Love-Winters Family Blog

OLD - Parent's Guide to Securing Anti-JAK Treatment

This is old and out of date. I'm leaving it around and archiving it for posterity. I wrote this in March of 2019, just after my daughter started this medicine and just after she stabilized from acute and severe developmental regression. I had little information and even less experience to share.

I am not a doctor. I may have mis-represented a doctor's opinion and recommendations with the following. I'm a parent that became obsessed with helping a daughter, partially blind to the risks of what I'm writing about. You can read about my daughter's outcome on this blog, but remember that this is an anecdote, not evidence.

Your child has just been diagnosed with AGS. It may turn out to be mild, it may turn out to be severe. If you did genetic testing it might be early; if so, work fast (it took me another month after diagnosis to get the pieces together and my daughter lost skills all the while). There are not any effective, textbook treatments for AGS. However, there have been some studies showing JAK inhibition to provide systemic benefits. AGS is an auto-inflammatory disease, and JAK inhibition appears to disrupt and quiet the immune signaling feedback loop that causes the brain and other organs to become chronically inflamed. The studies have not demonstrated that it can stop neurological damage, partially because they have not had many (maybe only a couple) children with AGS join their studies early enough. In at least two cases I've heard of, it has failed to prevent further episodes (possibly due to the severity of the child's disease). In my daughter's case, it appears to have halted her regression before it became severe. I believe that it would have worked earlier if we had the opportunity. Its effectiveness may be directly related to the severity of your child's disease. This has risks, but there is no other intervention a the moment. The principal investigators will not say that this is the right thing to do. At least two children have passed away while being treated with this drug, but I believe they had risk factors due to their advanced disease. If your child is strong and healthy, then they may be in a better position to take these risks.

If there is no clinical trial available to you, it may still be possible to get this drug. At the 2019 GLIA Conference, Dr. Vanderver and Dr. Adang struck a tone that I would interpret as opening the door for possible collaboration with your doctor. My family and a handful of others have made this therapy happen without CHOP (due to timing and circumstances), but it was difficult. There are a few major hurdles to overcome if you're trying to do the same.

  • Drug Access
  • Clinical Monitoring
  • Testing Interferon Score
  • Insurance Coverage for the Drug

Drug Access

In my opinion, baricitinib has the most relevant and promising research. In the U.S. both baricitinib and ruxolitinib are approved by the F.D.A. for something else and your doctor can prescribe them "off-label" for whatever they want. They will be nervous about doing so, but it's still possible. If you're outside of the U.S., your choice might be constrained by your government or health care system.

Both of these drugs have had promising research. Ruxolitinib has been used for treating AGS in only a few cases. Baricitinib has had larger studies done, perhaps with more depth. Dr. Goldbach-Manksy at the NIH has done diligent studies of the drug, working towards approval of the drug for "orphaned diseases" CANDLE and SAVI.

You will find that these papers reference work by Dr. Crow and others in establishing the theory for using JAK inhibitors to treat "inteferonopathies." Follow these references or make your doctor aware of them. I don't know whether ruxolitinib has demonstrated the same level of safety, but it's well understood that it has a very similar interaction profile. Both drugs pretty much inhibit the same kinases with the same specificity. Dr. Crow has communicated more discouragement to me about ruxolitinib than excitement, but CHOP (and Dr. Vanderver's) conclusions with baricitinib appear to be more encouraging.

If you are not involved in a clinical research study, you will have some trouble getting the drug. This drug isn't available in your neighborhood pharmacy. It was not available in our hospital. It had to be ordered and shipped to us overnight from a specialty pharmacy. Many insurance companies have their own. We initially ordered from Kroger Specialty pharmacy. You will have to pay out of pocket for at last a month or two, and it may cost you between four and six thousand dollars a month until you achieve insurance approval (I've provided the letter I wrote to get approval below).

Clinical Monitoring

You will need active monitoring by a doctor. This drug not only disrupts the immune system's alarm signals; it also disrupts signals your body uses to control the production of white blood cells and red blood cells and growth hormones. You will likely need to have blood tests run every couple of weeks for a few months to ensure that it does not suppress specific sets of white blood cells or cause any other organ problems. Your child will be at an increased risk for not only catching viral infections but also for reactivation of viruses that were dormant. Your doctor should do a comprehensive screening for all kinds of viruses and perform periodic follow ups to ensure that your child remains healthy. In particular, BK Virus, which can attack and destroy the kidneys, has been seen to re-activate due to the drug's suppression of the immune system and possibly due to its excretion by the kidneys. A child in Dr. Goldbach-Mansky's study died from BK related nephropathy. Her publications establish a safety and monitoring protocol that includes regular testing of a number of problematic viruses. They concluded that this therapy was safe enough, perhaps a commentary on the risk/benefit analysis in the context of the two devastating diseases they were focused on treating (CANDLE and SAVI).

