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As research laboratories across the world investigate new lupus treatments, efforts increasingly focus on suppressing B-cell activity. B-cells are major actors in the normal immune response. With lupus, the immune response is not normal and neither is the behavior of B-Cells. During an active disease phase, the immune system attacks organs and wreaks havoc. B-cells play an important role in this process.
Historically, lupus medicines have sought to control the aberrant immune response by tamping down the entire immune system. Established remedies (for example: glucocorticoids and cyclophosphamide) are not very specific in suppressing the immune system. Instead of acting on the parts of the system that are especially aggressive, older medicines depress the general immune response. While this approach is often effective in controlling symptoms, it can sometimes have a devastating impact on the overall health of the patient.
An analogy to the traditional approach might be found in the case of a broken light switch. In order to repair the switch, an electrician could shut down all the circuits in a house. This certainly would insure that electricity isn’t flowing to the broken switch–it would also insure that electricity isn’t flowing anywhere else in the house, either. A total shutdown might have far-reaching consequences–melting ice cream, for instance. However, if the electrician decided to shut off only the circuit associated with the broken switch–that is, if she/he targeted the problem area–disruption in the household would be minimized.
That’s the principle behind targeted B-cell suppression. If only B-cells are affected, the impact on the patient might not be as widespread as it would be if an older generation, immune-suppressant drugs were administered.
The problem with new generation, B-cell-targeting drugs is that, so far, they haven’t proven to be very effective. This is the case with belumimab and rituximab. While both of these drugs are prescribed at present and do help people in certain situations, neither has lived up to its early promise.
Epratuzumab is a B-cell-targeting drug with a difference. This drug doesn’t try to suppress all B-cell activity. It is designed to address only a specific part of the B-cell: CD-22, which is on the surface of the cell.
It is believed that a major benefit of epratuzumab over other B-cell-targeting drugs may be that it does not depopulate all of the B-cells in the course of treatment. It seems that epratuzumab only eliminates “up to 45% of circulating B-cells“. Rituximab, on the other hand, eliminates greater than 90% of circulating B-cells. Since B-cells are essential for a robust immune response, wiping these cells out increases the risk of infection. Keeping viable B-cells might help to limit that risk.
Epratuzumab has gone through Phases I and Phase II clinical trials. Phase III is currently underway. A January 2013 article published in the Annals of Rheumatology describes the drug as promising. The journal reports that epratuzumab was well tolerated by study participants, even at high doses (2400 mg. week); also, the journal reports, trial subjects who received the medication experienced better outcomes than the control group that received placebo.
In February 2015 Euroscan (a European evaluating organization) issued a report on the safety of epratuzumab and side effects experienced by study subjects. Side effects were noted to have occurred as follows: 10% experienced conjunctivitis; 45% upper respiratory infections; 28% diarrhea and 28% headache; 14% experienced migraine and 34% caught a cold; 24% experienced nausea; 24% had bronchitis; dizziness was reported by 10%; 10% ran a fever; sinusitis was reported in 31%; abdominal pain occurred in 31%; 10% had chest pain; 10 % had a cough.
Phase III of the epratuzumab clinical trial has 1400 participants; these patients have moderate to severe SLE. The final report on Phase III will be issued in 2019. The drug’s manufacturer, UCB and Immunomedics is optimistic, based on the results of Phase I and Phase II. UCB reports that study participants who received epratuzumab showed a “24.9% treatment advantage over placebo”.
Will epratuzumab be a ‘magic bullet’ for lupus patients? A lot of people certainly hope so. Clinical trials and actual practice will prove whether or not this hope is misplaced.
In September of 2012 I posted a blog about a biologic, Rituximab. Some researchers had hoped this medication would prove to be an effective treatment for SLE. Unfortunately, Rituximab did not live up to expectations. However, the drug has been used to treat SLE in rescue situations. As such, it is tried when other options have failed. In many of these cases, Rituximab has been effective, especially when used along with other drugs.
Even though clinical trials of Rituximab have not yielded promising results, investigation continues to see if it might be useful as part of a regimen with other lupus treatments. As experience with Rituximab accumulates–in doctors’ practices and in trials–data is collected about potential side effects. It is important for physicians and patients to be alert to these so that prompt action may be taken, if necessary.
