posted in Drugs used in lupus on June 5, 2022 by
The FDA is considering the possibility of approving the self-injectible form of Benlysta for children with SLE and lupus nephritis
Saphnelo and Benlysta are considered two standard therapies for systemic lupus erythematosus. I changed the wording “usual drugs” when referring to the other immunosuppressants to the “older drugs”
IV vs SQ Benlysta: which works best? I answer below
If you become pregnant on Benlysta contact MotherToBaby; if you become pregnant on Saphnelo, call AstraZeneca
A study of 4000 patients showed no statistical difference regarding suicidality using Benlysta compared to placebo
The European Union Against Rheumatism (EULAR) published updated guidelines for managing systemic lupus erythematosus (SLE). One of the most important changes from previous recommendations was the recommendation to consider using biologic drugs (Saphnelo and Benlysta) earlier in SLE.
“Prompt initiation of <immunosuppressants> and/or biological agents (anifrolumab, belimumab) should be considered to control the disease <SLE> and facilitate glucocorticoid <steroids> tapering and discontinuation.”
Reasons for this important change include the mounting evidence that Saphnelo (anifrolumab) and Benlysta (belimumab) decrease SLE organ damage and that steroids cause organ damage. Even very low-dose steroids are associated with cardiovascular events (hardening of the arteries, heart attacks, heart failure, strokes, blood clots) and infections.
My other favorite guideline (long-coming) is the recommendation to try to keep patients off steroids and, if they require ongoing steroid therapy, to keep the dose less than 5 mg daily of prednisone.
A EULAR 2023 abstract showed that Saphnelo is a disease-modifying agent in the 2-5 year time frame, while Benlysta and hydroxychloroquine have shown to be disease-modifying agents past the 5-year time frame (meaning that they continue to prevent or slow down organ damage past the 5-year mark of use). Saphnelo did not qualify since it did not have long enough studies.
Benlysta was FDA-approved to treat lupus nephritis in children as young as 5 years old in July 2022!
2023 Benlysta Pregnancy Registry data reported.
See the results of how patients on Saphnelo did during the COVID-19 pandemic
Benlysta is now regarded as a disease-modifying agent for treating systemic lupus erythematosus (SLE). Saphnelo joined the group of disease-modifying agents in 2023 for the 2-5 year mark, while Benlysta and hydroxychloroquine proved to be disease-modifying for over 5 years.
Only two medications (Benlysta and Saphnelo) have been approved by the U.S. Food and Drug Administration (FDA) to treat systemic lupus erythematosus (SLE) since the 1950s.
Patients often ask me, “Between Benlysta and Saphnelo, what is the best medicine for lupus?”
They both have some things in common. They are both biologic drugs (biologics). This means they are produced by expensive, living, biologic processes rather than simple chemical-reaction methods. However, most importantly, they were developed specifically to treat parts of the immune system that are particularly overactive in lupus.
Benlysta (belimumab) has been an important standard of care therapy for lupus patients since March 2011.
Saphnelo (anifrolumab) became the second biologic drug FDA-approved to treat systemic lupus erythematosus (SLE) in August 2022.
In this blog post, I present the pros and cons of both drugs. Then at the end, I give my opinion on which wins “Best Medicine for Lupus.”
Throughout this blog post, “the older lupus drugs” and “other lupus drugs” refer to these immunosuppressants and antimalarial drugs. Two important goals in treating lupus are achieving remission and having patients off steroids.
Everyone with systemic lupus erythematosus (SLE) should be on an antimalarial (hydroxychloroquine or chloroquine) due to their many benefits and proven long-term safety (as long as you get your two required eye tests yearly).
There is a good reason we call hydroxychloroquine (Plaquenil): “Lupus Life Insurance.” As Dr. Michelle Petri, Chief of the Lupus Center, Johns Hopkins Hospital often says, “Hydroxychloroquine is the only drug proven to prolong survival in lupus patients.”
Numerous other immunosuppressants help many patients with systemic lupus erythematosus (SLE) go into remission or low disease activity and lower their doses of steroids (or hopefully get off steroids). The primary advantage of these drugs is that they are less expensive than Saphnelo and Benlysta. A downside is that they require additional labs to monitor their safety and have a higher infection risk than Saphnelo and Benlysta.
These other immunosuppressants include”
NOTE: In 2023 and 2024, EULAR published new SLE management guidelines recommending that doctors consider Saphnelo and Benlysta “promptly” while treating SLE patients. Therefore, today, Saphnelo and Benlysta are part of the “standard lupus drugs” and “older lupus drugs” list. However, the term is used here because when the clinical trials (research studies) were done, proving to the FDA that they were safe and effective for treating SLE patients, they were new and not considered “standard of care” at the time of those particular research studies.
Lupkynis (voclosporin) was the first non-biologic drug FDA-approved for lupus kidney inflammation (lupus nephritis) but is not approved for the treatment of systemic lupus erythematosus (SLE).
Saphnelo (anifrolumab) is specifically designed to treat lupus by decreasing the effects of a cytokine called interferon type-1. Read my previous article on Saphnelo to learn more.
Doctors measured lupus disease activity in the Saphnelo clinical trials using the BICLA (British Isles Composite Lupus Assessment) measurement research tool. This is one of my favorite measurements in lupus research. It is very thorough by evaluating lupus inflammation in ninety-seven different body areas. Saphnelo decreased inflammation in all organ systems that had moderate to severe involvement. It is the only lupus drug to do this. To prove that Saphnelo worked sufficiently on a patient in the research studies (called clinical trials), that patient had to improve in every area moderately or severely affected by lupus. That is impressive!
