We are pleased to introduce Kanneboyina Nagaraju, DVM, MVSc, PhD. Dr. Nagaraju is a professor and founding chair of the department of pharmaceutical sciences at the school of pharmacy and pharmaceutical sciences at SUNY-Binghamton University in Upstate New York. A member of TMA's Medical Advisory Board, Dr. Nagaraju is an immunologist with expertise in translational research in autoimmune and genetic muscle diseases. His current work includes development of an alternative steroid compound that is highly effective at decreasing inflammation without the challenging side effects seen with prednisone. Thank you for joining us today, Dr. Nagaraju.Ask a Question
Clinical Trial UpdatesParticipant:
How soon can we get this alternative steroid compound??? I have been on 1500mg Cellcept, (only to now be turned down by my Aetna insurance as they told me it is not FDA approved for this disease) and 5 mg of prednisone. I am a very active person and am refusing to let this disease get me down.Kanneboyina Nagaraju, DVM, MVSc, PhD:
Clinical trials for the alternate steroid compound (Vamorolone) in children with Duchenne Muscular Dystrophy are currently ongoing. We will come to know whether Vamorolone is effective or not in kids with DMD in the latter half of 2018. Please check for clinical trial updates on the Reveragen Website (http://www.reveragen.com).
LDN and Muscle RegenerationParticipant:
Has there been any attention paid to the use of LDN or low-dose Naltrexone to stimulate the immune system in order to halt or help to regenerate muscle tissue for IBM? LDN has been shown to improve the conditions of MS sufferers.Kanneboyina Nagaraju, DVM, MVSc, PhD:
I am not aware of studies investigating effect of LDN on skeletal muscle regeneration in myositis. Clinical data supporting its effectiveness in chronic inflammatory diseases is very preliminary and needs to be validated before this treatment is recommended.
Autoantibody Locations in the BodyParticipant:
In IBM, do autoantibodies exist in all muscles of the body or in specific locations?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Autoantibodies circulate in the blood and are present throughout the body. We don’t know whether they cause any damage to specific muscle groups.
DM Without AntibodiesParticipant:
What does it tell us if we do not test positive for any known antibodies, but are diagnosed with DM through a muscle biopsy?Kanneboyina Nagaraju, DVM, MVSc, PhD:
It is not uncommon not to have autoantibodies in myositis patients. For example only 50% of PM and DM patients have myositis-specific autoantibodies. This means the other 50% of patients either have no autoantibodies or may have autoantibodies for something else that we haven’t discovered yet. New autoantibodies are being discovered regularly. It is likely that some of the patients who are negative today may be positive for new autoantibodies yet to be discovered.
TIF-1 Autoantibodies and CancerParticipant:
There is accumulating evidence of the strong correlation between diagnosis of various malignancies in PM and DM patients and the presence of the p150/144 (TIF-1) auto-antibody (percentage of patients who test positive varies by ethnicity and type of assay used to test for the presence of this antibody). Some subtypes of DM seem to have an even higher risk of cancer (specifically amyopathic DM or hypomyopathic DM). How convincing is this data? What is your view on the clinical significance of this correlation? Many insurance companies routinely reject CT and MRI scan orders written by PM or DM patients' physicians for cancer screenings if the patient has no cancer-related symptoms, isn't of a certain age, etc. How important do you think it is for DM and PM patients who are positive for TIF-1 auto antibodies to get comprehensive cancer screenings (not just age-appropriate screenings)? How often should such screenings be done?
Is it worthwhile to repeat auto antibody panel screenings periodically as a means to assess how well drug treatment is working?Kanneboyina Nagaraju, DVM, MVSc, PhD:
My review of the literature suggests a convincing association between TIF-1 autoantibodies and cancer in myositis. I think it is important to perform a comprehensive cancer screening in autoantibody positive patients.
Sensitivity to SodiumParticipant:
I have a sensitivity to sodium. Is any research being done to develop drugs without sodium?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Sorry, I am not aware of research on drugs without sodium.
Can your antibodies change or are they fixed and the only change is whether or not they can be identified?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Autoantibodies are not fixed, they are very dynamic and are known to change their reactivity from one antigen to another antigen with the passage of time.
Do you plan to initiate a clinical trial for your alternative steroid compound? If so, when, and who will be targeted?Kanneboyina Nagaraju, DVM, MVSc, PhD:
We have already initiated clinical trials for the alternate steroid compound (Vamorolone) in children with Duchenne Muscular Dystrophy. We will come to know whether Vamorolone is effective or not in DMD in the latter half of 2018. Please check for clinical trial updates on the Reveragen Website (http://www.reveragen.com).
Is there any drug on the market to replace prednisone?Kanneboyina Nagaraju, DVM, MVSc, PhD:
There are no true FDA-approved prednisone replacement currently on the market. One of the companies (Reveragen Biopharma) that I am associated with is currently developing a replacement drug called Vamorolone that potentially lacks some of the side effects of prednisone. This drug is still in clinical trials. If the drug is successful in these clinical trials it may take a couple of years to reach the market.
