Lauren M. Pachman

Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood

Juvenile dermatomyositis, the most common inflammatory myopathy of childhood, is a rare systemic autoimmune vasculopathy that is characterised by weakness in proximal muscles and pathognomonic skin rashes. The length of time before the initiation of treatment affects presenting symptoms, laboratory measures, and pathophysiology. It also affects disease outcomes, including the development of pathological calcifications, which are associated with increased morbidity. Both genetic and environmental risk factors seem to have a role in the cause of juvenile dermatomyositis; HLA B8-DRB1*0301 ancestral haplotype is a strong immunogenetic risk factor, and antecedent infections and birth seasonality suggest that environmental stimuli might increase risk. Activation of dendritic cells with upregulation of genes induced by type-1 interferon (alpha) in muscle and peripheral blood seems to be central to disease pathogenesis. Treatment often includes combinations of corticosteroids, methotrexate, and other immunosuppressive agents. Disease outcome, if treatment is initiated early, is generally good. Randomised controlled trials are needed to define the most effective treatments.

Gene Expression Profiling in DQA1*0501+ Children with Untreated Dermatomyositis: A Novel Model of Pathogenesis

Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is a systemic vasculopathy affecting young children. Epidemiology studies documenting an antecedent illness in the 3 mo before the first definite symptom (rash and/or weakness) of JDM are supported by immunologic data that suggest that the disease pathophysiology is Ag driven. The purpose of this study was to compare the gene expression profiles in muscle biopsies of four untreated DQA1*0501+ JDM children with profiles from children with a known necrotizing myopathy (Duchenne muscular dystrophy), as well as an in vitro antiviral model (NF90), and healthy pediatric controls. Nearly half (47%) of the dysregulated genes in JDM were associated with the immune response. In particular, increased expression of IFN-αβ-inducible genes 6-16, myxovirus resistance protein p78, latent cytosolic transcription factor, LMP2, and TAP1 was observed. This profile is consistent with an IFN-αβ transcription cascade seen in the in vitro viral resistance model. The IFN-αβ-inducible profile was superimposed on transcription profiles reflective of myofiber necrosis and regeneration shared with Duchenne muscular dystrophy. Expressed genes were confirmed by quantitative real-time PCR (6-16), immunofluorescence (thrombospondin 4), and immunolocalization (IFN-γ, p21). We hypothesize that these data support a model of Ag (?viral) induction of an apparent autoimmune disease based on dynamic interaction between the muscle, vascular, and immune systems in the genetically susceptible (DQA1*0501+) child.

Mutations in the Mu Heavy-Chain Gene in Patients with Agammaglobulinemia

BACKGROUND Most patients with congenital hypogammaglobulinemia and absent B cells are males with X-linked agammaglobulinemia, which is caused by mutations in the gene for Brutons tyrosine kinase (Btk); however, there are females with a similar disorder who do not have mutations in this gene. We studied two families with autosomal recessive defects in B-cell development and patients with presumed X-linked agammaglobulinemia who did not have mutations in Btk. METHODS A series of candidate genes that encode proteins involved in B-cell signal-transduction pathways were analyzed by linkage studies and mutation screening. RESULTS Four different mutations were identified in the mu heavy-chain gene on chromosome 14. In one family, there was a homozygous 75-to-100-kb deletion that included D-region genes, J-region genes, and the mu constant-region gene. In a second family, there was a homozygous base-pair substitution in the alternative splice site of the mu heavy-chain gene. This mutation would inhibit production of the membrane form of the mu chain and produce an amino acid substitution in the secreted form. In addition, a patient previously thought to have X-linked agammaglobulinemia was found to have an amino acid substitution on one chromosome at an invariant cysteine that is required for the intrachain disulfide bond and, on the other chromosome, a large deletion that included the immunoglobulin locus. CONCLUSIONS Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in humans. This implies that an intact membrane-bound mu chain is essential for B-cell development.