In all fairness, the BICLA was not developed until after the Benlysta clinical trials. The BICLA was not measured in the Benlysta research studies.
Therefore, it is impossible to say that Saphnelo is better than Benlysta when looking at this measurement.
Most medicines used to treat lupus are slow to work. However, Saphnelo can work fast. Some patients in the clinical trials had visible improvements after the first dose.
I’ll never forget the first patient I treated. She had failed all drugs, was around 90 years old at the time, and had horrible, itchy subacute cutaneous lupus. She was miserable and found it difficult to wear her clothing. Two weeks after the first dose, she was smiling, and every single inflammatory lesion was gone. It was nothing short of a miracle. (NOTE: not all patients respond this well, but many do. Some do not respond at all since all SLE patients are different).
“Clinical trial” in medicine is used as another word for “research study.” It does not mean trial as used in a legal court situation.
These are four of the most common and debilitating problems in systemic lupus erythematosus. Researchers evaluated 360 patients treated with Saphnelo in the phase 3 clinical trials. 54% of Saphnelo patients who met the study’s main target (primary endpoint) had improved energy. This was almost four times as often as the patients who did not respond.
Lupus often interferes with being intimate with one’s partner (due to pain, poor self-esteem, fatigue, loss of sexual desire, etc.). Almost four times as many Saphnelo patients who responded to treatment also had improvements in intimacy compared to those who did not respond. Patients on Saphnelo also had better improvements in numerous other quality of life and pain measures.
Steroids (like prednisone) are a double-edged sword. They are the only drugs that work immediately, and they can be lifesaving for patients with severe lupus. However, steroids cause side effects in virtually everyone who takes high enough doses and is on them long enough. One goal in treating lupus patients on steroids is to use safer medicines to get them off steroids or at least on lower doses (at least less than 5 mg daily). Rheumatologists call this “steroid-sparing.”
Saphnelo is the only drug to have “steroid-sparing” as a goal (called a “secondary endpoint” ) in the most important research performed (called a phase-3 clinical trial). It reached this goal. 72% more patients treated with Saphnelo plus other lupus drugs reduced their steroids to the target amount compared to lupus patients receiving placebo plus these other lupus drugs.
In other words, patients could lower their steroid doses better when Saphnelo was added to the older lupus treatments.
When we lower (taper) steroid doses, trying to get to the lowest amount possible or hopefully off steroids, it is important that patients not flare. Unfortunately, it is common for lupus to flare when steroid doses are lowered. Each lupus flare can cause organ damage, and we do not want that.
Only 20% of patients who received Saphnelo plus other lupus drugs flared during steroid tapering. In contrast, 50% of the patients receiving placebo plus other drugs flared. That is an enormous difference and is an important goal for me.
Cutaneous (skin) lupus erythematosus (CLE) is a major cause of feeling bad from lupus. This is partly due to its ability to cause permanent skin discoloration (especially the face) and permanent hair loss (as seen in this photo). It can also cause itching, which can be unbearable (like in the 90-year-old patient I mentioned above). Saphnelo is the only drug that evaluated its effects on CLE as an important goal (secondary endpoint) in its most important research study. After just three months, at least one out of two patients with CLE had at least a 50% reduction in skin inflammation. This was twice as many patients as those treated with placebo. Anyone who has seen the Saphnelo-treated cutaneous lupus pictures online would be impressed.
The number of side effects in the Saphnelo FDA-approved label that occurred in 2% or more of patients, and more often than placebo plus the older lupus drugs, is quite small. These included allergic reactions, infections, and infusion reactions.
When you look at this list of side effects, two things are important to point out—
You want to compare the percentage of those with that potential side effect on Saphnelo vs. those on placebo. For example, 9.4% of patients treated with Saphnelo had an infusion reaction. Infusion reactions include dizziness, headache, nausea, fatigue, and others. However, 7.1% of patients on placebo (received saline water instead of Saphnelo) had an infusion reaction. This was a small difference. Plus, it shows that simply getting an IV (intravenous, injected into a vein) of anything can make someone feel something perceived as a bad reaction.
Also, the clinical trials did not compare Saphnelo to just a placebo. All patients are on medicines that calm down or suppress the immune system (“other lupus drugs”). Therefore, when a patient gets a side effect, one of the other drugs may be the cause. It can be exceedingly difficult to know for sure.
For example, 4.8% of patients on Saphnelo had serious infections, while 5.6% of those on placebo did. Does this mean that sugar water causes more infections than Saphnelo? Of course not. These patients were also on strong immunosuppressants such as mycophenolate and were taking more steroids than those who were on Saphnelo.
Most of the older lupus drugs require us to draw blood work (most commonly the blood counts, kidney function, and liver function tests) frequently to monitor the drug and make sure it is not causing side effects. Patients often come in every 2 to 4 weeks for blood work on these medicines. Saphnelo does not need any extra labs to monitor side effects: easy-peasy.
Many to most IV drugs that we use in rheumatology require us to give our patients steroids, antihistamines, and acetaminophen (Tylenol) before we treat them (called “premedications”). Since Saphnelo rarely causes severe allergic and infusion reactions, patients do not require premedications. This is important because antihistamines and steroids can make people feel bad (drowsy, dizzy, body aches, insomnia, wired, etc.).
