don Thomas, MD, author of "The Lupus Encyclopedia" and "The Lupus Secrets"
DISCLAIMER: I am on the Speaker's Bureaus for both Benlysta and Lupkynis. I do this proudly as I believe strongly in how much these medications can improve the treatment of our lupus patients, helping them live longer, better lives. I hope you can agree that the information I presented above is unbiased, using the data from the research studies. However, the opinions expressed in what I would want for treatment and what I recommend for patients are my opinions, based upon the research results.
Should lupus patients use medical marijuana?
With the increasing popularity and availability of cannabis and CBD, many lupus patients are asking, "How about CBD and lupus?"
Marijuana (cannabis) and its active components (THC and CBD) has become more popular for medical treatments. As of this writing (April 2021), 42 states in the US allow the use of medical marijuana, and 11 states (and the District of Columbia) have fully legalized its use recreationally. Many of my patients ask about using it, so I think it is important to go over some important information about it.
My goal is to present the facts based on scientific evidence without bias.
Cannabinoids are the active compounds of the cannabis plant. There are over 140 different cannabis-derived cannabinoids known, and each acts differently in the body. The 2 most studied and well-known are cannabidiol (CBD) and tetrahydrocannabinol (THC). THC is the cannabinoid responsible for the “high,” intoxicating effects with recreational users. CBD does not make people “high.”
A potential new drug for lupus--
here are some early facts
I received this email today, 4/18/21, announcing the brand name!
I have never seen a brand name announced before official FDA-approval.
Someone must know something I do not know ... did they get wind of a pending nod from the FDA?
This drug has impressive results from its research studies ... let me share a few so all SLE patients who have failed other medications realize that there is HOPE!
Research results "in a nut shell" in easy-to-understand language
The clinical trials for anifrolumab were called the TULIP trials
TULIP comes from the full research study name: Treatment of Uncontrolled Lupus via the Interferon Pathway
How does it work?
Most (70%) of systemic lupus erythematosus (SLE) patients have high levels of interferons
Interferons cause inflammation of organs, leading to permanent organ damage
Anifrolumab competes with interferon by attaching to the attachments (receptors) on immune system cells
Normally, when interferons bind to those receptors, the immune system cells become more active
Then they alert more immune system cells to become more active and attack body organs
Anifrolumab decreases this cascade of events from happening
This leads to less inflammation
It is a biologic monoclonal antibody, so it will be expensive!
Anifrolumab (Saphnelo) works differently than any drug used in the past to treat lupus!
1st in its class!
How is it given?
Saphnelo is given intravenously (IV), 300 mg, every 4 weeks (I suspect it will be 300 mg)
What were the research results?
There was a 90% reduction of interferons at 6 months in the patients who started off with high levels
Other labs measuring lupus inflammation improved (anti-dsDNA, C3, C4, CH50)
Low white blood cell counts and low platelet counts improved
What other good things did it do for the SLE patients?
They had less disease activity
Even patients who started with normal interferon levels overall improved
In TULIP-2: 57% (46 placebo vs 72 anifrolumab patients) more patients who started with high interferon levels met the primary endpoint with anifrolumab
... 58% more patients! Impressive!
When looking at all patients, a 51% higher number of patients responded to anifrolumab, including those with normal interferon levels!
You do not have to have high interferon levels to respond!
Close to twice as many patients were able to decrease their steroids to goal (25 placebo vs 45 on anifrolumab)
Lower steroids is important because higher doses of steroids cause organ damage
Anifrolumab reduced lupus flares
It especially worked well for cutaneous lupus
Look at the picture above from one of the studies
This patient had an amazing improvement. Many others did just as well
They measured skin activity with a CLASI score and looked for more than a 50% improvement
CLASI stands for Cutaneous Lupus Erythematosus Disease Area and Severity Index
Twice as many anifrolumab patients responded compared to placebo!
The numbers were 25% of the placebo cutaneous lupus patients responded, while 49% on anifrolumab did
How fast does it work?
