Anifrolumab inhibits type 1 interferon from increasing immune system activity

Anifrolumab FDA approval to treat systemic lupus [Saphnelo]

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.

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Benlysta Reviews: Learn the amazing truth on how it works [Updated]

 

Picture shows how Benlysta works by interfering with B cell proliferation
How Benlysta works: it decreases the activation of autoreactive B-cells that make bad autoantibodies such as ANA and anti-DNA 

The pink guys are lymphocytes (T-cells in this case) under electron microscopy. photo from Texas Center for Cancer Nanomedicine

 

Benlysta (belimumab) Decreases the Cells that Make Bad Antinuclear Antibodies: See Benlysta Reviews Below

 

Read this and other Benlysta reviews to learn how amazing Benlysta works. There are very good reasons why it has achieved 3 FDA approvals for lupus (systemic lupus erythematosus or SLE, pediatric lupus, and lupus nephritis) in the past 10 years. It is safe and effective per many Benlysta reviews. It is used as an IV treatment for lupus as well as a self-injectable form. Before you get your Benlysta first infusion or self-injection, make sure to learn as much as you can from this and other Benlysta reviews. Today, we use Benlysta for lupus nephritis, SLE, and pediatric lupus. 

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Voclosporin for Lupus Nephritis: Great results in The Lancet [Update]

Graphs showing Lupkynis voclosporin efficacy in lupus nephritis Lancet article

Note the impressively higher response rates in the blue bars (Lupkynis + mycophenolate + steroids) compared to pink (standard of care without Lupkynis). Impressive! This graph comes from the Lancet article referenced below. This is what pops up when you link the study

Voclosporin for Lupus Nephritis Studied in 2 Phase-III Clinical Trials! It is a new treatment for lupus in 2021.

Voclosporin for Lupus Nephritis: Impressive Results

Voclosporin for lupus nephritis impressively improves lupus nephritis compared to when patients get mycophenolate plus steroids alone.

Updates September 2021 included below (including voclosporin side effects) because is it is a new treatment for lupus as of January 2021.

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Lupkynis vs Benlysta for Lupus Nephritis: Dr. Thomas Has His Verdict!

Which is better for lupus nephritis?
​Here is my answer!

Arm wrestling to see which is better for lupus nephritis: Lupkynis or Benlysta

Which is better for lupus nephritis? Benlysta or Lupkyinis? … and the winner is… (read below)
Updated 6/1/21: I included:
– The specifics on the complete renal responses Benlysta vs Lupkynis
– Included information on extra renal lupus
– Included information about the long term extension trial to 104 weeks with Lupkynis

​Background on lupus nephritis:

– Systemic lupus erythematosus (SLE) is an autoimmune disease where the immune system attacks the person’s own body.
– Around 40% of the time, it will attack the kidneys. This is called lupus nephritis (LN).
– It causes no symptoms whatsoever until it is severe and permanent damage is already occurring. This is why we ask our SLE patients to give a urine sample every 3 months to look for increased protein in the urine (proteinuria) as a sign of nephritis.
– Up to recently, our treatments have not been very good, with around 15% of our patients going into kidney failure by 10 years after their diagnosis. Then they need dialysis or a kidney biopsy. This is one reason why we need better treatments. “Standard of care” with mycophenolate and cyclophosphamide are NOT good enough.
– Our goal in treating LN is to get it into remission.
– Numerous drugs have been studied this past decade, trying to find better treatments. In those studies, only 22% to 32% of patients go into remission on the usual treatments of mycophenolate or cyclophosphamide. Remission is so important because this is the best way to prevent kidney failure and death.

Normal nephron (glomerulus). Cartoon drawing and a microscopic view

A normal nephron in the kidney. Also called a glomerulus. We have millions of these. They are the filters of the kidney. Photo = by OpenStax College from wikipedia.com glomerulus entry
Microscopic view of diffuse proliferative lupus nephritis (class IV)

Lupus class IV (diffuse proliferative nephritis). Photo by “nephron” at wikipedia.com diffuse proliferative glomerulonephritis entry
The role of the kidney biopsy:
– A kidney biopsy is essential to help figure out what to do. After numbing up the back under the ribcage, a tiny needle is inserted to grab a tiny piece of kidney. We then  look at it under the microscope.
– Above are two examples of kidney biopsies as seen under the microscope.
– Note the normal kidney top right. The glomerulus (nephron) is one of millions of tiny filters in our kidneys. Note all the white spaces. These white spaces are essential for waste products to fill up and flow into the urine.
– Now look at the LN kidney on the bottom affected by the worst form called “class IV diffuse proliferative nephritis.” Note how there is hardly any of the large white spaces that you see in the normal glomerulus. This filter (glomerulus) is unable to filter out waste products. Without good treatment, this patient would absolutely go into complete kidney failure.
FDA icon logo

Food and Drug Administration (FDA) = responsible for evaluating the safety and effectiveness of new drugs. Photo from Wikipedia
Prior to 2020, there were no FDA-approved drugs to treat LN

December 17, 2020: Benlysta (belimumab) was the 1st FDA-approved drug to treat adults with lupus nephritis (LN) when added on top of standard of care (high doses of steroids plus either mycophenolate or cyclophosphamide)

January 21, 2021: Lupkynis (voclosporin) was the first oral drug FDA-approved to treat adults with LN when added on top of standard of care (high dose steroids plus mycophenolate)

May 5, 2021: Benlysta is approved to treat adults with LN in the European Union!