I attended a fascinating lecture by Dr. Mary Crow in November 2021. Dr. Crow is one of the world’s experts on lupus and type-I interferon. She talked about how certain antibodies (anti-Smith, anti-RNP, anti-Ro, anti-SSA, anti-La, anti-SSB) may cause high levels of type-I interferon. She also showed interesting data from her lab (along with Dr. Jing Hua, Dr. M. Olferiev and Dr. K. Kirou). Patients with frequent clinic visits, highly active disease, and high interferon levels tended to have elevated levels of these antibodies. They were less likely to have high anti-dsDNA levels (interesting).
She hypothesized that since Saphnelo interferes with type-I interferon levels and activity, it may be especially helpful in patients positive for these antibodies.
Note that anifrolumab (Saphnelo), just like belimumab (Benlysta) also works well in SLE patients with and without hypocomplementemia or elevated anti-dsDNA. However, when you look at groups of patients who have higher success rates compared to other groups, one of the groups of patients with a higher, relative success rate are those with active serologies (low complements, high anti-dsDNA) compared to those with inactive serologies (normal or high C3/C4 and normal anti-dsDNA). Nonetheless, many patients with normal serologies do fantastic on both drugs.
As introduced in the graph above, Saphnelo has impressed the rheumatologic community by publishing its 3-year long-term extension study results. A long-term extension trial is a commonly done study where a pharmaceutical company continues to study patients who were in the original research studies that achieved FDA approval (phase-3 clinical trials), then follows them over a longer period of time to ensure the drug is safe and effective over a longer amount of time than just the shorter clinical trials. Most of the time, everyone in the clinical trials is offered the chance to continue into the longer trials, and all patients, including those on placebo, are treated with the actual drug (and not placebo).
However, Saphnelo has truly raised the bar on this type of study. Saphnelo conducted a randomized, placebo-controlled long-term extension study (Kalunian K et al). Some patients who were on placebo continued on placebo while the other half were then placed on Saphnelo 300 mg IV monthly (standard dosing). In addition, neither the research doctors nor the patients knew who was on Saphnelo and who was on placebo, allowing an unbiased assessment of how they did on Saphnelo vs placebo. Having a placebo group in a long-term extension trial is amazing (it strengthens the data results).
The patients, by the way, were completely aware they could be on placebo or Saphnelo. Yet, they were not truly on placebo (fake medicine). They still were taking the older lupus drugs (like hydroxychloroquine, methotrexate, mycophenolate, azathioprine, and steroids).
This helps answer the question: If you add Saphnelo on top of the older lupus drugs, do more people benefit, can you lower the steroid dose, and is it safe to use over a total of 4 years? (the original study, called the TULIP period, was one year, and the long-term extension, LTE, study was an additional three years).
You can read the entire paper (linked above) by Dr. Kenneth Kalunian et al above, but here are the bottom lines:
Since Saphnelo interferes with the effectiveness of type-I interferon, and interferon is important in fighting off viral infections, we must wonder if it could potentially increase problems from viral infections like COVID-19. Interestingly, the 3-year long-term extension trial above began on June 30, 2016, and was in full swing when the pandemic hit March 11, 2020. You can see the numbers of COVID-19 infections and deaths in table 4 of the study.
What really sticks out to me in these numbers are the following:
Could Saphnelo be the best medicine for lupus with all these positive benefits, or is it Benlysta with all of its positive benefits? Read on…
A European League Against Rheumatism 2023 abstract showed that Saphnelo is a disease-modifying agent in the 2 to 5-year time frame it was studied. It did not meet criteria for 5 years (see photo above) because it does not have studies going out that far yet as of the time the abstract was written.
Shingles is a very painful rash due to the chickenpox virus. People with systemic lupus erythematosus (SLE) are already three times more likely to get shingles than older healthy people.
The vast majority of those treated with Saphnelo did not get shingles. However, five times more Saphnelo patients got shingles than those treated with placebo.
I recommend that all my patients get a shingles vaccine (preferably Shingrix) before starting Saphnelo. The Shingrix vaccine is 95% effective at preventing shingles.
Medical professionals (usually nurses) give Saphnelo intravenously (IV) by infusing it into a vein. The patient usually needs to visit an infusion center every four weeks to get Saphnelo. It can be difficult for someone with a busy lifestyle (work, family) to carve out time for a monthly infusion. Doctors are studying a self-injectible form.
The clinical trials did not study people with severe kidney inflammation (lupus nephritis) or severe involvement of the brain or spinal cord (CNS lupus). Therefore, we do not know if it works for them. This is contrary to Benlysta, which helps severe lupus nephritis.
However, patients with less severe lupus nephritis were allowed in the Saphnelo clinical trials (as long as their serum creatinine was less than 2.0 mg/dL, urine protein was less than 2 grams per 24 hours, and they did not require pulse IV steroids or cyclophosphamide). Many patients with lupus nephritis responded well to Saphnelo. AstraZeneca is currently conducting a lupus nephritis clinical trial using Saphnelo (anifrolumab).
Patients with CNS lupus could also participate as long as they did not require pulse IV steroids or cyclophosphamide.
Saphnelo has not been studied in pregnant or breastfeeding women.
Saphnelo is a very large molecule, unlikely to pass through the placenta into the fetus until the middle of the second trimester. Breast milk is unlikely to contain very much Saphnelo, and if there were any, the baby’s stomach would destroy any in the milk. Therefore, many rheumatologists consider that the advantages of continuing Saphnelo during the first 1 1/2 trimesters of pregnancy and during breastfeeding outweigh the potential risks. Talk to your doctor if you wish to become pregnant.