Reduced disease activity was seen as early as 2 months
What were the side effects of anifrolumab
When comparing side effects, it is important to know that the placebo patients were not truly "placebo"
They were receiving standard of care therapy
In other words, most were on immunosuppressants and steroids that cause side effects themselves
The patients on anifrolumab were also on immunosuppressants and steroids
Therefore sorting out what anifrolumab may do vs the other drugs is very difficult
But, here are the numbers (combination of three different anifrolumab research studies):
Around 87% of anifrolumab patients and 80% of placebo patients had side effects
This include nuisance, mild side effects
The most common were viral upper respiratory tract (URI) and throat infections (cold-like infections)
Infusion reactions were the other most common
For example, 10% of the placebo (standard of care) patients had URIs, 18% on anifrolumab did
This is not surprising, interferon is important for fighting viral infections
Shingles occurred in around 6% of anifrolumab patients and 1%-2% of placebo patients
Again, not surprising since shingles is due to chicken pox virus
(MAKE SURE TO GET A SHINGLES VACCINE, SUCH AS SHINGRIX, BEFORE TREATMENT!)
6% of anifrolumab patients had to stop treatment due to side effects; 3% of placebo patients had to stop
What patients were not studied?
Patients with severe kidney inflammation (lupus nephritis, LN), brain, and nerve lupus (neuropsychiatric) were not
Therefore, we do not know if it works in them
However, I will go out on a limb and predict it will help LN patients
We know that interferon plays a role in LN
Just because we do not have study results for severe LN patients, this does not mean it does not work
What could possibly keep the FDA from approving it?
In the first TULIP-1 trial, it did not meet its primary endpoint (research goal called the SRI-4)
This could get some voting members to vote "no" for approval
However, lupus experts realize how hard it is to prove that lupus drugs work
They evaluated how the drug performed in the 1st trial
Patients did have significant improvements
They were able to lower their steroids and there was marked improvements in cutaneous lupus
One criticism is that some patients changed their NSAID (like ibuprofen) during the study
These patients were automatically labeled as a drug failure, though many of them had great responses
So they changed the primary endpoint for TULIP-2 based on their analysis of TULIP-1
The TULIP-2 trial did meet its primary end point
- Impressive results, especially for skin lupus
- Low rate of side effects (colds, sore throats, infusion reactions, shingles are the most important)
- Get your Shingrix shot before treatment
- I have a list of SLE patients who have failed everything who need to try this drug if it is FDA-approved!
Good luck to AstraZeneca who is the manufacturer of Saphnelo
Furie R, Khamashta M, Merrill JT, et al.; for the CD1013 Study Investigators. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody,in moderate-to-severe systemic lupus erythematosus.Arthritis Rheumatol. 2017;69(2):376–86.
Furie R, Morand EF, Bruce IN, Manzi S, Kalunian K, Vital EM, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1(4):e208–19.
Morand EF, Furie R, Tanaka Y, Bruce IN, Askanase AD, Richez C, et al.; TULIP-2 Trial Investigators. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020;382(3): 211–21.
Tanaka Y, Takeuchi T, Okada M, Ishii T, Nakajima H, Kawai S, et al. Safety and tolerability of anifrolumab, a monoclonal antibody targeting type I interferon receptor, in Japanese patients with systemic lupus erythematosus: a multicenter, phase 2, open label study. Mod Rheumatol. 2020;30(1):101–8.
A drug made from up to 100,000 healthy volunteers!
Intravenous Immune Globulin (IVIG)
Immune globulins (also called immunoglobulins) are antibodies. A large number of antibodies given in IVIG may help in some autoimmune disorders such as polymyositis and dermatomyositis. However, IVIG is not commonly used for SLE. It is useful in people who have a deficiency in IgG immune globulins (medically known as hypogammaglobulinemia) and have recurrent infections due to this. A person with hypogammaglobulinemia can benefit significantly from IVIG because it replaces the absent IgG globulins needed to fight infections.