So, which is better? Benlysta or Lupkynis?

I think that is best answered by looking at the pros and cons of both drugs:


Benlysta (belimumab)
Data below is from the phase III clinical trial (BLISS-LN) unless otherwise stated

PROS:
– 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

​CONS:

– 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. 

Lupkynis (voclosporin)
Data below is from the phase III clinical trial (AURORA trial) unless otherwise stated

PROS:
– 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.

​CONS:

– 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

THE COMPLETE RENAL RESPONSE CRITERIA OF EACH RESEARCH STUDY

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.


And the answer is (Benlysta vs Lupkynis) …

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. 

NOTE: I plan on adding, improving, and changing the pros and cons above over time as new information comes in. Also, if anyone can think of other pros and cons, just let me know in the comments section.

PLEASE COMMENT above. Would you add any other pros or cons? What are your questions about lupus nephritis, Benlysta, and Lupkynis?

REFERENCES:

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.
2011;67(pt 2):119‐123

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.
2013;53(8):819‐826.

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,
2020.

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.
Abstract/ePoster 283

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​

Author

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.

Saphnelo: New FDA-approved drug for lupus?

A potential new drug for lupus–
​here are some early facts

UPDATE: Anifrolumab (Saphnelo) was FDA-approved on August 2, 2021

Saphnelo: The next FDA-approved drug to treat lupus
Saphnelo: The next FDA-approved drug to treat lupus

Anifrolumab (Saphnelo) has the lupus community excited as the next FDA-approved drug for lupus.
Pronounced saf-NEH’-low

Saphnelo–the 2021 FDA-approved drug to treat lupus (at least the next biologic for systemic lupus). I received this email on 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. I suspect that anifrolumab will be the next FDA-approved drug for lupus. 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!

Cutaneous lupus responded very well to anifrolumab or Saphnelo

anifrolumab (Saphnelo) has impressive results. Many patients with cutaneous (skin) lupus had total to near total clearing of their skin inflammation as shown in this pic … NOTE… this picture comes directly from the following research study found on the internet. The photo is owned by the ACR’s Arthritis and Rheumatology journal: Furie R, Khamashta M, Merrill JT, Werth VP, et al; CD1013 Study Investigators. Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. PMID: 28130918; PMCID: PMC5299497.

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 PathwayHow 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! With it aimed at a major cause of lupus (high type-1 interferon levels), it should be the next FDA-approved drug for lupus. 

​Saphnelo, the next FDA-approved drug to treat lupus: 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: No wonder Saphnelo is the next FDA-approved drug to treat lupus

     -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

Bottom lines- Saphnelo, the next FDA-approved drug to treat lupus:

– 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!

As of August 2, 2021, anifrolumab became the next FDA-approved drug for lupus!

Good luck to AstraZeneca who is the manufacturer of Saphnelo

Update: August 2021

2020 and 2021 were monumental years for people who have lupus. Belimumab (Benlysta) became the first FDA-approved drug for lupus nephritis December 17, 2020. Voclosporin (Lupkynis) became the second FDA-approved drug for lupus nephritis on January 22, 2021 with the advantage of its being a pill rather than an injection. Then, anifrolumab (Saphnelo) was FDA-approved to treat lupus (the systemic form) on August 2, 2021!

Author

Don Thomas, MD, author of “The Lupus Encyclopedia” and “The Lupus Secrets

References: 

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.

Tanaka Y, Tummala R. Anifrolumab, a monoclonal antibody to the type I interferon receptor subunit 1, for the treatment of systemic lupus erythematosus: an overview from clinical trials. Mod Rheumatol. 2021 Jan;31(1):1-12. doi: 10.1080/14397595.2020.1812201. Epub 2020 Sep 17. PMID: 32814461.

Intravenous Immunoglobulin: IVIG for Systemic Lupus Erythematosus

A drug made from up to 100,000 healthy volunteers!

Lupus patient getting intravenous immunoglobulin

Intravenous (IV) means getting a medicine delivered into your vein

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.

A blood donor to make IVIG for lupus patients

It can take up to 100,000 healthy blood donors to produce one dose of IVIG!
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.

Antibody that makes up IVIG

Cartoon depiction of an immunoglobulin molecule. Photo: TimVickers at Wikipedia


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)
Headaches
Fatigue
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

Author

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

Melatonin For Lupus May be Good Per the Best Medical Evidence [NEW!]

Melatonin For Lupus: What does the Research Show?

 

Melatonin for lupus being produced by the pineal gland in lupus
Melatonin is produced by the brain when it starts to get dark. Melatonin for lupus– could it be a good, safe sleep aid? … Photo from Wikipedia “Melatonin” by Srruhh

 

 

(Updated August 2021)

Why do people think that melatonin for lupus patients is unsafe?