A 2015 Hindawi Journal article reports a case of early-onset neutropenia and thrombocytopenia that was associated with the administration of Rituximab. The patient’s treating physicians entertained the possibility that these conditions may not have been caused by Rituximab but may have been a manifestation of SLE. This analysis was rejected because the patient’s clinical profile did not support the conclusion.
This case of early-onset neutropenia and thrombocytopenia associated with Rituximab is unusual, if not unique. The authors of the Hindawi article contemplate the possibility that the side effects may have also occurred in other cases but were not detected.
In any event, both neutropenia and thrombocytopenia were transient in this case. The conditions cleared up 12 days after Rituximab therapy stopped.
A risk of neutropenia is infection; a risk of thrombocytopenia is bleeding.
One thing that should be remembered as side effects of Rituximab are discussed: the medicine is used for very sick people, people who may not have many other options. Side effects will likely not be a reason to avoid treatment, but being aware of those side effects may help to keep the patient safe while treatment proceeds.
By A. G. Moore 11/23/2013 Edward Jenner injecting James Phipps, his gardener's son, with cowpox Lithograph by Gaston Melengue Wikimedia Commons, public domain, Copyright expired
Sixty years ago, when Flannery O’Connor learned she had lupus, one medication was available to treat her disease: hydrocortisone. Twenty years before her diagnosis, Edward O’Connor, her father, learned that he had lupus. For him there was no treatment. Times have changed since Flannery and her father battled lupus. Today the list of treatment options is long. These options exist because researchers have worked tirelessly to solve the lupus puzzle and because they were aided in their efforts by the participation of countless lupus patients in clinical trials. While much of the work researchers do takes place in the laboratory, the proving ground for their investment is the clinical trial. Currently there are clinical trials underway that are exploring new theories in lupus therapy. One of these theories has been described by Dr. Timothy Niewold, who is a scientist affiliated with the Mayo Clinic. Dr. Niewold is investigating the role of interferon in lupus. There is clear evidence that in some people levels of interferon rise with disease activity. In certain instances, lupus has actually been precipitated by administration of interferon (for an unrelated illness). With the apparent association between interferon levels and lupus, it has been suggested that decreasing interferon production might temper symptoms of the disease. Drugs are being designed that are supposed to do just that. Targeting interferon is one example of the trend in lupus treatment to zero in on specific components of the immune response–rather than suppressing the entire immune system. When Flannery O’Connor was prescribed hydrocortisone, the drug was effective because it stopped her immune system from attacking her organs. However, shutting down the whole immune system is a rather blunt way of dealing with autoimmunity. It’s kind of like trying to weed the front lawn with a scythe; maybe the job gets done, but a whole lot of grass and flowers are sacrificed in the process. Shutting down the immune system can have devastating consequences. It is hoped that by targeting specific actors in the system, treatment may not only be more effective but may have less dramatic side effects. One of the interferon-targeting drugs currently under investigation is sifalimumab. Dr. Niewold (of the Mayo Clinic) explains that an important aspect of research on interferon-targeting medications is understanding how this cytokine acts in people from different ethnic backgrounds. As sifalimumab goes through its different trials, it is becoming clear that interferon does not have equal significance for all ethnic groups. For example, interferon activation in African American SLE patients is dependent on the presence of autoantibodies; this is not true for European Americans. Dr. Niewold states: “This heterogeneity may be clinically important, as therapeutics targeting this pathway are being developed.” Targeting specific aspects of the immune system is the theory behind the development of other lupus therapies. B and T cells, for example, are known to be very aggressive in active lupus. Belimumab , currently prescribed for certain types of lupus, targets B cells and Abatacept, which is an RA drug under consideration for lupus, targets T cells. Both drugs are currently in clinical trials. Clinical trials are essential if new therapies are to come on the market. They also may be of help to those who volunteer as subjects, because there is possibly the opportunity to receive novel and effective treatment. However, every person who volunteers as a subject should be clear about the goals of the study for which they have been recruited. Not every study has as a primary endpoint improvement in participants’ disease status. Some studies examine other aspects of drug development. Volunteers should never lose