Read my blog post on having a successful pregnancy for SLE patients.
If you become pregnant while taking Saphnelo, please contact the pregnancy registry so we can track how well women and babies do. Call AstraZeneca at 1-877-693-9268.
Both drugs are much more expensive than the “older lupus drugs.”However, there is a huge difference in health care costs between SLE patients who are under good control and are off steroids compared to those who have active disease and on steroids. Since both Sapnelo and Benlysta are steroid-sparing agents, reduce disease activity better than the older therapies, reduce flares, and improve quality of life, the costs are most likely well worth it to the patient and to society.
Like Saphnelo, Benlysta (belimumab) targets one overactive section of the immune system in lupus. Lupus experts designed Benlysta specifically for lupus. Read my previous blog post on this topic of how Benlysta works.
Since Benlysta and Saphnelo each target a different area of the lupus overactive immune system, each may work better in some patients than in others. See below where I discuss how I plan on using Benlysta and Saphnelo in different types of lupus patients.
All three pivotal phase III clinical trials used the SRI-4 (SLE Responder Index-4) as their main research goal (called the primary endpoint). Each clinical trial evaluated every lupus patient at the end of the research study to see if they met the SRI-4 goal. An SRI-4 result had to include all three of the following:
Reducing the SLEDAI score by four points is difficult as the SLEDAI scoring system is virtually close to an “all or nothing” approach. For example, if someone had a lupus rash (2 points), all rash inflammation had to be completely gone at the end of the study to count for a 2-point reduction.
The Saphnelo TULIP-2 trial used the BICLA score instead of the SRI-4 as its primary endpoint. Lupus problems (such as a rash) had to improve in severity, rather than resolve completely, in order to count as a BICLA positive response.
The BICLA and the SRI-4 have their pros and cons. Neither system is proven to be a better research goal than the other (though I lean more towards liking the BICLA since it is more
sensitive to improvements in disease activity than SRI-4, and it looks at many more lupus problems than the SRI-4 does). The BICLA measures 97 different lupus problems while the SRI-4
only evaluates 24 problems.
Benlysta studies in patients taking it for as long as 13 years show that it is safe and effective. Doctors call these “long-term extension” trials. Benlysta has met its primary endpoints (main goal of the study) in more research studies than any other SLE drug, repeatedly proving its effectiveness and safety when assessing a large number of SLE patients.
Just like Saphnelo, Benlysta improved the quality of life. Approximately twice as many patients on Benlysta (plus the older lupus drugs) ended up with a better quality of life than those on placebo plus the older lupus drugs.
Benlysta is a steroid-sparing drug, just like Saphnelo (as discussed above). Benlysta did not have a “steroid-sparing effect” as a secondary endpoint (as Saphnelo had). However, in over five studies, Benlysta lowered steroid doses in lupus patients. Therefore, Benlysta is a steroid-sparing drug.
The three main phase 3 clinical trials for Benlysta showed that it decreases lupus flares. There was a 43% reduction in severe flares in the BLISS-52 study and a 49% reduction in the BLISS-SC study. Both were statistically significant. The BLISS-76 study had a numerical difference in reducing severe flares, but it did not reach statistical significance.
Lupus attacks the kidneys (lupus nephritis) in approximately 40% of systemic lupus patients and is a major cause of doing badly from lupus.
Benlysta made history in December 2020 by becoming the first FDA-approved drug for lupus nephritis. Patients with lupus nephritis had a 74% greater odds of having a complete renal response (remission or close to remission) when Benlysta was added to mycophenolate or cyclophosphamide plus steroids than patients treated with the older treatment regimens (mycophenolate or cyclophosphamide plus steroids without Benlysta).
Unfortunately, children get SLE. Children and teenagers tend to have more severe lupus than older people with SLE. 20% of SLE adults developed lupus when they were children or teenagers. We need more FDA-approved drugs for juvenile-onset lupus.
In 2019, Benlysta again made history by becoming the only drug FDA-approved to treat children as young as 5 years old with systemic lupus erythematosus using the IV form.
Lupus nephritis (kidney inflammation) affects most pediatric SLE patients and is a major cause of their not doing well. Fortunately, Benlysta was proven to work better for pediatric lupus nephritis patients when added to older drugs compared to using the older drugs by themselves. Therefore, in July 2022, the FDA-approved IV Benlysta for children (as young as 5 years old) with lupus nephritis. This truly is a remarkable achievement for our pediatric population, who suffer from such severe disease.
GlaxoSmithKline (the producer of Benlysta) showed in a 2023 study that the subcutaneous form of Benlysta worked well in pediatric patients. Therefore, GSK asked the FDA in early 2024 to approve the self-injectible form for children with SLE. I hope hit gets approved. This would be wonderful news to many very busy parents who currently have to take their child to an infusion center monthly.
In 2022, Dr. Urowitz et al. published a paper showing significant reductions in organ damage, including kidney damage, in lupus patients using Benlysta long term. The authors concluded that this means Benlysta can be a disease-modifying agent for lupus. A 2023 study showed that Benlysta, Saphnelo, and hydroxychloroquine are disease-modifying agents for SLE.
Then, a European League Against Rheumatism 2023 abstract showed that Benlysta continues to be a disease-modifying agent after more than 5-years of use.