Many people think that melatonin for lupus and other autoimmune diseases is unsafe. I believe it is due to there being outdated websites and patient education pages that state this. For example, it even occurs on highly-acclaimed sites such as the Mayo Clinic.

However, how can the Mayo Clinic be wrong?
Without a doubt: many excellent websites produced their patient education pages a long time ago.
In addition, there are not enough staff to check and update them on a regular basis.
Certainly the doctors are way too busy to do this: they are taking care of patients and doing research.

 

Read more

DHEA and Lupus: Research shows it to be useful and good in some

Use of DHEA in lupus patients

Other Facts about DHEA and lupus

– DHEA and lupus: 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.

– The research studies used 200 mg a day. However, this is more likely to cause acne and unwanted hair growth.

– It is best to get DHEA from a compounding pharmacist to ensure high quality. Ask your rheumatologist to write you a prescription. Over-the-counter products are not as reliable.

– It is available as a prescription vaginal preparation to help decrease pain from intercourse in women who have vaginal atrophy (tissue thinning usually due to aging).

– It does not look like the pharmaceutical company who produced Prasterone is going to pursue FDA-approval for treating systemic lupus erythematosus. Previous attempts to do this, backed up by positive recommendations from lupus experts failed.

– Using DHEA is one of the Lupus Secrets.

Want to learn more about DHEA and lupus? Read this online article that is free to download and read for everyone:

Sawalha AH, Kovats S. Dehydroepiandrosterone in systemic lupus erythematosus. Curr Rheumatol Rep. 2008;10(4):286-291. doi:10.1007/s11926-008-0046-1

Thanks to Kelli Roseta of More Than Lupus for publishing “Ask Dr. T”

Author

Donald Thomas, MD 

Lupus and Stress Management: How to lessen stress life

Lupus and Stress Management: The Science of Stress and the Immune System

The video below goes over lupus and stress management, while also discussing how stress affects the immune system adversely.The Lupus Foundation of America filed this video of me during their Living and Learning series December 2020 at the height of the COVID-19 epidemic and during the holiday season. Stress can increase lupus onset and lupus flares. Learnhow to lower stress can possibly help decrease the effects of lupus.

– The 1st part of the video goes over some of the science behind how stress abnormally affects the immune system. stress worsens cancer, autoimmune diseases, and cause increased death. Why is it that optimistic people who deal with stress well tend to live longer than pessimistic people who are easily stressed? Stress does have bad effects on our immune systems.

– Then I go over how people who are genetically predisposed to having lupus have a greater chance of developing lupus if they have had major stressors in their life (child abuse, physical abuse, sexual abuse, etc.)

– Then I go over how stress can cause lupus flares.

– Interestingly, easily stressed people can learn to deal with stress better. Some habits are easy and incredibly healthy in many other ways. Examples include exercising regularly, and practicing mindfulness daily.

​- I end the video with practical pointers on how to decrease stress.

Download my free stress management handout from my Lupus Secrets

SHARE with everyone who has an autoimmune disease

COMMENT above: how do you deal with and prevent stress?

​What advice do you have for others?


Author

Don Thomas, MD, author of “The Lupus Encyclopedia” and “The Lupus Secrets



Lupus and Vitamin D Advice: Can be lowest in women of color

Lupus and vitamin D in Women of Color. Why and what to do-

Ask Dr. T!” question of the week

Vitamin D in women of color with lupus is an important problem. Women of color tend to have lower vitamin D levels, and this can be associated with worse lupus disease activity. 

Lupus and Vitamin D in Women of Color is a Big Problem for Many Reasons:

Here’s this weeks question:

Lupus patient:

I am a black woman with lupus and am constantly dealing with low vitamin d levels. Are low levels of d common in people of color? And can having low levels be making my lupus worse?

Dr. Donald Thomas replies:

I LOVE this question because it is so important.

Vitamin D is essential for the immune system to work properly. White blood cells have receptors (attachments) on their surfaces that bind to the active forms of vitamin D that float around in our bodies. This vitamin D attachment is vital for the immune system to work properly. When vitamin D levels are low, the immune system works abnormally, increasing inflammation and lupus disease activity. Correcting vitamin D levels can reverse this problem and it is so easy and safe to do.

Lupus vitamin D deficiency symptoms? Low levels of vitamin D can be associated with fatigue and body aches. Of course, when it causes lupus to become more active, it can lead to the butterfly rash, pleurisy, and other problems. Dr. Michelle Petri even showed that correcting low vitamin D can reduce flares and reduce proteinuria!

Several studies now show that if we keep the level at 40ng/mL and higher (but not higher than 80), lupus disease activity is better. Lupus flares are associated with low vitamin D levels. People of color have lower vitamin D levels because the melanin (pigment) of the skin decreases ultraviolet light from entering the skin deep enough to help the body produce vitamin D. So, this is a common problem.

However, it is incredibly easy to treat! Everyone’s body is different, and the required dose varies a lot from person to person.

Taking vitamin D regularly and using sunscreen religiously every day are two of the safest drugs used to help treat lupus. I always include them in my patients’ medication lists.

produced by Kelli Roseta’s “More Than Lupus

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