TNFα-308A allele in juvenile dermatomyositis: Association with increased production of tumor necrosis factor α, disease duration, and pathologic calcifications

Objective To characterize the association between the TNFα-308A allele and 1) duration of active disease, 2) peripheral blood mononuclear cell (PBMC) synthesis of tumor necrosis factor α (TNFα) in vitro, and 3) pathologic calcifications in patients with juvenile dermatomyositis (DM). Methods The TNFα-308 alleles were determined by polymerase chain reaction in 37 white patients with juvenile DM and in 29 control subjects. Patients were grouped according to duration of immunosuppressive therapy: long (≥36 months) or short (<36 months). Unstimulated PBMC were examined by enzyme-linked immunosorbent assay for TNFα production in vitro. Sixty-five white patients with juvenile DM were examined for pathologic calcifications. Results TNFα-308A was identified in 18 of 37 patients with juvenile DM, in contrast with 5 of 29 controls (P = 0.009). Sixteen of the 18 patients with juvenile DM who had the TNFα-308A allele had a disease course ≥36 months, compared with 6 of 19 patients with TNFα-308G (P = 0.001). PBMC from 16 of the 18 juvenile DM patients with TNFα-308A synthesized more TNFα (median 53 pg/ml) compared with PBMC from 9 of 19 patients with TNFα-308G (median 19 pg/ml) (P = 0.007). Nineteen of 22 juvenile DM patients requiring therapy for ≥36 months produced more TNFα (median 20.5 pg/ml) in comparison with 6 of 15 juvenile DM patients with a <36-month treatment course (median TNFα 0.0 pg/ml) (P = 0.005). Detectable calcifications were present in 3 of 8 children with juvenile DM who had TNFα-308AA, compared with 2 of 21 children with TNFα-308AG and 1 of 36 children who had TNFα-308GG (P = 0.017). Conclusion A long course of juvenile DM and the presence of pathologic calcifications were associated with the TNFα-308A allele and with the increased production of TNFα, which may perpetuate the inflammatory response.

Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies: II. The childhood myositis assessment scale (CMAS): a quantitative tool for the evaluation of muscle function

OBJECTIVE To develop, validate, and determine the measurement characteristics of a quantitative tool for assessing the severity of muscle involvement in children with idiopathic inflammatory myopathies. METHODS The Childhood Myositis Assessment Scale (CMAS) was developed from 2 existing observational functional assessment tools to assess muscle function in the areas of strength and endurance across a wide range of ability and ages. The 14 ordinal items included were chosen to assess primarily axial and proximal muscle groups and are ranked with standard performance and scoring methods. Following the development of the CMAS, a training video and written instructions were developed and reviewed by the physicians participating in this study. Subsequently, utilizing a randomized block design, 12 physicians independently scored 10 children (9 with dermatomyositis, 1 with polymyositis; ages 4-15 years) twice in one day (morning and afternoon) on the CMAS. A pediatric physical therapist performed quantitative manual muscle strength testing (MMT) twice on each child (morning and afternoon), including the neck, trunk, and proximal and distal extremity muscle groups. RESULTS The CMAS has a potential range of 0-51, with higher scores indicating greater muscle strength and endurance. The observed mean for the 10 patients was 36.4 (median 44, SD 14.1, observed range 5-51). The total score for the CMAS correlated with the physicians global assessment (by visual analog scale) of disease activity, the MMT score, serum creatine kinase level, and the Juvenile Arthritis Functional Assessment Report score. The score on the CMAS was not correlated with patient age. Interrater reliability (Kendalls coefficient of concordance) ranged from 0.77 to 1.0 for individual items (all P < 0.001), and overall, it was 0.95 (P < 0.001). Intrarater reliability for the individual physicians was measured by correlation of the CMAS scores for each patient on 2 separate evaluations and ranged from 0.97 to 0.99, with an overall correlation for all physicians of 0.98 (all P < 0.001). CONCLUSION The CMAS demonstrated an acceptable range of observed scores, excellent convergent validity, and excellent inter- and intrarater reliability. The CMAS is validated to quantitatively assess muscle function in the areas of strength and endurance in children with idiopathic inflammatory myopathies. It can be used in routine clinical care as well as therapeutic trials.

Epstein-Barr virus-induced diseases in boys with the X-linked lymphoproliferative syndrome (XLP): Update on studies of the registry