Patients taking Benlysta plus the older lupus drugs were 60% less likely to have ongoing organ damage each year during a 7-year study period than patients taking the older lupus drugs (without Benlysta). This is excellent news. I have many patients on Benlysta who are doing very well and off steroids because of Benlysta. When they ask me if they can stop Benlysta or not, I point out this study.
I always like to put myself in a patient’s place when I give them advice. If I had systemic lupus erythematosus (SLE) and were doing well on Benlysta plus hydroxychloroquine, I would continue Benlysta with hydroxychloroquine to prevent organ damage.
The list of potential side effects from Benlysta is relatively short, as noted in the chart in the FDA-approved label showing those side effects that occurred in at least 3% of patients taking Benlysta plus the older lupus drugs and occurred at least 1% more frequently than placebo plus the older lupus drugs.
Important caveats are similar, as noted above in the Saphnelo section regarding the importance of realizing that all patients were on drugs other than Benlysta and placebo. For example, 0.7% of patients taking Benlysta stopped it because of infections, while 1.0% of those on placebo did. This does not mean that placebo caused more infections resulting in drug discontinuation. These patients were on other immunosuppressant drugs.
Remarkably, there were few side effects when one thinks about it.
Like Saphnelo, Benlysta does not need additional labs to monitor side effects.
Life Saphnelo, the IV form of Benlysta does not require premedications.
Like Saphnelo, Benlysta comes in an IV monthly form. However, patients can also inject it underneath the skin (subcutaneous, SC or SQ) at home. Patients inject Benlysta under the skin once weekly and is easy.
People who prefer that a professional (usually a nurse) administer the drug often choose the IV (intravenous) form over the SQ form.
I hope that the SQ form will become FDA-approved for children with SLE in 2024.
Neither form has been proven to be more effective than the other. Over many years, I have had many patients switch between IV and SQ Benlysta. Some on IV Benlysta start to flare a few days to a week before each infusion and prefer the weekly self-injections. Others state that a large, monthly IV dose works best for them (the IV form is based on body weight).
Proving that a drug works for lupus is extremely hard since every lupus patient is different. Most drugs studied for lupus fail to prove they work. Benlysta reached its main goal (called a primary endpoint) in all three phase-III clinical trials (BLISS-52, BLISS-76, and BLISS-SC). Benlysta has achieved its primary endpoint in more phase 3 clinical trials than any lupus drug. It has also been formally studied in more lupus patients than any other drug. These are amazing feats!
Benlysta has subsequently shown to be safe and effective in eight clinical trials! A very nice summary of these Benlysta research studies is in the journal “Lupus.”
Identifying what patients may respond best to a drug is an important goal. We usually have to use “trial and error” in most lupus patients, trying different medicines until we find the best combination. Doctors and patients often have to try multiple drug combinations before they figure this out. Not only can this be very expensive (up to tens of thousands of wasted dollars), but it results in undue patient suffering and a feeling of failure by the doctor who is trying their best to help the patient.
The Benlysta EMBRACE trial showed that patients with low C3, low C4, or a high anti-dsDNA level tended to be most likely to respond. Also, patients with the most severe disease tended to be more likely to respond than patients with milder disease. The EMBRACE trial also showed that Benlysta works well and is safe for people of African ancestry. This prompted the FDA to remove the statement to “use caution” when using Benlysta in African American patients.
When I have a lupus patient with severe fatigue, arthritis pain, and other lupus problems, if they also have these lab abnormalities, I usually recommend trying Benlysta. Most patients in this situation usually do much better, achieving more energy and less arthritis pain.
Note that anifrolumab (Saphnelo), just like belimumab (Benlysta) also works well in SLE patients with and without hypocomplementemia or high anti-dsDNA. However, when you look at groups of patients who have higher success rates compared to other groups, one of the groups of patients with a higher, relative success rate are those with active serologies (low complements, high anti-dsDNA) compared to those with inactive serologies (normal or high C3/C4 and normal anti-dsDNA). Nonetheless, many patients with normal serologies do fantastic on both drugs.
Read my blog post on having a successful pregnancy for SLE patients.
Benlysta was shown to be safe and effective during pregnancy in a March 2023 study and after an evaluation of the Benlysta Pregnancy Registry.
Note, this opinion is based upon the science and has not been formally accepted into the 2020 American College of Rheumatology Reproductive Guidelines. However, these guidelines were formulated before this data was available. When these Guidelines are updated, I’d be very surprised if Benlysta is not included among the list of safe drugs during pregnancy.
The Benlysta FDA-approved label recommends not taking it during pregnancy or breastfeeding because it was not studied formally in the clinical trials. Note that even if it becomes included in the list of safe drugs for pregnancy per the ACR Reproductive Guidelines, the label will most likely remain the same since pregnancy was not studied in the clinical trials. It is very hard to change FDA drug labels (package inserts) once published. One example is for men using methotrexate while trying to get their partner pregnant. The methotrexate package insert (published decades ago) still recommends that men stop taking it three months prior to conception. However, numerous studies prove it is safe to continue methotrexate, and the 2020 ACR Reproductive Guidelines specifically address this issue.
An ongoing pregnancy registry has kept track of pregnant Benlysta patients. Around the Spring of each year, the results are typically made public on how patients on Benlysta do when they get pregnant. In 2023, GSK handed over its pregnancy registry to the organization MotherToBaby. Combining their data should come up with larger, useful numbers and give us better insight into the use of Benlysta during pregnancy. I look forward to these results. If you become pregnant on Benlysta, please contact MotherToBaby at the link in the previous paragraph.
