Comparison of Lesional Juvenile Myositis and Lupus Skin Reveals Overlapping Yet Unique Disease Pathophysiology.

OBJECTIVE: Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood-onset systemic lupus erythematosus (SLE). METHODS: We used formalin-fixed paraffin-embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood-onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of up-regulated genes representing interferon (IFN)-stimulated genes. CXCL10, CXCL9, and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q < 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood-onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA, and SLURP1. Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP-2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx-1 immunostaining, both in keratinocytes and perivascular regions. CONCLUSION: Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP-2 autoantibodies may provide insight into disease endotypes and pathogenesis.

Effect of botulinum toxin type A, motor imagery and motor observation on motor function of hemiparetic upper limb after stroke.

BACKGROUND: In rehabilitation settings, motor imagery, motor observation and mirror therapy serve as techniques for the recovery of paretic upper limb in patients with movement disorders after stroke, whereas botulinum toxin type A (BTX-A) offers the best treatment for focal spasticity. CASE REPORTS: After haemorrhagic stroke, three patients (two men and one woman, mean age: 61.2 +/- 7.03) presented with hemiparesis of the left or right hand and arm with flexion of fingers, wrist and elbow, with no disturbance to sensitivity but with loss of use handoff the limb to write, eat or dress. After BTX-A injections, the patients underwent a daily rehabilitation programme based on motor imagery and motor observation for 1 month. Before and after the combined treatment, the motor function, spasticity and functional deficits of the patient were extensively measured. After a 3-month follow-up, upper limb spasticity measured with the Modified Ashworth Scale had worsened, yet the associated score remained lower than that at baseline. However, in these three patients a large improvement of motor function of the hemiparetic upper limb was observed. CONCLUSION: Combined treatment may be a viable rehabilitation option in post-stroke patients with disability to upper-extremity motor function, however further investigations are needed to determine its reproducibility in larger case series or clinical trials.

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.

OBJECTIVE: Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction-related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. METHODS: In total, 39 biomarkers related to activation of endothelial cells, endothelial dysfunction, and inflammation were measured using multiplex technology in serum samples from treatment-naive patients with juvenile DM from 2 independent cohorts (n = 30 and n = 29). Data were analyzed by unsupervised hierarchical clustering, nonparametric tests with correction for multiple comparisons, and Kaplan-Meier tests with Cox proportional hazards models for analysis of treatment duration. Myositis-specific antibodies (MSAs) were measured in the patients' serum using line blot assays. RESULTS: Severe vasculopathy in patients with juvenile DM was associated with low serum levels of intercellular adhesion molecule 1 (Spearman's rho [rs ] = 0.465, P = 0.0111) and high serum levels of endoglin (rs = -0.67, P < 0.0001). In the discovery cohort, unsupervised hierarchical clustering analysis of the biomarker profiles yielded 2 distinct patient clusters, of which the smaller cluster (cluster 1; n = 8) exhibited high serum levels of CXCL13, CCL19, galectin-9, CXCL10, tumor necrosis factor receptor type II (TNFRII), and galectin-1 (false discovery rate <0.0001), and this cluster had greater severity of muscle disease and global disease activity (each P < 0.05 versus cluster 2). In the validation cohort, correlations between the serum levels of galectin-9, CXCL10, TNFRII, and galectin-1 and the severity of global disease activity were confirmed (rs = 0.40-0.52, P < 0.05). Stratification of patients according to the 4 confirmed biomarkers identified a cluster of patients with severe symptoms (comprising 64.7% of patients) who were considered at high risk of requiring more intensive treatment in the first 3 months after diagnosis (P = 0.0437 versus other cluster). Moreover, high serum levels of galectin-9, CXCL10, and TNFRII were predictive of a longer total treatment duration (P < 0.05). The biomarker-based clusters were not evidently correlated with patients' MSA serotypes. CONCLUSION: Results of this study confirm the heterogeneity of new-onset juvenile DM based on serum biomarker profiles. Patients with high serum levels of galectin-9, CXCL10, TNFRII, and galectin-1 may respond suboptimally to conventional treatment, and may therefore benefit from more intensive monitoring and/or treatment.

Decreased CD3-CD16+CD56+ natural killer cell counts in children with orbital myositis: a clue to disease activity.

