Cutaneous Dermatomyositis Disease Area And Severity Index Activity Scores Research Articles

Efficacy and safety of repository corticotropin injection for refractory cutaneous dermatomyositis: a prospective, open-label study.

Cutaneous dermatomyositis (DM) is often refractory to multiple medications. Repository corticotropin injection (RCI) is FDA-approved for DM, but little is known about its efficacy and safety for treating cutaneous DM. We conducted a prospective, open-label trial assessing efficacy and safety of RCI for treating refractory cutaneous DM. DM patients with moderate-to-severe cutaneous activity [Cutaneous Dermatomyositis Disease Area and Severity Index activity (CDASI-A)] >14 despite prior treatment with ≥2 systemic agents were enrolled. Patients were initiated on 80 u RCI twice weekly for 6 months. Primary outcomes included significant decreases in CDASI-A and Physician's Global Assessment (PGA) scores at 6 months. Of nineteen patients enrolled, fifteen patients (11 females, 4 males) with DM (7 classic, 8 amyopathic) completed 6 months of RCI treatment. Patients were treated with a median 3.0 systemic medications prior to enrolment and were taking a median of 2.0 systemic medications at enrolment. Median baseline CDASI-A score was 19.0 and median PGA activity score was 2.5/10. For patient-reported outcomes, baseline median patient global skin score (PtGSS) was 3.0/10 and median dermatology life quality index (DLQI) score was 7.0/10. At 6 months, there were statistically significant improvements in CDASI-A scores (median= 10.0), PGA scores (median= 0.8/10), PtGSS scores (median= 7.0) and DLQI scores (median= 2.0), among others. Adverse effects were mild. RCI treatment resulted in statistically significant and clinically meaningful improvement in cutaneous DM activity and quality of life. Our results suggest RCI is an effective, safe, and well-tolerated treatment for patients with refractory cutaneous dermatomyositis. This clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01906372).

Pruritogenic molecules in the skin of patients with dermatomyositis.

Pruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM. We looked for correlations between the investigated pruriceptive signaling molecules, disease activity, and itching sensation of DM patients. Interleukins (IL-33 and IL-6), tumor necrosis factor α (TNF-α), peroxisome proliferator-activated receptor γ (PPAR-γ), and ion channels belonging to the transient receptor potential (TRP) family were analyzed. The expression of TNF-α, PPAR-γ, IL-33, IL-6, and TRP channels in lesional DM skin was evaluated by RT-qPCR and immunohistochemistry and was compared with non-lesional DM skin samples. Pruritus, disease activity, and damage of DM were evaluated by the 5-D itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 28 software. A total of 17 active DM patients participated in the study. We could show that the itching score was positively correlated with the CDASI activity score (Kendall's tau-b = 0.571; p = 0.003). TNF-α gene expression was significantly higher in lesional DM skin than in non-lesional DM skin (p = 0.009) and differed in the subgroups of patients with different itch intensities (p = 0.038). The mRNA expression of lesional IL-6 correlated positively with 5-D itch and CDASI activity score (Kendall's tau-b = 0.585; p = 0.008 and 0.45; p = 0.013, respectively). TRPV4 expressions were positively correlated with CDASI damage score (Kendall's tau-b = 0.626; p < 0.001), but the mRNA expressions of the TRP family, PPAR-γ, IL-6, and IL-33 were not different in lesional and non-lesional samples. Immunohistochemistry analysis did not find significant alterations in the expressions of TNF-α, PPAR-γ, IL-6, and IL-33 in lesional and non-lesional regions. Our results argue that cutaneous disease activity, TNF-α, and IL-6 might play a central role in DM-associated itch, while TRPV4 plays a central role in tissue regeneration.

Study of Tofacitinib in Refractory Dermatomyositis: An Open-Label Pilot Study of Ten Patients.

This open-label 12-week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment-refractory active dermatomyositis (DM). Tofacitinib in extended-release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid-sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety. At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin. This is the first prospective, open-label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan-JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.

Evaluating important change in cutaneous disease activity as an efficacy measure for clinical trials in dermatomyositis.