Biologics, like Benlysta, are large molecules. They do not cross the placenta and go into the fetus very much in the first two trimesters. Research shows that some biologics appear safe during the 1st two trimesters. On the other hand, undertreated, active lupus inflammation is dangerous for the baby and mother.
For a nice summary of pregnancy registry data of Benlysta in lupus patients, see the 2023 analysis by Dr. Michelle Petri, et al.
Benlysta molecules are large, and minuscule amounts enter breast milk. If any small amounts were to enter the baby’s digestive track, their stomach and intestines would destroy the drug. That is why we must give it by IV or SQ and cannot give it in pill form. Studies show that biologics are safe during breastfeeding.
Suppose a lupus patient wanted to breastfeed and needed to be on Benlysta. In that case, I would prescribe it if she understands that it has not been formally studied and is “off label.” However, having a healthy mother whose SLE is under good control is essential for the best care of the baby.
The two intravenous phase-3 clinical trials (BLISS-52 and BLISS-76) and a study called the BASE (Belimumab for Adults with active SLE) trial had an increased number of depression and suicidality events. The differences between Benlysta and placebo were not statistically significant, but there were numerical differences. Two people using IV Benlysta in the clinical trials committed suicide.
Interestingly, the BLISS-SC phase 3 clinical trial (using self-injectable Benlysta) did not increase depression or suicidality. However, people with major psychiatric problems did not participate in the research study.
Are depression and suicidality true side effects? I have prescribed Benlysta for many patients since 2011, I have had only one patient stop Benlysta for this possibility. If it does, it is a very uncommon side effect.
To illustrate this, the BASE trial (mentioned above) evaluated over 4000 patients. It compared patients using IV Benlysta (plus older drugs) vs IV placebo (plus older drugs) over a period of one year. There were around 2000 patients in each group. At the end of the study, 28 patients on Benlysta experienced suicidal thoughts. Yet, 23 patients on “placebo” had suicidal thoughts. There were no suicides in the study. This is only a difference of 5 patients out of a total of 4000 patients. This is a minuscule number. When one realizes that many SLE patients have significant depression (due to dealing with a chronic disease or possibly related to SLE affecting the central nervous system), it is not a surprise that some patients had suicidal thoughts.
If you are on Benlysta and have a history of major psychiatric issues, let your doctor know if you become more depressed.
SPECIAL NOTE: Because of the two suicides in the Benlysta phase 3 clinical trials, the FDA has mandated that patients with significant psychiatric disorders, depression, and suicidality are unable to participate in future SLE clinical trials. This is important to note because other drugs (such as Saphnelo) cannot boast that they do not cause suicidality. Patients who are at high risk are not even allowed in their studies. (One must know these fine details when comparing these sorts of side effects).
As with Saphnelo, people with severe CNS (brain and spinal cord) lupus did not participate in the clinical trials. Therefore, we do not know how they will do when treated with Benlysta.
Many African Americans have been hesitant about using Benlysta for their SLE. This is partly due to the FDA requiring the following statement on the Benlysta package insert: “In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies. Use with caution in black/African-American patients.]”
In my opinion, they are both a “Best Medicine for Lupus.”
When added to the older lupus drugs, they lower disease activity, pain, and fatigue, while improving quality of life. They also are well tolerated by most patients with few major side effects.
Both Saphnelo and Benlysta are excellent drugs. Both can be used right away if hydroxychloroquine does not achieve remission quickly or if patients are unable to get off steroids (per the EULAR management guidelines).
Saphnelo can work incredibly fast. The first patient I put on Saphnelo had severe skin lupus. Two weeks after her infusion, all her skin inflammation was gone. Therefore, in patients with particularly bothersome SLE problems (severe arthritis pain, disabling fatigue, severe rash), I’ll offer then Saphnelo in the hopes that if it works, it could potentially occur sooner than later.
However, I always leave the decision up to the patient. Suppose an SLE patient requires something besides hydroxychloroquine to better control their lupus. In that case, I discuss the options: mycophenolate, methotrexate, azathioprine, Benlysta, and now Saphnelo. I present the pros and cons and leave it up to the patient.
One deal breaker is IV infusions vs. self-injectibles. People with very busy lives (work, family, etc) can find it difficult to visit an infusion center monthly to get Saphnelo (it does not come in a self-injectable form). These patients often will choose Benlsyta for its convenience. (Note that AstraZeneca is studying Saphnelo in a SQ form at this moment).
However, the insurance companies have the last say. Some will cover the IV form and not the SQ form (especially Medicare and Medicaid act this way). Others prefer SQ over IV and, therefore, want their members to use Benlysta.
Both should not be used for severe CNS lupus
Both drugs are fantastic choices for lupus patients, and both are a candidate for “Best Medicine for Lupus.” The future is becoming brighter for patients suffering from lupus.
If you have taken Benlysta or Saphnelo for lupus, what has your experience been? What do you recommend for other patients?
Do you have any questions to ask Dr. Thomas?
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Donald Thomas, MD, author of The Lupus Encyclopedia
To learn all about Saphnelo in detail, read my previous post.
Read about Benlysta here.
Dr. Thomas is on the Speakers’ Bureaus of GSK (producer of Benlysta) and AstraZeneca (producer of Saphnelo). The views expressed in this blog post are solely my own. I am not writing this post as an agent or representative of GSK or AstraZeneca.