Studies evaluating IVIG use in cutaneous lupus (chapter 8), lupus nephritis, muscle inflammation, low blood cell counts (to include myelofibrosis), lupus lung inflammation, myocarditis, arthritis, severe antiphospholipid syndrome, and neuropsychiatric lupus, have had encouraging results. A small 2012 study also suggested that it may help prevent congenital heart block in women with lupus who are SSA or SSB antibody positive. However, larger studies will be needed to see if IVIG should be used more often to treat lupus.
IVIG is produced from the antibodies of healthy blood donors. It takes anywhere between 1,000 and 100,000 donors for one dose. The preparation undergoes treatments to kill any potential germs and is thoroughly tested before using it for therapy.
How IVIG works: IVIG can decrease immune system overactivity.
What benefits to expect from IVIG: IVIG can decrease infections in people with low levels of IgG globulins. It can help the conditions noted in the paragraph above. In some people, it works rapidly, even within days after the first treatment.
How IVIG is given: Usually given as an intravenous (IV) infusion once or twice a month. A self-injectable form that can be given at home is available.
If you miss a dose of IVIG: Reschedule as soon as you realize that you missed your dose, then reset your schedule from that point. Consult with your prescribing doctor to double-check these instructions, but these guidelines will be enough for most people.
What needs to be monitored while you get IVIG: You will need to have periodic lab tests, including blood cell counts and kidney function tests.
Reasons not to take IVIG: Many IVIG brands are unsafe to receive if you have a deficiency in IgA globulins. Your IgA globulin level can be measured using a blood test similar to the one that measures IgG globulin levels. Gammagard S/D and Polygam brands of IVIG are generally safe to use if you are IgA deficient. Pre-existing heart disease, kidney disease, and a history of blood clots may increase your risk of having these sorts of problems on IVIG. Discuss these possibilities with your doctor.
If you have severe IgA deficiency, you should receive IVIG that does not contain IgA, or it should be provided in a hospital setting. Patients with severe IgA deficiency can sometimes develop severe allergic reactions (anaphylaxis) to IVIG containing IgA immunoglobulins.
While taking IVIG therapy: See your doctor regularly for appropriate blood tests. Seek medical attention immediately if you develop a red, painful, swollen leg; shortness of breath; chest pain; slurred speech; or arm or leg weakness.
Vaccines and IVIG: No need to stop drug or time dosing with inactivated vaccines (such as for influenza, pneumonia, and COVID-19). IVIG may decrease the response to some live vaccines. Ask your doctor about timing with any live vaccines (such as Zostavax, yellow fever, MMR, and others).
Pregnancy and breastfeeding while on IVIG: IVIG can be used for severe lupus flares during pregnancy. Some think it may help prevent congenital heart block progression due to anti-SSA antibodies.
It can be used during breast-feeding.
Older people and IVIG: There may be an increased risk for side effects such as kidney problems, heart problems, and blood clots.
What to do at the time of surgery with IVIG: IVIG can potentially increase blood clots and probably should not be used close to the time of surgery. Check with the prescribing rheumatologist and infusion doctor for more information.
Potential Side Effects of IVIG
Nuisance side effects
Mild infusion reactions (headache, muscle and joint aches, fever, hives, chills, stomach upset, nausea, abdominal pain)
Elevated liver enzymes
Anemia and low white blood cell counts
Rash, skin vasculitis
Serious side effects
High blood pressure = common, treated with blood pressure medicines
Severe allergic reaction (anaphylaxis, low blood pressure, wheezing) = uncommon, treated by the nurses during the infusion
Severe headache, aseptic meningitis = uncommon. May be prevented with antihistamines, steroids, and pain medicines. May need to stop medicine.
Kidney failure = rare
Increase in lupus flares = rare
Blood clots = rare
Side effect incidence key (approximations, as side effects can vary widely study to study): rare < 1% occurrence; uncommon 1%–5% occurrence; common > 5% occurrence
If you have been treated with IVIG, what was your experience like? Please share in the Comments section above
The above is an excerpt from "The Lupus Encyclopedia" by Johns Hopkins University Press. This is a preliminary draft for the 2nd edition, before print
Don Thomas, MD, author of "The Lupus Encyclopedia" and "The Lupus Secrets"
There is no evidence that it is unsafe in lupus: read on!