Patients may experience improved quality of life (QoL) without complete clearance of skin disease. The Cutaneous Dermatomyositis Disease Area and Severity Index Activity (CDASI-A) score correlates with the Symptoms and Emotions subscales of Skindex-29, a measure of QoL, down to CDASI-A scores of 7 points (for Symptoms) and 10 points (for Emotions). Our goal was to define an important change in disease activity, as measured by the CDASI-A, that results in a meaningful change in QoL in patients with dermatomyositis. In 103 patients, we assessed the percentage change and actual change in CDASI-A scores needed to achieve a meaningful improvement in QoL, using linear regression models. We found that meaningful improvement correlates with 7·86 points (P < 0·001) in Symptoms, and 10·29 points (P < 0·001) in Emotions, after correlating Skindex-29 to an established definition of meaningful change in the Dermatology Life Quality Index (DLQI). For patients with initial CDASI-A scores > 14 points, a 40% change in CDASI-A between the first two visits suggests a meaningful change in Skindex-29. In patients with moderate initial CDASI-A (15-26 points), the changes in CDASI-A resulting in meaningful changes in Symptoms and Emotions were 6 points (P<0·001) and 7 points (P < 0·001), respectively. For initial CDASI-A scores in the severe range (27-35 points), an improvement in CDASI-A by 11 points (P=0·030) and 9 points (P = 0·021) leads to a meaningful change in Symptoms and Emotions, respectively. In patients with an initial CDASI-A score > 14 points, a 40% change in the CDASI-A score can be used to indicate a meaningful change in QoL in future dermatomyositis trials. What's already known about this topic? The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) is a validated disease assessment tool used to capture the extent of cutaneous activity and damage. The Skindex-29 and Dermatology Life Quality Index are standardized and validated measures of quality of life (QoL) for clinical trials and correlate with CDASI Activity (CDASI-A) scores. What does this study add? We identified what change in Skindex-29 scores over two consecutive visits would indicate an important change (a minimal clinically important difference) in QoL. We determined which change in CDASI-A scores over two consecutive visits would lead to a meaningful change in QoL. For patients with an initial CDASI-A score > 14 points, a 40% change in the CDASI-A score over two visits is associated with a meaningful change in QoL. What are the clinical implications of this work? Clinical trials can consider using a 40% change in the CDASI-A score as an end point when assessing the clinical efficacy of drugs.

Cutaneous dermatomyositis disease course followed over time using the Cutaneous Dermatomyositis Disease Area and Severity Index

Limitedstudies describe the longitudinal course of cutaneous dermatomyositis (DM). To characterize disease course in treated cutaneous DM by using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), a validated outcome instrument. A retrospective cohort included patients with DM who had their CDASI activity subscore recorded for at least 2years. Disease progression was classified as improved, worsened, or stable, and disease course was classified as monophasic, polyphasic, or chronic. Subjects were divided into groups with disease of mild (n=16) and moderate-to-severe (n=24) baseline severity. A total of 40 patients with DM met inclusion criteria. The majority demonstrated improvement in disease activity (n=21 [52.5%]) rather than worsening (n=7 [17.5%]) and stable (n=12 [30.0%]) disease. Most patients with mild disease remained stable (n=10 [62.5%]), whereas most with moderate-to-severe disease improved (n=19 [79.2%]). A polyphasic course (n=33 [82.5%]) predominated over monophasic (n=5 [12.5%]) and chronic (n=2 [5%]) courses. The average number of flares per year per number of years of follow-up was independent of baseline disease activity. The retrospective design, potential referral bias, and cutoff values in classification criteria are limitations. Baseline CDASI activity score is associated with particular patterns of disease course and progression in cutaneous DM.

Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis.

Dermatomyositis (DM) is an autoimmune disease primarily affecting skin and muscle. The purpose of this study was to determine whether an association exists between clinical skin disease activity as measured by the validated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and type 1 interferon (IFN) pathway biomarkers in the blood of patients with DM. Forty-two patients with DM and 25 healthy volunteers were prospectively enrolled. CDASI scores were obtained, and serum and blood RNA were isolated from all participants. Associations between CDASI activity and type 1 IFN-inducible gene signature were assessed cross-sectionally in all patient samples and longitudinally on 13 paired visits via transcriptional profiling analyses. By RNAseq analysis, type 1 IFN-inducible genes were the most highly differentially regulated. A CDASI activity threshold of 12 was correlated with an elevated type 1 IFN gene signature and with serum IFN-β, but not with IFN-α protein. Expression analysis showed that all patients with mild disease activity had a low type 1 IFN gene signature, while 93% of patients with moderate-to-high disease activity had elevated gene signature. In longitudinal analysis, changes in CDASI activity showed nonsignificant trends with concordant directional changes in gene signature. A type 1 IFN pathway signature biomarker in blood is highly correlated with CDASI activity scores in DM, and may be a promising surrogate clinical trial end point. The correlation of serum IFN-β, but not IFN-α, with both a gene signature and CDASI suggests that IFN-β drives disease activity in DM.

Design Considerations for Clinical Trials Using the Cutaneous Dermatomyositis Disease Area and Severity Index as a Primary Endpoint