Do not accept this information as direct medical advice. Only your doctor can help you decide the best treatments for your condition.
Read more in The Lupus Encyclopedia, edition 2
Look up your symptoms, conditions, and medications in the Index of The Lupus Encyclopedia
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If you have lupus, what has your experience been? What do you recommend for other patients?
Do you have any questions to ask Dr. Thomas?
Please click on “Leave a Comment” above to comment.
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You mention Saphnelo being effective for those with ‘high interferon levels.’ Would testing for those help decide which infusion would be a better choice? And if so, which specific lab test would be most helpful?
Also, since the drugs target lupus in different ways, could they be used concurrently?
ARW: You as the million dollar questions! Doctors regularly ask these questions during lectures about Saphnelo.
The studies showed that Saphnelo worked in patients in what we call “high interferon gene signatures” as well as in those with low levels. However, they response was numerically higher in those with high levels. We are unable to measure these at this current time in clinical practice. I suspect this will be a future possibility to help with these decisions.
We are hesitant to use two biologics together since previous biologic combination treatments have shown increased infections. We’d have to show a study to show if it is safe or not.
Thanks for your questions.
Donald Thomas, MD
I’ve been on Plaquenil for a few years, and then all within six months I started Imuran, Benlysta, and IVIG. Seems like quite a bit of medication for a previously healthy 30-year-old, and in the back of my mind I’m always wondering, ‘What’s next? What will I do if even all of this together isn’t effective enough?’
I have been receiving benlysta via IV for about 14 months. I felt remarkably better after about 3 months. Now I seldom have pain or skin rashes. When I do get a skin rash it is very mild, no way as severe as they used to be before benlysta and often the rash just goes away on its own or with a very low dose of prednisone (2.5 mg per day or every other day). I was on 500mg of cellcept too during the transition to benlysta for a few months while reducing prednisone. I also take 200mg plaquenil. For me benlysta is a life saver.
Hello. I was only able to tolerate Benlysta for 1 month (4 injections, once weekly) and had to stop due to side-effects such as worsening diarrhea, headache, severe joint pain and body aches which occurred approximately 24 hours after each injection, severe fatigue for approximately 24 hours, feeling feverish and skin issues such as itching and pain. My butterfly rash became very prominent. I also take hydroxychloroquine. Not totally sure if the above side-effects where due to Benlysta but that was the only new medication introduced.
Thanks
I was diagnosed in late 2020 after presenting with neurological symptoms (severe headaches, trigeminal neuralgia and RCVS),levido reticularis and raynaud’s. I had +ANA, +cardiolipin antibodies, +SCL-70 ab and low C4. I was started on hydroxychloroquine and prednisone in December 2020. My rheumatologist then added Rituximab due to vasculitis. I underwent microvascular decompression surgery for TN which improved greatly but did not resolve the issues. I continued with severe joint pains and was started on MTX. I took for 3 months but stopped due to severe S/Es. I continued on Rituximab which was helping to prevent flares. 5 months after Rituximab, I started to develop debilitating fatigue, hair loss, severe joint aches, oral ulcers and worsening vascular issues including neurological symptoms. I was started on Azathioprine and switched to Rituximab q 3 months instead of q 6. I became neutropenic so aza was stopped and I was switched to MMF. I have been on high dose steroids on and off and have never been able to get off of them without worsening of symptoms.
I am also on IVIG for IgG deficiency every 6 weeks. In May, I developed chest pain and shortness of breath and was found to have a pericardial effusion and pericarditis. My rheumatologist has recommended I switch to Saphnelo and stop Rituximab. She did not recommend Benlysta because it basically works via same pathway as Rituximab and she feels its not the best option for me and I agree. I have done some research on both medications. I am an oncology NP and try my best to do research and make sure I am making the best possible decisions with my doctors. I continue on all other SLE medications. My insurance is denying authorization for Saphnelo because I am on IVIG. Is there a specific reason this is not allowed? I do not get IVIG for SLE (although, I found it has helped my lower extremity weakness SIGNIFICANTLY). IVIG has spared me from recurrent infections which were mostly upper/lower respiratory infections even on prophylactic antibiotics. Any insight would be greatly appreciated.
So sorry to hear that, especially with all the difficulties you have been through. There is absolutely no contraindication between using Saphnelo and IVIG. That makes no sense whatsoever. Also, I would give up on Benlysta in the future. I have patients doing great on Benlysta who had failed Rituxan (Rituxan was available before we had Benlysta). They work to interfere with B-cells at very different times in B-cell and plasma cell development. I sure hope your insurance comes around. I suspect an appeals letter and a talk to the medical director of the insurance company would straighten things out.
Donald Thomas, MD
First off, I can’t thank you enough for providing such a wealth of information about these drugs in a format that’s easy to understand!
I’m currently on week 5 of Benlysta self-injections, and I haven’t noticed an improvement in my symptoms yet (waiting for the 3-mo. mark).
I am curious, though, about which medication you would lean toward in a patient with these antibodies/labs:
– anti-Ro, anti-SSA, anti-La, anti-SSB
– decreased C3 & C4
– hypergammaglobulinemia
– leukopenia
Knowing that there is the potential for either Benlysta or Saphnelo to help a patient with these characteristics, what would be your approach?
Thanks again for sharing, it’s fascinating to learn more about biologics.
Olivia: Thanks for your kind words. It is amazing we have the capacity to help people via the internet.
Benlysta would be one of my drugs of choice. In the clinical trials, patients who had hypocomplementemia (low C3 and C4) especially had a better chance of responding.