Why do people with lupus think it is unsafe to take melatonin?
It is because there are outdated websites and patient education pages that state this. It even occurs on highly-acclaimed sites such as the Mayo Clinic.
How can the Mayo Clinic be wrong?
Most likely: there are tons of patient education pages that were produced a long time ago.
There is probably no one who polices and up dates them.
Certainly the doctors are way too busy to do this: they are taking care of patients and doing research.
Theoretically, melatonin may improve the immune system in lupus
and other autoimmune diseases
- One problem in lupus is that there are lower numbers of important white blood cells called Tregs (regulatory T-cells).
- Tregs help to normalize the immune system and prevent overactivity.
- With less Tregs, bad B-cells that make dangerous lupus autoantibodies (such as anti-dsDNA) can live a very long time (and even forever, "immortal").
- Melatonin does effect the immune system. One of the things it can do is increase these important Tregs that could be helpful in lupus and other autoimmune diseases
- The 2013 research article referenced below by Lin GJ et al and the 2019 article by Zhao et al go into detail about this
What happens to lupus mice when they are given melatonin
- When melatonin is given to female mice that are prone to getting lupus, it prevents them from getting lupus!
- This was shown in a 2010 study by Zou LL et al and another in 2008 by Jimenez-Caliani AJ et al (referenced below)
How about humans?
- There are no studies of using melatonin in people with lupus.
- This is a huge reason why it is incorrect to tell people with lupus not to use melatonin. There is no evidence to support that recommendation.
- However, there is a study in people with rheumatoid arthritis (a related autoimmune disease).
- Melatonin did NOT worsen rheumatoid arthritis in these patients (Maestroni et al, referenced below)
I do not ask my patients with lupus to avoid melatonin.
There is actually more evidence that it may be beneficial rather than harmful.
Lupus patient education websites should remove their recommendations to avoid melatonin.
These sites and pages are outdated.
- DHEA stands for DeHydroEpiAndrosterone
- It is produced by the adrenal glands
- It is made from cholesterol (yes, cholesterol is a necessary part of our body)
- It is both a steroid and a hormone
- It has both female hormone activity and male hormone activity
- It is used by the body to produce estrogen (female) and testosterone (male)
- It is the most abundant hormone in the human body
- Many lupus patients have lower than normal DHEA levels. This is what started the research to use it for treatment
- The prescription form of DHEA goes by the brand name Prasterone. The FDA would not approve its use for lupus due to the clinical trials not being strong enough to support FDA-approval.
Thanks to Kelli Roseta of More Than Lupus for publishing "Ask Dr. T"
Don Thomas, MD
Do not automatically stop hydroxychloroquine if your eye doctor tells you your patient has HCQ-retinopathy!
Heed my practical advice below
SD-OCT and VF 10-2 results have false positives. Don't stop your lupus patient's most important medicine without doing the following:
- If your ophthalmologist advises you to stop HCQ based upon either an SD-OCT or VF 10-2 result, refer that patient to a good retinologist who has a mf-ERG machine
- 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 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.
Don Thomas, MD, author of "The Lupus Encyclopedia" and "The Lupus Secrets"
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.
New guidelines from the American College of Rheumatology for the COVID-19 vaccine
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.
ALSO: They make other important recommendations as listed below. Make sure to share this with your family, friends, and other patients
- Do not do any of these without asking your rheumatologist first (let them know that you did read these up to date recommendations here)
- PRINT these out for future reference for other vaccines
- 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)
- I agree with all of these, except, I differ with the methotrexate recommendation, as per below
The link to the full recommendations is below at the bottom of the post.