Your average neurologist may not be in a position to offer this kind of clinical care. If you're doing this outside of clinical research studies, your doctor may need to exercise an abundance of caution. They will not have experience with this drug, and the small amount of evidence of its safety does not apply to children. You will need to find a brave doctor in a position to provide this kind of care for an at risk child. In our case, we're working with the Bone Marrow Transplant group. They have a 24/7 clinic where they monitor and help children that are undergoing treatments that have a much stronger suppressive effect on their immune systems. At our hospital, this was the perfect group and the only one in a position to help us. They would not have been involved nor even aware of my daughter's condition or circumstances if I hadn't contacted them directly. You will need to become the mediator for a number of different kinds of doctors to make this happen.

Testing Interferon Score

In order to find the optimal dosage with minimal side effects, your doctor will need to send blood samples to one of the clinical research labs in a position to do this testing. This test measures the activity of genes that are stimulated by the disease's immune dysregulation. Increased activity of these genes has been established (in research) as a strong biomarker for AGS.

There is not any commercially available test, and the labs doing this (NIH, CHOP) have been doing it for research purposes. At the 2019 GLIA Conference, Dr. Vanderver fielded a question about where doctors should send these blood samples for testing and she said that you should contact either her or Dr. Goldbach-Mansky and that they were working on making it available as a clinical test. Their methods are described in Development of a Validated Interferon Score Using NanoString Technology.

As an alternative for those outside of the U.S., you may be able to get support from Dr. Yanick Crow at the University of Edinburgh and his colleagues in France. His group has used a different method for measuring interferon stimulated genes, qPCR. See Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease. It's important to know that this method is different and potentially less reliable. You may not be able to compare these scores with any research being done by Dr. Goldbach-Manksy or Dr. Vanderver. However, at first glance, the upcoming clinical trial at CHOP reads as if they will be using PCR, perhaps they have found this method to be reliable enough for treating patients.

As far as I'm aware, you only have three options:

Insurance Coverage for the Drug

You are welcome to adapt the appeal letter I sent to our insurance company. Know that I had a purpose in writing this letter, to save $4-6k a month. I wouldn't defend the veracity of this letter. This drug is expensive, and the evidence for it is considered weak. You will be denied. We eventually succeeded after multiple appeals.

Dear Medical Reviewer,

I write in appeal of your company’s decision to deny my child the life saving medication baricitinib/Olumiant for her extremely rare genetic disorder, Aicardi-Goutieres Syndrome (AGS). I do so on the advice provided to my doctor by a Cigna medical reviewer that submission of my appeal would not jeopardize or in any way hamper a similar second level appeal expected by our doctor. Considering the likelihood of your lack of familiarity with Aicardi-Goutieres Syndrome and treatments, I request that you read my references carefully before considering our appeal. We are remarkably fortunate to have received a rapid, genetically confirmed diagnosis and access to an effective drug therapy that has already halted the progression of my child’s disease and neurological decline [1]. At this time, there do not exist alternatives to this medication that are capable of mediating this disorder’s chronically elevated interferon signaling. I’m confident that you’ll find the remarkable nature of my child’s condition and relevant research compelling enough to overturn your original decision.

Your decision to deny my child this medication puts her at risk of death (19.3% of AGS patients die in early childhood [11]) and, should she survive, will certainly increase her medical costs many fold, destroying her quality of life in the process. Without treatment, my child may end up among the 73% of patients that are “profoundly disabled, with no useful motor, speech and intellectual function” [11]. I encourage you to take a moment and consider what that means. Had we not successfully intervened for my child with baricitinib or should we fail to continue treatment for financial reasons, she faces an overwhelming risk of ending up in a virtually vegetative state, incapable of intentional movement and communication. Even in the best of outcomes, she will be devastatingly changed. In the largest study of its kind, “only 14 of 294 patients [...] were able to walk with no/ minimal support.” [11]. She will likely suffer from among “chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus” and other serious and life threatening medical complications [11]. I find this to directly contradict your decision to deny our expedited appeal on the grounds that this “does not involve an imminent and serious threat to the health of the member.” This reflects a lack of seriousness on your part in consideration of the extreme threat that this disease poses to my child, and I find it completely unacceptable. Please read the following carefully, as I’ve gone to great pains to provide you with scientific and clinical research that supports our use of this medication.