No Autoantibodies After Multiple TestsParticipant:
I was tested more than one time for a panel of autoantibodies but never found positive. What this mean? Do I have the antibodies, or it is false negative?Kanneboyina Nagaraju, DVM, MVSc, PhD:
It is not uncommon NOT to have autoantibodies in myositis patients. For example only 50% of PM and DM patients have myositis specific autoantibodies. This means the other 50% of patients either have no autoantibodies or may have autoantibodies for something else that we haven’t identified yet. New autoantibodies are being discovered regularly. It is likely that some of the patients who are negative today may be positive for new autoantibodies yet to be discovered.
Negative Autoantibody ResultsParticipant:
I was tested for a panel of autoantibodies more than one time but all results were negative. I was diagnosed for DM. What do the testing results mean? False negative? Or simply I don't carrier the antibodies?Kanneboyina Nagaraju, DVM, MVSc, PhD:
It means you are negative for the antibodies currently available on the testing panel. You may still be positive for autoantibodies that are not identified yet for DM.
Symptoms Linger with MedicationParticipant:
I was diagnosed with dermatomyositis this past December 13th. Currently am on 50mg prednisone/day, adding 200mg Plaquenil twice a day since mid-January, and 15mg methotrexate injections weekly since mid-February to try to wean off the prednisone. I am still experiencing cuticle redness, soreness, and overgrowth. My ANA was 1:320 in late October, then 1:160 a month later after some high-dose prednisone therapy (60mg, then 40mg), and two weeks of tapering to 5mg. None of the panel antibodies were elevated before diagnosis. CPK has been normal since December and inflammation markers (ESR, CRP) have always been normal. If my antibody, enzyme, and inflammation levels aren't that high, why don't the symptoms all disappear with all these medications?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Great question!! Generally autoantibodies help to diagnose a disease. Their role in actually causing muscle or skin damage in DM is debatable. Likewise emerging evidence indicates that inflammatory cells are not the sole mediators of tissue damage in myositis. There are non-immune or inflammatory mechanisms that also cause muscle weakness and damage. Currently we don’t have effective drugs in the market that can tackle these non-inflammatory mechanisms of damage. My laboratory is actively working on finding agents that block these new mechanisms.
Re-Testing Autoimmune AntibodiesParticipant:
Under what circumstances would you recommend someone have their autoimmune antibodies re-checked? If for example you had a standard panel taken more than ten years ago, are any new discoveries likely to hold additional information relative to your disease or treatment? (When I was diagnosed with PM in 1999, IMNM wasn't well-known if at all. Now, I discover that is what I really have.) Thank you.Kanneboyina Nagaraju, DVM, MVSc, PhD:
The advent of new molecular biology techniques is helping in the discovery of new autoantibodies in myositis. This discovery process is slow for myositis because of inadequate funding and a limited number of researchers dedicated to this research area. I would suggest at least once in 4-5 years is good timing to reevaluate the autoantibody status, especially as and when new autoantibodies are added to the testing panels.
Should all patients with myositis be tested for autoantibodies? Which autoantibodies should I ask my doctor to test me for?Kanneboyina Nagaraju, DVM, MVSc, PhD:
I think it is a good idea to ask for autoantibody testing. For example, the presence of certain autoantibodies (e.g., Mi-2 autoantibodies in DM) inform physicians whether medications will work or not.
Alternative Steroid ResearchParticipant:
Does your research into this alternative steroid hold any hope for those of us who have inclusion body myositis (IBM)? Thank you for your time and research.Kanneboyina Nagaraju, DVM, MVSc, PhD:
It is hard to predict whether alternate steroid will work or not in IBM at this time.
Do people with IBM have autoantibodies? What does this mean in terms of symptoms and prognosis?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Yes! Some people with IBM have autoantibodies. Their role in disease pathogenesis is not known and is currently being investigated in many labs.
Lung Disease and Antisynthetase Syndrome RiskParticipant:
If someone has tested positive for anti-Jo-1, does that mean they will always develop lung disease and antisynthetase syndrome?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Not always, but these patients have a high propensity to develop antisynthetase syndrome.
Alternative Steroid CompoundParticipant:
Please tell us about the development of this alternative steroid compound that is highly effective at decreasing inflammation without the challenging side effects seen with prednisone? At what stage of clinical development is the drug? Which company is the sponsor of the drug?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Clinical trials for the alternate steroid compound (Vamorolone) in children with Duchenne Muscular Dystrophy are ongoing. We will come to know whether Vamorolone is effective or not in DMD in the latter half of 2018. Please check for clinical trial updates on the Reveragen Website (http://www.reveragen.com).
Can you talk about antisynthetase syndrome and the autoantibodies associated with it? What do these autoantibody profiles tell us about prognosis and treatment options?Kanneboyina Nagaraju, DVM, MVSc, PhD:
In antisynthetase syndrome, antibodies to aminoacyl-tRNA synthetases generally predict the development of interstitial lung disease (ILD). This disease is a clearly distinct clinical entity; with features of myositis, ILD, fever, arthritis, and mechanic’s hands. Diagnosis generally aids in selection of therapeutic options such as immunosuppressive agents.