Drug recommendations summary:
Abatacept SQ (Orencia self injectable): Hold SQ abatacept both one week prior to and one week after the first
COVID-19 vaccine dose (only); no interruption around the second vaccine dose
Azathioprine (Imuran): No modification needed
Belimumab (Benlysta): No modification needed
Cyclophosphamide: No modification needed for pills. For the IV form, time CYC administration so that it will occur approximately 1 week after each vaccine dose, when feasible.
Hydroxychloroquine (Plaquenil): No modification needed
IVIG: No modification needed
JAK inhibitors (Xeljanz, Olumiant, Rinvoq): Hold JAKi for 1 week after each vaccine dose
Kineret: No modification needed
Leflunomide (Arava): No modification needed
Methotrexate: Hold MTX 1 week after each vaccine dose, for those with well-controlled disease
NOTE Dr. Thomas' recommendations to his patients: "Hold MTX dose for 2 doses after each vaccine if you are doing well and in remission" (do not do without talking to your own doctor). This is based on the latest study results with the flu shot and methotrexate.
Mycophenolate (CellCept, Myfortic): No modification needed
Prednisone: No modification needed
Rituximab (Rituxan): Assuming that patient's COVID-19 risk is low or is able to be mitigated by preventive health measures (e.g., self-isolation), schedule vaccination so that the vaccine series is initiated approximately 4 weeks prior to next scheduled rituximab cycle; after vaccination, delay RTX 2-4 weeks after 2nd vaccine dose, if disease activity allows.
Sulfasalazine: No modification needed
Tacrolimus and cyclosporine A: No modification needed
TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab): No modification needed
Tocilizumab (Actemra): No modification needed
Voclosporin (Lupkynis): No modification needed
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.
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!
How hydroxychloroquine kills malaria-
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.
Feel free to comment above.
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.
Don Thomas, MD, author of "The Lupus Encyclopedia" and "The Lupus Secrets"
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 nephritis?
"I have lupus nephritis and just heard that Benlysta has been approved to treat it. I have stage 3 disease. Is this medication more for people with mild nephritis?"
Dr. T's Answer:
"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 ARB or ACEi medicine to lower protein in the urine). Podocytopathy could also be considered a "mild" type of lupus nephritis. Usually 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.
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. "
Thanks to Kelli of "More than Lupus" for producing the "Ask Dr. T" series!
Don 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.
I got mine, #1, today on 12/29/20! Please get yours.
Read my previous post on why lupus patients should get the COVID-19 vaccination
I got my Moderna COVID-19 vaccine on 12/29/20. I'll post how I do day by day below at the bottom of this post. However, 1st, I'll go over how this interesting vaccine works!
How the COVID-19 vaccine works "in a nutshell"
This is fascinating!
- It helps to know how RNA works (specifically mRNA)
- Look at the cell above
- We are all born with DNA that codes everything our cells produce. It is responsible for our having blue eyes instead of brown, or black hair instead of blond, or, yes... having funny smelling pee after eating asparagus (or not)
- Our DNA is "transcribed" (think it is as being translated) into RNA, and eventually messenger RNA (mRNA)
- Then, a part of our cells called ribosomes can read this mRNA like a food recipe and produce a particular protein (such as the one responsible for your 2nd toe being shorter, instead of longer, than your big toe)
- Ingeniously, they contain the virus' mRNA that codes for those spikes you see on the outside in all the pics
- These spikes look somewhat like a crown. Latin for "crown" is corona, hence, coronavirus
- The mRNA of the virus (in the vaccine) is injected into your muscle
- It spreads quickly throughout your blood stream and body
- The mRNA is absorbed into our own cells
- Our own cells mistakenly think this mRNA came from our own DNA and instructs those cells to produce this protein
- The protein is the same one found in the spikes of the SARS-CoV-2 coronavirus responsible for COVID-19
- In other words, our cells produce just those pink spikes you see in the pic below, not the entire virus
- The viral spike protein ends up on the surfaces of our cells
- Our very smart T-cells of the immune system actually DO recognize these as being foreign
- They say, "we need to fight this off and protect us"
- They summon other players of the immune system as well to the battle
DaOur B-cells then learn to produce antibodies that quickly recognize those COVID-19 spikes
- The booster shot you get a few weeks later strengthens this memory
- If you were to actually get infected with COVID-19 in the future, your B-cells would recognize those tell-tale spikes
- Those smart B-cells would say, "This is a foreign invader we must destroy"
- They summon the rest of the immune system to attack the virus and protect us
- Note that many people will get a very sore arm, redness, swelling, aches, pains, fever for a few days after the vaccine
- This is actually the immune system learning to mount an attack. Think of it as a sign of the vaccine working
WHAT HAPPENED AFTER MY SHOT
Day #1: It has just been a few hours since my vaccine
I took some Tylenol and Advil to decrease my chances for the above side effects
If you get the vaccine (which I hope you do), ask your doctor before you consider taking Tylenol and/or Advil or Aleve
Day #2: Woke up with a sore upper arm muscle (deltoid) in the area of the shot. However, I expected this as usual with a good, strong vaccine. I'll just take Tylenol plus Advil around the clock today to lower the risk of pain and to lower my risk of a flu-like syndrome reaction.