sight of the fact that participation may carry with it significant risks. One research paper I came across illustrates the importance of being informed before becoming a volunteer. This paper gives the results of a clinical trial in which sifalimumab was studied. The primary purpose of the trial is described: “..to evaluate the safety and tolerability of multiple doses of intravenous (IV) sifalimumab in patients with moderate-to-severe SLE.” Secondary objectives of the trial are also described: “..to evaluate the PK (Pharmacokinetics) and immunogenicity” of the drug. Only as a third and almost incidental objective is observation of the effect sifalimumab has on disease activity. The research paper describes this third objective in the following words: “…measurements of disease activity…were included only as an exploratory end point… ” The clinical trial described by this research paper has obvious significance for lupus treatment; finding out dose tolerance and learning about adverse side effects are important pieces in the development of a possibly valuable lupus intervention. However, these are findings that have general importance and likely will not immediately benefit study participants. It does not seem that those who conducted the study expected subjects in the clinical trial to experience sustained improvement in disease status; that was not the study’s defined prime objective. This leads me to repeat the following: if you are considering being a volunteer in a clinical trial, make sure you understand what it is that the researchers hope to learn from that trial. Does the trial offer participants an opportunity to reap the benefits of new lupus treatment, or are participants merely being mined, as it were, for information that may contribute some day to a good lupus intervention? Know that there are risks associated with participation. In the study described above, for example, some participants did die. Whether or not these deaths were attributable to sifalimumab is not certain, though, as the paper states, for at least two of the deaths, “… a potential role of the drug in contributing to the infection cannot be excluded.” Without clinical trials there cannot be new drugs to treat lupus. Volunteers for these trials are essential if the trials are to succeed. However, if you choose to become a subject, be clear about what it is you are submitting to. And then, if you are satisfied with the risk/reward ratio, go for it. You and everyone else with lupus may benefit.
What is Lupus?
By A. G. Moore
Autoimmune disease: auto, from the Greek, means self (as in automobile: a self-moving vehicle). An autoimmune reaction, in which the body essentially makes itself sick, can be as simple as a rash induced by contact with poison ivy, or a full-blown case of systemic lupus.
The analogy to a car is helpful here: a car (automobile) operates automatically only in the sense that someone turns it on, turns it off and directs its path. However, from time to time reports appear in the newspapers of cars that are out of control—cars that somehow accelerate on their own or fail to respond to instructions to stop, or turn. These automobiles, instead of being dutiful and useful servants, become dangerous agents. This is sort of what happens in an autoimmune disease.
The immune system exists to protect the body. A complex set of interactions go into operation when the body is under assault. The system includes the ability to surround and consume an alien entity (such as bacteria). The trigger—or ignition, if comparing it to a car—for the immune system to go into action is an external threat. In a healthy individual, when the threat is removed the immune system becomes quiet.
However, when autoimmune disease takes hold, the immune system goes haywire, like a car out of control. It starts attacking things that aren’t foreign because it sees healthy tissue as an enemy. In lupus, the attacking immune cells can go after just about anything—the lungs, heart, blood, brain, etc.
The mystery of why this happens is only vaguely understood. Some of the triggers that set off the autoimmune attack have been identified—Espstein-Barr and UV exposure, for example. But on the whole, the autoimmune syndrome that is at the heart of lupus remains a mystery. Once this mystery is solved, then a cure, or even a way of preventing the disease, may be found.
Right now, medicine can offer people who have lupus only one thing: possible control of their symptoms. In most cases this is achievable, though sometimes at great cost.
Lupus can be very resistant to treatment. Since it is still a mystery and since the remedies for the disease are diverse and variably effective, it makes sense that someone with lupus find the smartest, most skilled physician available to treat their disease. Only a doctor with insight, experience and top-notch training should be enlisted in the war against lupus, an obstinate and potentially fatal autoimmune illness.
By A. G. Moore
One of the first medications a lupus patient may be offered is Plaquenil. While every drug has side effects, Plaquenil is generally considered to be “safer” than many other medicines prescribed to treat lupus.
