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With limited treatment options available for dermatomyositis, the investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with refractory cutaneous dermatomyositis.
The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with refractory cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months.
Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, creatine kinase, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as 4 points increase in the cutaneous dermatomyositis disease area and severity index (CDASI) score, worsening of muscle disease by manual muscle testing (MMT-8) score and 5 points increase in dermatomyositis life quality index (DLQI).
5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains.
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II. PRODUCT INFORMATION
III. CONCEPT DESIGN AND RATIONAL
4-If other specify: None
This case was accepted as a poster presentation at the 2018 Annual Meeting of the American Academy of Dermatology "Poster #: 6672 - Apremilast: a Potential Treatment for Dermatomyositis." Following this successful outcome, the investigators initiated apremilast in 3 other patients with recalcitrant dermatomyositis. Two patients had recalcitrant cutaneous disease and responded to add on therapy of apremilast in 2 months with significant improvement of their skin disease. The third patient had refractory dermatomyositis to several steroid-sparing agents and with severe muscle disease was started on apremilast for arthritis. She experienced significant improvement of her muscle weakness together with decrease in her muscle enzyme creatine kinase.
These very exciting findings triggered the idea of studying apremilast as an adjunct treatment for recalcitrant cutaneous disease in dermatomyositis patients. This is a novel idea; apremilast was never studied for dermatomyositis. Apremilast may have more advantages in dermatomyositis compared to other immunosuppressive treatments. Dermatomyositis patients may have lung involvement, and apremilast is an agent that doesn't have lung side effects in contrast to methotrexate for example which is one of the main steroid sparing agents used for dermatomyositis.
The pathogenesis of dermatomyositis is multifactorial with environmental, genetic and immune factors contribution.T helper-1 (Th1) and T helper-2 (Th2) immune pathways play a fundamental role in dermatomyositis.There is increase in proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL) 1, IL 6, and interferon (INF) α,γ shifting the immune balance to a Th1 response.Th1 immune response was also involved in the pathogenesis of interstitial pneumonia in the setting of dermatomyositis.IL4 released by lymphocytes infiltrating skin and muscles in dermatomyositis patients contributes to increase in Th2 response in conjunction with Th1 response.
Apremilast is a PD4-E inhibitor currently used for psoriasis and psoriatic arthritis.However, its usage on patients with dermatomyositis has not been investigated.
By inhibiting PDE-4 apremilast increases the level of cyclic adenosine monophosphate (c-AMP), leading to decreased expression of proinflammatory cytokines including TNF-α and INF-γ thus inhibiting Th1 response. Apremilast can also block Th2 response by interfering with the level of IL6 secreted by type2 macrophages.While the mechanism of action of apremilast in dermatomyositis is unknown, we suggest that apremilast can be a potential treatment option for dermatomyositis through interfering with Th1 and Th2 response.
Apremilast is a well-tolerated oral medicine with transient gastrointestinal side effects. Apremilast offers an additional treatment option for those patients with recalcitrant dermatomyositis, unresponsive to more conventional therapy.
Treatment and Dosing: Investigators will enroll patients seen at our facilities with a known diagnosis of dermatomyositis who are still experiencing cutaneous disease after a trial of systemic steroids and one steroid-sparing agent. Investigators will add apremilast to their treatment regimen according to the approved dosage for psoriasis and psoriatic arthritis: 10 mg orally one time on day 1, 10 mg orally twice daily on day 2, 10 mg orally in AM and 20 mg orally in PM on day 3, 20 mg orally twice daily on day 4, 20 mg orally in AM and 30 mg orally in PM on day 5, then 30 mg orally twice daily thereafter.
Brief Study Synopsis: With limited treatment options available for dermatomyositis, investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on treatment in patients with recalcitrant cutaneous dermatomyositis.
The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg twice daily to patients with recalcitrant cutaneous dermatomyositis. Clinical response will be assessed at 1 and 3 months. Patients will also be evaluated for durability of their response for up to 6 months.
Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood tests (CBC, CMP, CK, aldolase). Treatment will be discontinued at disease progression or unacceptable adverse events. Disease progression is defined as a 4 points increase in CDASI score, worsening of muscle disease by MMT-8 score and 5 points increase in DLQI.
5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and after 3 months of treatment for gene expression profiling and confirmatory immunohistochemical stains.
Although, the proposed mechanism of action of apremilast is though PDE-4 inhibition resulting in c-AMP upregulation, the exact biological process that leads to dermatological response in dermatomyositis remains ill-defined.Investigators propose to perform gene expression profiling (GEP) using RNA sequencing on skin biopsies collected before and after treatment with apremilast. In addition, we plan to confirm our GEP findings at the protein level using immunohistochemical (IHC) stains.
A. Tissue sampling and preparation
B. Correlative Analysis
Determining the mechanism of action of apremilast in dermatomyositis.
Gene expression profiling RNA extracted form skin biopsies collected before and after in vivo treatment with apremilast (as detailed above) will be subjected to RNA sequencing. Illumina strand-specific TruSeq libraries will be prepared from the polyA selected RNA and subjected to 1x100 base sequencing on an Illumina HiSeq2500 machine. The number of samples proposed here (10 samples before treatment and 10 samples after treatment) is expected to yield sufficient statistical power for this approach; smaller numbers have been used in similar approaches to investigate drugs' mechanism of action (usually three samples).
RNA-seq analysis will be performed in conjunction with the Tulane Cancer Crusaders Next Generation Sequence Analysis Core (Tulane Cancer Center - https://tulane.edu/som/cancer/research/core-facilities/cancer-crusaders/). Gene and isoform expression will be determined using RSEM and differential expression will be analyzed using EB-seq. Genes that are identified as differentially expressed between the two groups with a False Discovery Rate (FDR) of < 0.05 will be subjected to analysis by Ingenuity (IPA, Redwood City, CA). This analysis will group the identified genes into specific pathways, cell types, or disease process. A similar approach will be conducted using Gene Set Enrichment Analysis (GSEA). These experiments and GEP analysis will be performed in conjunction with our collaborator's (Dr. Nakhle Saba) lab, given his extensive experience in this field.
Protein analysis Information identified by Ingenuity or GSEA (signaling pathways, regulatory molecules, etc...) will be verified using IHC staining on select samples.
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Increasing or changing dose of topical therapy within 14 days of study day 0 (including but not limited to topical corticosteroids, tacrolimus, pimecrolimus).
Increasing or changing systemic steroids dosing within 28 days of study day 0.
Increasing or changing dosing for concurrent therapy agents within 28 days or 5 half-lives of the biologic agent, whichever is longer, before study day 0: methotrexate, azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, leflunomide, cyclosporine, biologic agents (anti-TNFs), IVIG, rituximab.
History of any clinically significant (as determined by the investigators) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major uncontrolled disease.
Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
Pregnant or breastfeeding.
Untreated Latent Mycobacterium tuberculosis infection or active tuberculosis infection as indicated by a positive Purified Protein Derivative (PPD) skin test or T-spot.
Any condition, including the presence of laboratory abnormalities that places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
Patients with acute dermatomyositis onset and rapid progression of muscle disease or significant systemic involvement including pulmonary diseases associated with DM.
Prior major surgery or major life-threatening medical illness within 2 weeks.
Inflammatory bowel disease, malabsorption or any other gastrointestinal motility disorders that limit the absorption of the study drug.
Active hepatitis B or C infection with detectible viral nucleic acid in the blood or known Human Immunodeficiency Virus (HIV) positivity.
Prior history of suicide attempt at any time in the patient's lifetime prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years.
Active substance abuse or a history of substance abuse within 6 months prior to screening.
Use of any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer).
Prior treatment with apremilast.
Any severe systemic illness requiring IV antibiotics within the two weeks prior to initiation of the study drug.
Malignancy or history of malignancy within the past four years, except for:
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Data sourced from clinicaltrials.gov
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