Day #3: Mild, tolerable arm soreness. I feel great! I am optimistic about getting vaccinated and feeling safer.
Is it important to take vitamin D if you have lupus?
"Ask Dr. T!" question of the week
Low vitamin D levels are associated with higher lupus disease activity
The mission of the More Than Lupus Foundation is to provide programs and support for those living with lupus, advocate for their needs, and collaborate with other government and lupus organizations to strive toward improving quality of life, and ultimately finding a cure.
AuthorDon Thomas, MD author of "The Lupus Encyclopedia" and "The Lupus Secrets"
References: Under chapter 38
Watch this YouTube video -- patients' important questions are answered about living with lupus
Moderator and questions are asked by lupus warrior Molly McCabe
Lupus questions about "The Lupus Secrets" and living with lupus are answered by Don Thomas, MD
Hydroxychloroquine (Plaquenil) dosing, safety, how to avoid eye problems
Belimumab (Benlysta) safety and helpfulness for lupus
How long does it take for Benlysta to work?
Which lupus patients are the best candidates for Benlysta treatment
Genetics and epigenetics that can predispose people to getting lupus
Why lupus occurs more often in people of color (African descent, Hispanic, Asian, indigenous peoples)
The treatment of lupus and rheumatoid arthritis overlap, also called rhupus
What is the significance of an antinuclear antibody (ANA) test becoming negative in a lupus patient?
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Don Thomas, MD, author of "The Lupus Encyclopedia" and brought to you by Kelli Roseta of "More Than Lupus" and author of "My Special Butterfly"
Dr. Thomas is on the Speakers' Bureau of GlaxoSmithKline for belimumab (Benlysta). He mentions this in his answers as well in the video
We have 3 drugs that are vying for FDA approval soon: Benlysta (belimumab) for lupus nephritis, voclosporin for lupus nephritis, and anifrolumab for systemic lupus erythematosus (SLE). All three were successful in the final research studies (called phase 3 clinical trials). In medical-speak, we say that "they met their primary endpoints."
My (Don Thomas, MD) prediction:
Though meeting the primary endpoints in phase III clinical trials never guarantees FDA-approval (many do not), these did so well, I predict they will be the next 3 FDA-approved therapies! They all did so well, along with having excellent safety profiles (low side effects for the amount of benefits they provided).
SHARE this with all lupus patients. Everyone needs some optimism.
Why is this so joyous? In March 2011, Benlysta was the very first FDA-approved drug for lupus since President Eisenhower was president (it took over 50 years!). That is a travesty. However, the approval of Benlysta showed pharmaceutical companies that it was worth their time, effort, and money to actively research lupus in more depth and that drugs could be proven to be helpful in treating SLE. And now... we have possibly 2 new drugs just around the corner (voclosporin and anifrolumab)? Yes, it is time to rejoice, hope, and pray that the FDA finds the research results to be as good as they appear.
