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NEWSLETTER
Summer, 2020

CURE JM-FUNDED STUDY

Flare Predication and Risk Profiling in Juvenile Dermatomyositis (JDM)

Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool For Treatment Response in Two Independent Cohorts of Patients with Juvenile Dermatomyositis

Judith Wienke, Lauren M. Pachman, Gabrielle A. Morgan, Joo Guan Yeo, Maria C. Amoruso, Victoria Hans, Sylvia S. M. Kamphuis, Esther P. A. H. Hoppenreijs, Wineke Armbrust, J. Merlijn van den Berg, Petra C. E. Hissink Muller, Kyra A. Gelderman, Thaschawee Arkachaisri, Femke van Wijk, Annet van Royen‐Kerkhof.

Study summary by Cure JM CSO, Andrew Heaton, PhD.

Annet-van-Royen-Kerkhof

Lead author, Annet van Royen-Kerkhof, MD, PhD.

Why is this paper important?

As with any disease a clinician's aim in caring for JDM patients is to correctly diagnose the disease and then schedule a range of treatments. The goal being to ameliorate the effects of the disease and return the patient to health. To uncover the full impact of this paper it is important to dissect each of these two aspects: diagnosis and treatment.

Diagnosing JDM is not straightforward, in part this is due to JDM being heterogenous with patients presenting with a spectrum of symptoms. Embedded in the range of symptoms that JDM patients present with there are also a range of myositis specific autoantibodies, which distinguish between different phenotypes of the disease.

Only once a detailed diagnosis has been completed can a clinician then start a treatment protocol for a patient, which may include everything from physical therapy to a range of therapeutic interventions.

As the diagnosis and treatment are intertwined it is critical that the diagnostic tools that are being used can also aid in initial treatment decisions and critically, decisions on when it is appropriate to stop treatments.

The underlying science in this paper is utilizing a range of diagnostic tools that can be applied rapidly and with minimally invasive techniques. Muscle biopsies, a highly valuable diagnostic tool in JDM, often require an initial MRI scan then taking a biopsy sample. A muscle biopsy is a highly invasive technique, requiring general anesthesia of the patients. For this reason, developing non-invasive, but scientifically validated, diagnostic tool kit in JDM is of tremendous need and value. It is well established that endothelial cells, cells associated with controlling the flow of fluid and substances between blood vessels and tissues, are dysregulated in JDM patients. When endothelial cells functionality is disrupted their normal communication pathways are disrupted, this manifests as different levels of endothelial cell communication proteins. If a range of these endothelial cell signaling molecules can be identified that act as a marker for how much tissue damage is occurring in JDM patients, then diagnosis will be less invasive, requiring only a blood sample. Furthermore, these signaling molecules may then subsequently be used to flag how effective different treatment regimens are.

This paper is thus significant in identifying markers in the blood of endothelial function that can be used to diagnose the severity of JDM and then be used to track how well patients respond to different treatment regimes.

The identification of biomarkers to be used as a diagnostic and treatment marker need to be thoroughly examined and validated. This paper is also significant in not only having a robust method to identify potential biomarkers, but then tests the validity of these biomarkers in samples collected from JDM patients from the EU, Singapore and the USA.

What are the results of this paper?

This paper aimed to look for correlations between endothelial signaling molecules and key markers of JDM disease status. A panel of molecules were chosen that have a well understood role in endothelial signaling and are able to be measured by many commercial/hospital laboratories.

The panel of signaling molecules were mapped against key JDM disease markers, specifically:

  • The degree of muscle disease activity (measured via a variety of techniques and an important indicator of how severely affected muscle strength is in JDM patients).
  • The degree of disease vasculopathy (the amount of damaged, or abnormal, blood vessels).
  • The Myositis Specific Autoantibody identified (important in classifying a patient as having a predominant skin, muscle or lung component of JDM).