Researchers are finding out more about this drug all the time; the current state of science indicates that Plaquenil is effective against lupus, and some other inflammatory diseases, because it creates an inhospitable environment for some actors in the immune process. In this way Plaquenil inhibits the immune response and thus also inhibits inflammation.
Though Plaquenil is considered to be relatively “safe”, there are several populations in whom great care should be taken before the medicine is prescribed. If you are over the age of 60, the chance for retinal damage increases. If you have psoriasis or porphyria, taking this drug may exacerbate your condition. Anyone with reduced liver or kidney function should also consider carefully if the risks of the drugs outweigh its benefits. Plaquenil can be extremely dangerous for children, especially children under the age of 6. People who have a metabolic disorder called G6PD run the risk of developing severe anemia on Plaquenil therapy.
The most commonly addressed side effect of Plaquenil therapy is retinal damage. Every responsible opinion I have read prescribes a visual screening before therapy begins and then a re-check several weeks later. While it is rare for eye damage to occur, especially if therapy lasts less than five years, it is important to keep in mind that once damage occurs, it is most likely irreversible. And the changes in the retina may not be noticed subjectively but can be detected by sophisticated testing in the ophthalmologist’s office. Many doctors recommend a yearly check-up; some recommend six months. If I were on Plaquenil I would go for six months because I’d like to detect damage before it goes very far.
With all of the warnings listed above (this is just a partial list of possible side effects) it would seem that Plaquenil is a dreadful drug. It really isn’t for most people. Lupus is a dreadful disease and sometimes you have to take out a big gun to control it. Plaquenil is actually one of the smaller guns in the arsenal against lupus.
Originally used as a treatment for malaria, Plaquenil is useful not only in treating SLE (though not severe SLE), but also other inflammatory diseases. The drug is supposed to be particularly effective at treating discoid lupus.
All of the sources I consulted implicate higher-dose and longer-term Plaquenil treatment in increased risk of eye damage. So if you are on Plaquenil for many years, certainly as many as 8, your doctor might begin a conversation with you about switching to an alternative treatment.
Several helpful sources I used in order to get information for this article were:
Plaquenil Data Sheet: http://www.medsafe.govt.nz/profs/datasheet/p/Plaqueniltab.pdf
I think anybody contemplating taking this medication should read and understand each of these sources. In making this recommendation I am operating on the theory that, though we may not know everything the doctor knows, we always should be vigilant in supervising our own medical care.
By A. G. Moore
This isn’t about basketball or hair management; this is about autoimmunity. It seems that one of the latest cuplrits to be discovered in the search for lupus antagonists is something called the neutrophil extracellular trap(see http://www.jimmunol.org/content/187/1/538.short). Neutophils are the most plentiful disease-fighting cells in the immune system. The role of neutrophils is to attack and kill invading organisms. These highly motivated soldiers in the immune system’s army are willing to commit suicide in order to fulfill their mission. They do this by releasing chemicals between the cells. The chemicals from different neutrophils join together and form a trap, which serves as a kind of net to capture and destroy pathogens. In order to release enough of the deadly material to be effective, the neutrophil has to deplete its own supply and die. It does so willingly.
Unfortunately, this ally of the body, in waging war, sometimes does damage to the very organism it seeks to protect. When the NETs (neutrophil extracelluar traps) are floating around in the bloodstream they can cause inflammation.
The discovery of the role that NETs play in the development of inflammation is very important to understanding the mechanism which precipitates lupus flares. The more researchers understand this process, the closer they get to thwarting the process. Not only may it be possible to design better therapies so that many of the damaging effects of lupus can be avoided; it may also be possible, with an understanding of the role that NETs play in inflammation, to find a cure and maybe even prevent lupus.
By A. G. Moore
This week I read several posts on Lupus UK which addressed the question of whether Quinoric was as effective as Plaquenil in treating lupus. Several people on the site suggested that the only difference between the two drugs was in the “filler” added to the active ingredient, hydroxychloroquine. And several people added that their pharmacist, or doctor, had assured them the preparations were “identical”. Which suggests to me a larger issue: are generics and substitute formulations for established drugs truly “identical” in formulation and do they behave identically when consumed?