This post, though, is all about Benlysta. Just this week, the New England Journal of Medicine published the positive results of their research study called BLISS-LN (Link to the study is below). This stands for "BeLImumab in Subjects with SLE with Lupus Nephritis study." It showed that Benlysta is effective for lupus nephritis.
Let's 1st briefly discuss lupus nephritis ...
This is why rheumatologists ask to see their patients every 3 months. We want a urine sample to evaluate and make sure our patient isn't getting lupus nephritis. When I see it as a possibility, I pounce on it and treat it aggressively. Using this approach, my only patients who have gone into kidney failure and dialysis, and then kidney transplantation were my patients who were poorly adherent to their therapy. By the way, don't let that happen to you!
Read and abide by my Lupus Secrets. If you follow them, you'll successfully fight your lupus.
They had 224 patients in the placebo group and 224 patients on Benlysta. However, it wasn't really placebo. The "placebo" group was getting standard of care (steroids plus either cyclophosphamide or CellCept, mycophenolate). Those who received Benlysta had their Benlysta in addition to the "standard of care."
It had some impressive results after 104 weeks:
30% of the Benlysta group had a complete response to therapy while 20% of the placebo group did. That is 50% greater in the Benlysta group compared to standard of care plus placebo group. This is impressive. The "placebo group" is how we currently treat lupus nephritis patients! Imagine getting a 50% higher response rate by adding another medicine.
By the way, you may think, well an additional drug! That could mean more side effects. Guess what? ... Serious adverse events occurred in 30% of those on standard of care treatment plus placebo, while 26% of those on Benlysta plus standard of care had serious side effects. This is actually less in the Benlysta group. However, that does not mean that Benlysta causes less side effects. This is actually not statistically significant.
Also, don't think this is "horrible" that 30% of patients had "serious adverse events." Guess what would have happened without these treatments? ... virtually 100% serious adverse events would have occurred due to the lupus nephritis leading to kidney failure, dialysis, kidney transplantations and deaths. (the benefits of the medicines greatly outweigh their potential side effects compared to this).
By the way, there were other impressive positive results in the study, but I wanted to hone in on the "complete renal response" result above.
Remarkably, there were only 3 deaths (2 on placebo, 1 on Benlysta), only one patient went into complete kidney failure (a placebo patient). Impressive when you realize how horrible the alternative without treatment would have been.
I've been using Benlysta since 2011, and I have many SLE patients who are in low disease activity and remission after failing other treatments. This includes quite a few lupus nephritis patients. In my experience, it is one of the safest medicines we have for SLE. Plaquenil is probably the only safer drug.
It comes in two forms of dosing ... a self injectable every other week form, or a monthly IV (intravenous form). According to UpToDate.com, the self-injectable form costs close to US$ 30,000 a year. The IV form is more expensive (nurses, IV equipment, etc.)
So some big, important questions are:
Which patients will benefit the most?
Can we figure out which patients are at highest risk for not responding completely to standard of care therapy (CellCept and cyclophosphamide)?
If we could figure this out, then those patients should be the ones who get it.
It will be interesting to see what happens if it gets FDA-approved for lupus nephritis. I cannot imagine it not getting FDA approval, by the way. The study was that impressive.
Bottom Line?: Lots of exciting stuff happening in lupus!
Please COMMENT in "LEAVE A REPLY" below.
Are you on Benlysta? How are you doing? What is your experience like? Do you have lupus nephritis? How have you done?
I love giving good news!
- Don Thomas, MD
P.S. Remember to download my Lupus Secrets to learn more!
Reference: Furie R, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. NEJM SEP 2020;383:1117-1128
Disclosure: I am on the Speaker's Bureau for GSK, maker of Benlysta. This is the only pharmaceutical Speaker's Bureau I am on. I truly believe in Benlysta as being a great therapy for SLE patients. It is not for everyone, but many do great on it.
Don Thomas, MD
I specialize in taking care of patients with systemic lupus. I enjoy sharing helpful, practical information for them to use and be better able to live with and successfully fight against their disease. Make sure to read and follow my Lupus Secrets
DONALD THOMAS, MD
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