A variety of well-established statistical tools were utilized to not only uncover potential biomarkers, but then validate these biomarkers in an independent cohort of patients. The study was successful in identifying the following biomarkers:

  • Galectin-9
  • CXCL-10
  • TNFRII
  • Galectin-1

The paper demonstrated that JDM patients with relatively high levels of these biomarkers may require intense treatment during the first three months after diagnosis. The paper also looked at how the levels of these biomarkers correlated to drug-free-remission times after first diagnosis. The paper indicated there was significant correlation of patients with high levels of these biomarkers taking longer to reach drug-free-remission, when compared to low levels of these biomarkers. It was also noted that patients with higher levels of galectin-9 and CXCL-10 at diagnosis were more likely to have a flare within the first 12 months of diagnosis.

How are these results going to impact diagnosis/treatment protocols in new JDM patients?

The measurement of these four biomarkers may aid clinicians in making treatment decisions and follow-up planning. Those patients with high biomarker levels are potentially "at risk" and should be flagged for more intensive monitoring. The use of treatment intensification and monitoring how well these "at risk" patients are responding to treatments may help alleviate a future flare and may also help reduce the time to drug-free-remission. Further, larger numbers are required to validate the use of these biomarkers for JDM disease trajectory and treatment/monitoring intensity. Other studies are ongoing at this hospital to uncover other biomarkers of response and identification of when a patient is at risk of a future flare or should be targeted for intense monitoring.

Read the full study here.

CURE JM-FUNDED STUDY

High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal Muscle

Travis B. Kinder, Patricia K. Dranchak, James Inglese.

Travis B. Kinder, PhD, James Inglese, PhD, Patricia K. Dranchak, PhD.

Authors from left to right: Travis B. Kinder, PhD, James Inglese, PhD, Patricia K. Dranchak, PhD.

Study Summary

Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows that the pro-inflammatory type I interferons (IFN) and a downstream product major histocompatibility complex (MHC) class I are pathogenic in myositis. We conducted quantitative high-throughput screening on >4500 compounds, including all approved drugs, through a series of cell-based assays to identify those that inhibit the type I IFN–MHC class I pathway in muscle precursor cells (myoblasts). The primary screen utilized CRISPR/Cas9 genome-engineered human myoblasts containing a pro-luminescent reporter HiBit fused to the C-terminus of endogenous MHC class I. Active compounds were counter-screened for cytotoxicity and validated by MHC class I immunofluorescence, Western blot, and RT-qPCR. Actives included Janus kinase inhibitors, with the most potent being ruxolitinib, and epigenetic/transcriptional modulators like histone deacetylase inhibitors and the hypoxia-inducible factor 1 inhibitor echinomycin. Testing in animal models and clinical trials is necessary to translate these therapies to myositis patients. These robust assay technologies can be further utilized to interrogate the basic mechanisms of the type I IFN–MHC class I pathway, identify novel molecular probes, and elucidate possible environmental triggers that may lead to myositis.

Read supplemental information and figures here.


Juvenile Dermatomyositis Consensus Treatment Protocols

Recently, some of the best physicians in the world that diagnose and treat JDM patients pooled their collective experience and published a series of consensus plans to standardize and optimize treatment for a variety of JDM patients.

For patients that met the criteria of moderate JDM, the panel of physicians agreed on three, possible treatment plans (Figure 1).

Moderate JDM Patient
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Treatment A

IV steroids: 30mg/kg for 3 days, then weekly

AND

Metho­trexate: 15mg/m2 or 1mg/kg

AND

Prednisone: 2mg/kg/day for 4 weeks, then decrease by 20%

 

Treatment B

IV steroids: 30mg/kg for 3 days, then weekly

AND

Metho­trexate: 15mg/m2 or 1mg/kg

AND

Prednisone: 2mg/kg/day for 4 weeks, then decrease by 20%

AND

IVIG: 2g/kg q2weeks X 3 doses, then monthly

 

Treatment C

Metho­trexate: 15mg/m2 or 1mg/kg

AND

Prednisone: 2mg/kg/day for 4 weeks, then decrease by 20%

CLICK HERE TO LEARN MORE


This issue is brought to you with the support of Bristol Myers Squibb.

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