In 2013, O'Shea et al. reviewed the emerging Janus Kinase inhibitors (or jakinibs), remarking on how they offered “new therapies for diverse clinical entities ranging from malignancy to autoimmunity” [12] on the basis that “an increasing body of evidence implicates specific cytokines and cell subsets as drivers of pathogenesis in different autoimmune diseases.” [12] Furthermore, “many use the Jak/STAT pathway to exert their effects, rendering them amenable to therapeutic blockade with Jakinibs.” [12] In direct and relevant fashion to my child’s neurodegenerative disease, Yan et al. in 2016 concluded that “the involvement of JAK/STAT signaling in the pathogenesis of neuroinflammatory diseases suggests that inhibition of JAK/STAT signaling could provide therapeutic benefit,” [13] remarking that “pre-clinical studies have demonstrated efficacy of JAK/STAT inhibition in neuroinflammatory diseases.” [13] Just prior, in 2015, Crow and Manel painfully explained the molecular function of proteins and signalling pathways in AGS that lead “to activation of the transcription factor complex ISGF3” (which include STAT1 and STAT2) directly implicating the JAK/STAT pathway in disease pathogenesis [15]. Furthermore, Crow postulated in 2015 that after “defining a disturbance of type I interferon as relevant to the pathogenesis of a disease,” strategies of treatment “could include the use of [...] JAK inhibitors.” [14] With great foresight Crow shared his prediction “that the field is likely to develop rapidly, providing hope for the development of rational therapies for this devastating group of human diseases.” [14] The buildup to clinical trials using JAK inhibitors for treating AGS and other interferonopathies occured very quickly and within the last decade, and their use in open label clinical trials has commenced within the last few years.

I request that you seek guidance from Dr. Rafaela Goldbach-Mansky (​​, 1-301-761-7553), chief and principal investigator of the National Institute of Health NIAID (National Institute of Allergy and Infectious Diseases) Translational Autoinflammatory Disease Studies (TADS) Unit. Dr. Goldbach-Manksy’s (and her group’s) work involve many years of clinical research using baricitinib to successfully treat patients with AGS and other “mendelian interferonopathies” [2,3,4]. Additionally, I request that you seek consultation with Dr. Yanick Crow of the MRC Institute of Genetics and Molecular Medicine (IGMM) at the University of Edinburgh, (​​, +44 (0) 131 651 1041), who in assessing potential therapies for interferonopathies in the Journal of Experimental Medicine related success with a functionally equivalent agent and related Janus Kinase inhibitor (ruxolitinib), “we observed highly promising efficacy in all aspects of the clinical phenotype (systemic inflammation, destructive skin lesions, and pulmonary disease.” [5,6] Further studies by Dr. Crow in Europe have demonstrated the effectiveness of Janus Kinase (JAK) inhibition [7,8,9]. And finally, should you continue to find the above unconvincing, I request that you consult with Dr. Adeline Vanderver (​​, 1-215-590-3068), program director of the Leukodystrophy Center of Excellence, Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at the Children's Hospital of Philadelphia, and member of the medical and scientific advisory board of the United Leukodystrophy Foundation. Dr. Vanderver’s clinical research has demonstrated baricitinib to impart a “significant decrease in interferon scores and improvement in clinical scores” [10] in AGS patients and her team has concluded that baricitinib “may be an effective approach in AGS to decrease interferon signaling” [10]. Dr. Vanderver and the Leukodystrophy Center of Excellence continue to treat patients with baricitinib that were enrolled in their compassionate use trial. Their expanded/compassionate use clinical research trial, was forced to stop enrolling when baricitinib became FDA approved, but they are actively planning and pursuing a follow-up with Eli Lilly and the FDA. In communication with our team in North Carolina, she communicated her belief that baricitinib “blocks the IFN mediated end organ damage” and shows promise in children with AGS. Unsurprisingly, after evaluating my child in Philadelphia on 3/7/2019, Dr. Vanderver deduced that baricitinib likely interrupted the disease process that began at the beginning of 2019, bestowing a remarkable benefit to my child in the context of such a devastating disorder. I assure you that there are no greater experts of AGS and interferonopathies (a term first coined by Dr. Crow [16]) than these three doctors and principal investigators. I’ve been in contact with all three seeking advice in my efforts to save my child, and it’s revealing that all three have been involved in developing the theory for and in driving clinical research trials with JAK inhibitors for AGS patients. Their conclusions and publications should weigh strongly in favor of my appeal.