The study aimed to document the utility of the absolute number of natural killer cells as a biomarker in paediatric orbital myositis (OM). Extracted data from four children with OM included demographics, laboratory values, imaging and treatment response. Stored sera (-80°C) were tested for IgG4 levels in three cases and antibody to Coxsackie B in two cases. Their first symptom was at 14.4±1.2 years (mean±SD). At diagnosis three had creatine phosphokinase (CPK) of 97.3±44.2, aldolase of 8.5±2.8 (n=2), alanine aminotransferase (ALT) of 13±2.8 (n=2) and aspartate aminotransferase (AST) of 21.3±2.9. IG4 level was 87.7±66 (normal=8-89 mg/dL); two sera (patients 1and4) were positive (>1:8 dilution) for anti-Coxsackievirus antigen B5. The CD3-CD16+CD56+ natural killer absolute count was 96.7±28.7 (lower limit of normal=138), increasing to 163±57.2 with disease resolution in three patients. The fourth patient was followed elsewhere. CT showed involvement of bilateral superior oblique, lateral rectus or the left medial rectus muscles. Treatment included intravenous methylprednisolone, methotrexate (n=2) and other immunosuppressants. Paediatric OM disease activity was associated with initially low absolute CD3-CD16+CD56+ natural killer cell counts, which normalised with improvement. We speculate (1) infection, such as Coxsackie B virus, may be associated with paediatric OM; and (2) the absolute count of circulating CD3-CD16+CD56+ natural killer lymphocytes may serve as a biomarker to guide medical therapy.

Lack of achievement of a full score on the childhood myositis assessment scale by healthy four-year-olds and those recovering from juvenile dermatomyositis.

OBJECTIVE: To test 4-year-olds, using 14 maneuvers of the Childhood Myositis Assessment Scale (CMAS), comparing healthy children with those with juvenile dermatomyositis (DM). METHODS: Healthy 4-year-olds (n = 28) completed the CMAS. Their scores were compared with children with juvenile DM (n = 18) who had a muscle Disease Activity Score (DAS-M) of 0. RESULTS: The healthy children achieved a mean ± SD CMAS score of 46.6 ± 2.3 (interquartile range 46-47). There were no significant differences between boys and girls, and the scores were not significantly associated with height or weight. The greatest variation involved items that assessed endurance. Item 1, neck raise, yielded a mean ± SD score of 28.2 ± 19.3 seconds, with a mean ± SD CMAS score of 2.5 ± 0.9 (maximum score 5). Item 3, leg lift, yielded a mean ± SD score of 55.5 ± 37.3 seconds, with a mean ± SD CMAS score of 3.1 ± 1.1 (maximum score 5). Item 5, sit-ups maneuver, yielded a mean ± SD score of 5.3 ± 1.1 sit-ups. Almost identical data were obtained for the 18 treated children with juvenile DM who had normal strength on the DAS-M. CONCLUSION: Healthy children ages 4 years do not achieve the total CMAS score of 52 attained by older children. Both boys and girls were remarkably consistent, with a mean CMAS score of 46.6. Children ages 4 years with juvenile DM with a DAS-M of 0 also achieved a CMAS score of 46.6. We conclude that half of 4-year-old children achieve a mean CMAS score of 46 or 47, not a total CMAS score of 52, suggesting that weakness may be overdiagnosed in 4-year-olds with an inflammatory myopathy.

Effect of intrathecal baclofen, botulinum toxin type A and a rehabilitation programme on locomotor function after spinal cord injury: a case report.

OBJECTIVE: A few studies have reported the use of botulinum toxin injections after spinal cord injury, as this is the gold standard to treat focal spasticity. We report such a case here. CASE REPORT: A 38-year-old woman who had become paraplegic and care-dependent secondary to cervico-thoracic intramedullary ependymoma, presented 8 months later with painful lower limb spasticity, which was being treated with oral anti-spastic and benzodiazepine drugs with no therapeutic effect. We treated the patient with intrathecal baclofen to reduce her spasticity and in order to avoid the major side-effects of high dosages of oral baclofen. After motor rehabilitation programmes, which included functional electrical stimulation, the patient was able to wear an advanced reciprocating gait orthosis. However, she experienced painful muscle spasms in her toes of the feet that limited her gait. Therefore, she was also treated with bilateral injections of botulinum toxin type A into the flexor digitorum brevis muscles. The patient reported relief of spasms and pain, enabling her to wear an advanced reciprocating gait orthosis and facilitating rehabilitation programmes. CONCLUSION: The use of botulinum toxin type A may be an important adjunctive therapy to increase the therapeutic effect of baclofen on spasticity in small muscles, resulting in a more focal effect, and improving the use of orthoses and the effectiveness of rehabilitation programmes in patients after spinal cord injury.