Analyses of 100 subjects with the X-linked lymphoproliferative syndrome (XLP) in 25 kindreds revealed four major interrelated phenotypes: infectious mononucleosis, malignant B-cell lymphoma, aplastic anemia, and hypogammaglobulinemia. Eighty-one of the patients died. Two male subjects were asymptomatic but showed immunodeficiency to Epstein-Barr virus (EBV). Seventy-five subjects had the infectious mononucleosis phenotype and concurrently, 17 subjects of this group had aplastic anemia. All subjects with aplastic anemia died within a week. Aplastic anemia did not accompany hypogammaglobulinemia or malignant lymphoma phenotypes. Hypogammaglobulinemia had been detected before infectious mononucleosis in three subjects, after infectious mononucleosis in five subjects, and was not associated with infectious mononucleosis in 11 boys with hypogammaglobulinemia. In nine subjects infectious mononucleosis appeared to have evolved into malignant lymphoma; however, the majority of patients with malignant lymphoma showed no obvious antecedent infectious mononucleosis. One subject had infectious mononucleosis following recurrent malignant lymphoma. Twenty-six of 35 lymphomas were in the terminal ileum. Results of immunologic and virologic studies of 15 survivors revealed combined variable immunodeficiency and deficient antibody responses to EBV-specific antigens. Mothers of boys with XLP exhibited abnormally elevated titers of antibodies of EBV. Subjects of both sexes with phenotypes of XLP should be investigated for immunodeficiency to EBV. Persons with inherited or acquired immunodeficiency may be vulnerable to life-threatening EBV-induced diseases.

Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies.

To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM).

Juvenile dermatomyositis: A clinical and immunologic study

Twenty-one children were diagnosed as having juvenile dermatomyositis on the basis of the strict criteria of Bohan and Peter. In addition to the typical skin and muscle changes, abnormalities of esophageal motility (eight of 19), pulmonary function (14 of 17), ECG (10 of 20), and gastrointestinal absorption of D-xylose (two of eight) with active disease were observed. Clinical signs of other collagen vascular disease appeared in five children. Serologic evaluation demonstrated that ANA and rheumatoid factor were transiently positive in six; one child developed a persistently positive rheumatoid factor after four years of disease inactivity. Antibody to ENA was negative in all, but antibody to PM-1 antigen was present in four of 18. Six had a low C3 or C4; evidence of immune complexes was demonstrated by Clq or Raji binding in eight with active disease. One child was IgA deficient. The HLA-B8 antigen was present in 72% of the Caucasian children as compared with the expected incidence of 21%. Therefore, classical dermatomyositis in children has more systemic involvement then previously appreciated, may be related to the presence of circulating immune complexes, and appears to be under immunogenetic control.

Juvenile dermatomyositis: Pathophysiology and disease expression

In summary, the child who develops the symptoms of the specific rash, proximal muscle weakness, or fatigue should seek medical care promptly. With the advances in physical and medical therapy, many of the consequences of the disease can now be ameliorated. Data suggest that JDMS and PM may each have a different pathophysiology, but more evidence is needed. The next few years will be exciting as there is a national effort by an increased number of investigators to determine the epidemiologic and genetic factors that influence JDMS disease susceptibility and severity.

Persistent Association of Nailfold Capillaroscopy Changes and Skin Involvement Over Thirty-Six Months With Duration of Untreated Disease in Patients With Juvenile Dermatomyositis

OBJECTIVE To determine the association of changes on nailfold capillaroscopy with clinical findings and genotype in children with juvenile dermatomyositis (DM), in order to identify potential differences in disease course over 36 months. METHODS At diagnosis of juvenile DM in 61 children prior to the initiation of treatment, tumor necrosis factor alpha (TNFalpha) -308 allele and DQA1*0501 status was determined, juvenile DM Disease Activity Scores (DAS) were obtained, and nailfold capillaroscopy was performed. The disease course was monitored for 36 months. Variations within and between patients were assessed by regression analysis. RESULTS At diagnosis, shorter duration of untreated disease (P = 0.05) and a lower juvenile DM skin DAS (P = 0.035) were associated with a unicyclic disease course. Over 36 months, end-row loop (ERL) regeneration was associated with lower skin DAS (P < 0.001) but not muscle DAS (P = 0.98); ERL regeneration and decreased bushy loops were associated with a shorter duration of untreated disease (P = 0.04 for both). At 36 months, increased ERL regeneration (P = 0.007) and improvement of skin DAS (P < 0.001) and muscle DAS (P = 0.025) were associated with a unicyclic disease course. CONCLUSION Early treatment of juvenile DM may lead to a unicyclic disease course. The non-unicyclic disease course usually involves continuing skin manifestations with persistent nailfold capillaroscopy changes. The correlation of nailfold capillaroscopy results with cutaneous but not with musculoskeletal signs of juvenile DM over a 36-month period suggests that the cutaneous and muscle vasculopathies have different pathophysiologic mechanisms. These findings indicate that efforts to identify the optimal treatment of cutaneous features in juvenile DM require greater attention.