OTC or Herbal SupplementsParticipant:
This isn't an autoantibody question.....What is your view on myositis patients trying out various OTC or herbal supplements that have anti-inflammatory properties such as fish oil and turmeric?Kanneboyina Nagaraju, DVM, MVSc, PhD:
There are publications that support anti-inflammatory properties of turmeric and fish oil. Most of these experiments were done on cells in the lab not proper clinical trials with human subjects. I worry about taking them, because they may have some impurities that are not good for the body. Further, their manufacturing is not regulated therefore it’s hard to know their authenticity.
Anti-Jo-1 and MDA5 AntibodiesParticipant:
Doctors believe anti-Jo-1 and MDA5 antibodies are radically different in spite of the similarities of symptoms ("It quacks like a duck, but it's not a duck"). Has anyone tried to approach these two antibodies as one and the same, and tried to find in these completely different antibodies a similarity? It might help us understand better what an autoimmune disease is. Thank you for answering my question.Kanneboyina Nagaraju, DVM, MVSc, PhD:
They are clearly target two distinct and different antigens in the body despite their association with similar symptoms. We know a little bit about the function of Jo-1 antigen but not a lot about MDA5.
Inflammatory Response CauseParticipant:
Thank you for holding this conference call. Do we know what causes the inflammatory response in myositis?Kanneboyina Nagaraju, DVM, MVSc, PhD:
We do not know the cause of myositis. It is unlikely that there is a single agent that causes myositis. I think multiple common agents (e.g, virus, bacteria, drugs, chemicals, UV) may be involved in initiating the disease in people who have susceptible genetic backgrounds.
What are autoantibodies? Why are they important for a myositis patient to know? How does one find out if they have autoantibodies?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Our immune system is designed to react and counter pathogens entering our body (non-self proteins). However in a small (less than 1% of populations) proportion of people our immune system reacts to our own body proteins (self-proteins) and damages the organ or tissue expressing these self proteins. People who develop antibodies to self proteins have autoimmune diseases such as myositis, rheumatoid arthritis, lupus, etc. Autoantibodies help to diagnose a disease, which in turn will help treatment strategy and prognosis in some cases. Generally patients’ serum samples are screened for known auto antigens.
New Drug to Reduce InflammationParticipant:
Would your new drug be effective in reducing inflammation in patients with IBM, or is it exclusively for either/both dermamyositis or polymyositis patients? And how quickly would it be effective?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Theoretically, this alternate steroid should work in all inflammatory diseases. There is no way to predict this at this time.
Transition from SteroidsParticipant:
Regarding the alternative steroid compound you are developing, how difficult would it be for a patient who has been taking steroids long term to make a transition to this new treatment? Describe how this transition would be made. I've heard about a subset of antibodies that have a sialic acid component that may make IVIg more effective. Is there a way to isolate these and/or add these to a treatment? Is there a way yet to determine which batch or brand may be more effective for different patients? Also, are you familiar with IV vitamin C therapy to reduce inflammation? Is that relevant to myositis patients?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Clinical trials with the alternate steroid are still ongoing. If it is effective in these trials, FDA will approve this drug. Transition is simple: you stop regular prednisone and start the new drug.
How useful is periodic re-testing for presence and titer of autoantibodies? Does a decreasing (or undetectable) titer equate to decreased disease severity and/or decreased autoinflammation? Does it matter if a positive test result derived from an ELISA versus immunoprecipation versus Western blot in terms of accuracy and specificity of result? Which clinical labs are best at testing for myositis specific and myositis associated antibodies?Kanneboyina Nagaraju, DVM, MVSc, PhD:
I think it is useful to retest autoantibody titers periodically. For some antibodies there is an association with disease severity but this not true for all autoantibodies.
If I didn't have myositis autoantibodies when I was diagnosed, will I develop them later? Should I be tested regularly for autoantibodies? Do levels of autoantibodies go up and down according to my symptoms?Kanneboyina Nagaraju, DVM, MVSc, PhD:
Regular testing for autoantibodies is always a good idea! Some but not all autoantibody levels correlate with disease activity.
Is there a relationship between cancer and occurrences of myositis?Kanneboyina Nagaraju, DVM, MVSc, PhD:
How Antibodies Work in the BodyParticipant:
Can you please explain how the antibodies work in the body. It seems that some antibodies are associated with increased cancer risk (antibody Jo, for example), and others indicate a person more likely to respond to treatment. I don't understand these differences.Kanneboyina Nagaraju, DVM, MVSc, PhD:
One way to explain this is, for example, if autoantibodies are associated with cancer, it does not mean they actually cause cancer; it only means they are either present in higher proportions of patients with cancer. In the same way, those who have antibodies to Mi-2 aremore likley to respond better to treatment, but it doesn’t mean that Mi-2 antibodies help treatment.
Thank you Dr. Kanneboyina Nagaraju for taking time out of your busy schedule to answer questions for TMA members. This concludes today's discussion. Thanks to all of the members who participated.Kanneboyina Nagaraju, DVM, MVSc, PhD:
Thanks you all!! Nice chatting with you today.