Additionally, given the context of this or any other extremely rare disease, the burden of evidence for approving treatment must be considered from a unique perspective. It would be cruel and inhumane to expect a randomized, placebo controlled study to assess the efficacy of treatment for a ruinous disease of which only 374 cases were known to have occurred as of 2015 [11]. Both the rarity and morbidity of AGS make it difficult to assemble a suitable population for study. Consider Hoffman et al., describing Dr. Goldbach-Mansky’s work with baricitinib, “it should be noted that a similar comprehensive protocol was the basis for FDA licensing and orphan disease approval of anakinra for neonatal-onset multisystem inflammatory disease (NOMID), without the traditional large-scale, placebo-controlled study typical of pivotal clinical trials.” [17] Hoffman unambiguously commends Dr. Goldbach-Mansky for her work stating that it “further [establishes] this patient-focused approach as the definitive method for therapeutic intervention in rare diseases.” [17] The rarity of this disease must be considered in regards to our appeal.

Astoundingly and despite the rarity of this disease, this life-saving and life-sustaining medication has been effectively demonstrated in a substantial and compelling proportion of the affected AGS population and remains a promising and effective therapy in ongoing clinical research [3,6,7,8,9,10]. The genetic and biomolecular causes of the AGS disease pathology are well understood [5,15,16] and have very recently led to this opportunity presented to my child. I implore you to recognize the strength of the evidence and costs and consequences (personal, financial, and otherwise) of not approving my appeal. There is simply no alternative treatment, and my child’s life balances on your decision.

Sincerely, Patrick Winters


  1. [Child’s Medical Record, Visit Notes]
  2. Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041-3052.
  3. Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes. Identifier: NCT01724580
  4. Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still'S-like Diseases, and Other Undifferentiated Autoinflammatory Diseases). Identifier: NCT02974595
  5. Rodero, M. P., & Crow, Y. J. (2016). Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. The Journal of experimental medicine, 213(12), 2527-2538.
  6. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children Frémond, Marie-Louise et al. Journal of Allergy and Clinical Immunology , Volume 138 , Issue 6 , 1752 - 1755
  7. An open-label trial of JAK 1/2 blockade in progressive IFIH1-associated neuroinflammation Kavitha Kothur, Sushil Bandodkar, Stephanie Chu, Louise Wienholt, Alexandra Johnson, Peter Barclay, Paul A. Brogan, Gillian I. Rice, Yanick J. Crow, Russell C. Dale Neurology Feb 2018, 90 (6) 289-291; DOI: 10.1212/WNL.0000000000004921
  8. Briand C, Frémond M, Bessis D, et al Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency Annals of the Rheumatic Diseases 2019;78:431-433.
  9. McLellan, K.E., Martin, N., Davidson, J.E. et al. JAK 1/2 Blockade in MDA5 Gain-of-Function. J Clin Immunol (2018) 38: 844.
  10. Pilot study of the use of Janus Kinase Inhibitor, Baricitinib, in the treatment of heritable interferonopathy Aicardi Goutières Syndrome (P3.323) Adeline Vanderver, Ulrick Nicole, Francesco Gavazzi, Asako Takanohashi, Thais Armangue, Jullie Rhee, Jamie Koh, Sarah Woidill, Justine Shults, Deborah Foerster, Raphaela Goldbach-Mansky, Laura Adang, Amy Waldman Neurology Apr 2018, 90 (15 Supplement) P3.323;
  11. Crow YJ, Chase DS, Lowenstein Schmidt J, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A(2):296-312.
  12. O'Shea JJ, Kontzias A, Yamaoka K, et al Janus kinase inhibitors in autoimmune diseases Annals of the Rheumatic Diseases 2013;72:ii111-ii115.
  13. Zhaoqi Yan, Sara A. Gibson, Jessica A. Buckley, Hongwei Qin, Etty N. Benveniste, Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases, Clinical Immunology (2016), doi: 10.1016/j.clim.2016.09.01
  14. Crow Y.J. 2015. Type I interferonopathies: Mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32:7–12. 10.1016/j.coi.2014.10.005
  15. Crow Y.J., and Manel N. 2015. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15:429–440. 10.1038/nri3850
  16. Crow, Y. J. Type I interferonopathies: a novel set of inborn errors of immunity. Ann. NY Acad. Sci. 1238, 91–98 (2011).
  17. JAK inhibitors in autoinflammation. Hal M. Hoffman, Lori Broderick. J Clin Invest. 2018 Jul 2; 128(7): 2760–2762. Published online 2018 Jun 11. doi: 10.1172/JCI121526