In an effort to examine the interchangeability of generics for established drugs, I took a close look at Plaquenil and Quinoric. Are these two “identical”? Can one drug be substituted seamlessly for the other? I found a list of constituent ingredients for each of these drugs so I could make a comparison.
Both drugs, I discovered, do contain the same active ingredient in equal quantity: 200 mgs of hydroxychloroquine. The differences between the drugs, as some people suspected, is in the “fillers”. So I looked at those “fillers”.
Plaquenil (Manufacturer Sanofi. List derived from:http://www.drugs.com/pro/plaquenil.html)
Calcium Phosphate, Dibasic, Anhydrous
Polyethylene glycol 400
Quinoric (Manufacturer Bristol Labs. List derived from
Calcium Hydrogen Phosphate dihydrate
Colloidal anhydrous silica
While the two lists of constituent ingredients are similar, they certainly are not the same. But the question remains, do these differences matter? I took a look at one ingredient that appears to be almost identical.: PEG.
On the Plaquenil list PEG (Polyethylene glycol) is described as Polyethylene glycol 400. On the Quinoric list PEG comes in a different formulation: Macrogol 6000. In industry, these two forms of PEG have different uses because they interact with environments differently. One, Macrogol 6000, is commonly used as a laxative, among other things. The other, Polyethylene glycol 400, has a lower molecular weight and is more liquid: this chemical is often used in printer ink, as well as in pharmaceuticl preparations. It’s impossible for me to say if these two forms of PEG are processed identically in the human body.
There’s one “filler” included on the list for Quinoric which is not included on the list for Plaquenil: silica (Colloidal anydrous silica). Silica is abundant in the environment. This compound has been linked to a numboer of autimmune diseases. Whether inhaled, absorbed through the skin or ingested orally, silica has a well-established association with lupus and rheumatoid arthritis, among other other inflammatory conditions. Silica is almost ubiquitous. It’s in soaps, cleaning products, paints and other common household items. Some sources that discuss silica’s role in autoimmunity are: http://ntp.niehs.nih.gov/NTP/Noms/Support_Docs
So, I ask, what is silica doing in a preparation that’s prescribed for people who have lupus?
There is a pat response to this and other questions I raise in this essay: these substances are harmless, they are inactive and largely inert. They serve merely as vehicles for delivery of crucial medication.
I’m going to refute these glib reassurances by turning to Dr. Phil Lieberman of the American Academy of Asthma, Allergy & Immunology. Dr. Liebermans is asked about an adverse reaction a patient had to one constituent ingredient in Quinoric: Macrolog 6000. The doctor responds: “..it is best to try and avoid polyethylene glycol as carefully as possible. This is a difficult task given the ubiquitous nature of these substances, but it is clearly the safest strategy to employ.”( see: http://www.aaaai.org/ask-the-expert/anaphylaxis-to-polyethylene-glycol.aspx ).
I’m not a chemist, pharmacist or doctor. But I do know what the word identical means. And I do know that when there is a change in formulation—say from PEG 400 to Macrolog 6000—it’s because one formulation behaves differently from another. And if two substances are not the same, then they are not the same.
Plaquenil and Quinoric are prescribed for a very particular population, a population of people who have heightened immune responses. Allergies, even rare allergies, are common in this population. Extreme caution should be taken when introducing any new element into the environment of someone with such a heightened and unpredictable response to potential antagonists.
Plaquenil and Quinoric are not identical; they may not be absorbed the same into the bloodstream, or processed in exactly the same way by the digestive system. There may be constituent ingredients that are irritating in one and not the other.
This issue is not unique to Plaquenil and Quinoric; the issue of interchangeability between knock-off drugs and brand name drugs is one that affects every single person who has to take medicine: that is, all of us. Glib rejoinders that medicines are “identical” do not address the matter. More honest would be an admission that there are differences in manufacturing and processing between knock-offs and brand drugs. For most people, in most cases, these differences may have no consequence. However, there’s no telling how a particular formulation will be tolerated by a particular individual.
This is the truth—perhaps not convenient, but nonetheless true. And truth is something every patient has a right to expect from a medical provider.