Here is a link to a study about it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099508/
Regarding it working… it is very slow. You really have to give it 6 mo to a year and usually it is very gradual. I commonly hear at 3- 6 months “I think I’m feeling better, I might have more energy” … then by a year is when they truly know if it is working or not. I hope it does a great job for you.
Donald Thomas, MD
I’m a refractory SLE patient whose tried just about everything. I did 5 months of IV Benlysta and went off of it because I was severely depressed (and it wasn’t helping). Now I’ve been on Saphnelo for 6 months, which has helped greatly with severe ulcers and hair loss. Overall I’m doing better, but I still have fatigue, psychiatric issues, and joint pains (mild compared to what I used to experience). It’s enough to keep me on disability and from returning to work.
Interally I have kidney involvement and some CNS involvement (migraines, psychiatric issues) and I have positive DSDNA, anti-Smith, and anti-RNP. I also have positive anti-neuronal cell antibodies. My kidneys are in a partial remission, but all the mentioned antibodies are still high.
Would it be better to try out the injectable Benlysta and stop Saphnelo? I’m concerned about my ulcers and hair loss coming back, but I also want to get the rest of my disease under control. I wish I could take both, since they seem to help with different things.
Mary: That is a question that only your rheumatologist could answer (as they know your entire history). I can say that in the clinical trials, there were increasing improvements in patients over time. So, one option is to continue your regimen and see if you continue to improve (I usually tell patients to give it a year).
Certainly, the other option is switching to Benlysta SQ.
I hope you continue to get better.
Donald Thomas, MD
What about when both Benlysta and Saphnelo fail to bring the C3, C4, and ds-dna antibodies under control. Where do you turn next? I am already on hydroxychloroquine, imuran, and IVIG along with the Benlysta currently. Wondering whether a different infusion, like Rituximab, would be worth considering.
ARW: Sorry, just saw your comment. Our goal is not to bring the C3, C4, and anti-dsDNA under control (though we do like to see them improve). What I mean by that is we want to control the active inflammatory disease (rash, kidney inflammation, joint inflammation) and usually these markers also improve, which is reassuring.
If someone fails BEL, SAP, HCQ, Imuran, IVIG, then other therapies I also consider are methotrexate, mycophenolate, leflunomide, tacrolimus, sirolimus, and rituximab.
Make sure your vit D level is around 40 ng/mL and your HCQ drug level is at 1000 – 1200 ng/mL = often missed easy things to check on and not always done. Ensuring the proper doses of vitamin D and HCQ are very important
Donald Thomas, MD
I am a lupus patient in remission for the last 4 years without medication. The main problem I ever had was hemolytic anemia that would leave me with very low blood counts and they never got quite to normal, despite transfusions and erythropoietin and Benlysta infusions for a couple of years. I was on a maintenance dose of 5 mg of prednisone for more years. Sorry to be another hack promoting natural cures, but going vegan and cutting out all sweeteners and most processed foods is what worked for me, even calmed my heart way down.
Martha: that is not at all a “hack!” I wish all my patients approached treatment from all sides: meds to calm down the immune system, eating an anti-inflammatory diet (like vegan, getting rid of processed foods etc), exercising, not smoke, avoid pollution, do strict UV protection, getting enough sleep. If I have 5 patients with exactly the same disease problems, and one does all of these things while the others only do one or two… the first will almost always do best.
Thanks for your important comment.
Donald Thomas, MD
I tried Benlysta for 4months and developed crushing insomnia ( great solid sleeper until this). Now off the drug and just in plaquenil and MTX. Would Sephnelo be a good choice or would it have similar adverse reactions. I am ANA, autoantibody negative but skin biopsy positive with very low C3,C4, migratory arthritis, muscle pain and stiffness,fevers, rashes, mouth ulcers and fatigue. MTX works well for some of these in long stretches but still have debilitating flares of fever fatigue pain and rashes requiring steroid bursts several times a year.
Edie: Interesting you mention the insomnia. I have seen it quite a few times and am convinced that it is a potential side effect from Benlysta in a few patients.
I have never seen this with Saphnelo, though. If a patient fails Benlysta (works best in B cell-driven disease), then I try Saphnelo (which theoretically should work better in interferon type I-driven disease). Saphnelo also appears to work better in patients with low C3/C4, rash and fatigue…. good luck, I hope your docs find the best therapy for you.
I wish we had a way to predict which med to try in which patient.
Donald Thomas, MD
Hello!
I hope you don’t mind me popping in to reply on another’s comment, but I was hoping for you to explain where you mentioned that Saphnelo appears to work better in patients with low c3/c4, etc. In the blog post and in another comment, you mention and reference studies that show Benlysta may work better for those with hypocomplementemia. Do both work well for that? I’m reading and doing my research about them and I want to make the best choice on which may be best to try first. I’m following my rheumatologist’s advice, but I also want to be well informed. For reference, I have low c3/c4 and high anti-dsDNA, so that’s why I’m curious about the conflicting comments!
Thanks!
Aly: Both belimumab and anifrolumab work well in many SLE patients with and without hypocomplementemia. However, when you look at groups of patients who have higher success rates compared to other groups, one of those is those with active serologies (low complements, high anti-dsDNA) compared to those with inactive serologies (normal or high C3/C4 and normal anti-dsDNA).
I should reword it better as they both work well in this group of patients
Good luck with your treatment!
Donald Thomas, MD
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