Objective: Skin inflammation is a universal characteristic of the multisystem inflammatory myopathy dermatomyositis (DM). About 35% of DM patients have a polycyclic or chronic disease course, usually due to active skin disease, despite standard of care therapy, demonstrating a significant unmet need for novel treatment options. To test the efficacy of novel therapeutics, feasible prospective clinical trials must be designed that employ quantitative endpoints. The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) is a validated, reliable, and responsive measurement of cutaneous DM disease activity and damage. The primary objectives were to identify requisite design parameters (e.g., target trial population, duration, frequency of assessments, treatment difference, sample size) for a proofofconcept clinical trial of a novel therapy in patients with DM. Methods: Trial simulations were conducted to determine sample size and statistical power. Simulation inputs were obtained from analyses of CDASI natural history data obtained from 115 adult DM patients followed at Stanford University. Results: A population with baseline CDASI Activity scores ≥ 15 was simulated to eliminate a potential floor effect in patients with milder disease and to mimic a clinical trial population with moderate to severe skin disease. Given a 24 weeks trial with monthly disease assessments, simulations demonstrated that 45 patients per group were required to detect a 5 point treatment difference and 12 patients per group were required to detect a 10 point treatment difference with 80% statistical power using a 2 sided test. Conclusion: This study provides evidence that the CDASI is a practical and feasible primary efficacy endpoint for DM clinical trials and lays out a framework for a clinical trial using CDASI as a primary endpoint.

The reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) among dermatologists, rheumatologists and neurologists.

Previous studies have shown that skin disease in dermatomyositis (DM) is best assessed using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). Although the CDASI has been validated for use by dermatologists, it has not been validated for use by other physicians such as rheumatologists and neurologists, who also manage patients with DM and assess skin activity in clinical trials. To assess the reliability of the CDASI among dermatologists, rheumatologists and neurologists. Fifteen patients with cutaneous DM were assessed using the CDASI and the Physician Global Assessment (PGA) by five dermatologists, five rheumatologists and five neurologists. The mean CDASI activity scores for dermatologists, rheumatologists and neurologists were 21·0, 21·8 and 20·8, respectively. These mean scores were not different among the specialists. The CDASI damage score means for dermatologists, rheumatologists and neurologists were 5·3, 7·0 and 4·8, respectively. The mean scores between dermatologists and rheumatologists were significantly different, but the means between dermatologists and neurologists were not. The intraclass correlation coefficients (ICCs) for interrater reliability for CDASI activity and damage were good to excellent for dermatologists and rheumatologists, and moderate to excellent for neurologists. The ICCs for intrarater reliability for CDASI activity and damage were excellent for dermatologists and rheumatologists and moderate to excellent for neurologists. The PGA displayed lower interrater and intrarater reliability relative to the CDASI. Our results confirm the reliability of the CDASI when used by dermatologists and rheumatologists. The data for its use by neurologists were not as robust.

Validation of the Cutaneous Dermatomyositis Disease Area and Severity Index: characterizing disease severity and assessing responsiveness to clinical change

The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) was developed for use in clinical trials and longitudinal patient assessment. To characterize disease severity using the CDASI and assess the responsiveness of this instrument to clinically meaningful changes in disease activity. Patients with cutaneous dermatomyositis at the University of Pennsylvania (UPenn, n=93) and Stanford University (Stanford, n=106) were prospectively evaluated using the CDASI, physician global assessment (PGA) Likert scales and a visual analogue scale (VAS). Data was analysed using logistic regression models and receiver operating characteristic curves to select cut-offs. Baseline CDASI activity scores for the patients evaluated at UPenn ranged from 0 to 47 (median 17), and baseline PGA VAS scores ranged from 0 to 9·6 (median 1·1). At UPenn a CDASI activity score of 19 differentiated mild from moderate and severe disease. At Stanford baseline CDASI scores ranged from 0 to 48 (median 21), baseline PGA VAS scores ranged from 0 to 9·7 (median 4·2) and CDASI activity scores of 14 or less characterized mild disease. When a 2-cm change in the PGA VAS was regarded as a clinically significant improvement, a 4-point (UPenn) or 5-point (Stanford) change in CDASI reflected a minimal clinically significant response. The CDASI is a valid and responsive measure that can be used to characterize cutaneous dermatomyositis severity and detect improvement in disease activity. Variations in cut-offs may be due to differences in disease severity between the two populations or inter-rater variations in the use of the external gold measures.

Improvement in the cutaneous disease activity of patients with dermatomyositis is associated with a better quality of life.

Cutaneous dermatomyositis (DM) disease activity is associated with decreased quality of life. To assess if an improvement in quality of life, as measured by the Skindex-29 and patient-reported itch and pain on a 10-point visual analogue scale (VAS), correlated with an improvement in cutaneous DM disease activity. Patients with a completed cutaneous DM disease area and severity index [Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI)] at two visits separated by at least 2months were classified into responder (n=15) and nonresponder (n=30) groups according to the point change in the CDASI activity scores between visits. Responders had at least a four-point improvement in CDASI activity, indicating clinically relevant improvement. The change from baseline to the follow-up visit of the Skindex-29 subscale scores for the responders vs. the nonresponders were significantly different for emotions (P<0·01), functioning (P<0·01) and symptoms (P<0·01). The change in VAS score between responders and nonresponders was also significant for itch (P=0·01) and pain (P=0·04). There was no significant difference between the groups in terms of disease subtype, sex, race, age, treatment for DM, smoking history or a history of malignancy within 5years of a diagnosis of DM. This is the first study to demonstrate that the quality of life of patients with DM improved as their cutaneous disease activity decreased.