What more can we learn from muscle histopathology in children with dermatomyositis/polymyositis?

OBJECTIVE: To correlate disease course and complications in children with juvenile dermatomyositis (JDM) and polymyositis (JPM) with specific features of muscle pathology on biopsy. METHODS: This is a retrospective cohort analysis of 59 children diagnosed with JDM or JPM between 1965 and 1998 and followed at the Cincinnati Children's Hospital Medical Center (CCHMC) for a mean duration of 7.3 years (range 1.1-24.5 years). Disease course was characterized as limited, chronic non-ulcerative or chronic ulcerative, similar to previously defined disease course subtypes reported by Crowe et al.(1). All subjects had diagnostic muscle biopsies performed at CCHMC and had disease for at least two years' duration in order to classify their disease course as either limited or chronic. Features of muscle histopathology that were evaluated included loss of the intramuscular capillary bed, infarct, perifascicular myopathy, direct immunofluorescence (DIF) staining of the intramuscular vasculature and specifically, the locale of DIF staining, i.e., small arteries or capillaries. Disease complications that were assessed included calcinosis, contractures, muscle atrophy, lipodystrophy, gastrointestinal ulceration, cutaneous ulceration and death. Data analysis was completed using Chi-square or Fisher's exact tests and logistic regression modeling. RESULTS: Twenty-two children (37%) had limited disease, 24 (41%) had chronic non-ulcerative disease and 13 (22%) had chronic ulcerative disease. Neither loss of the intramuscular capillary bed nor perifascicular myopathy on muscle biopsy significantly correlated with disease course or the various complications evaluated in this study. DIF staining of intramuscular vessels overall was not significantly associated with clinical disease course, but the localization of DIF staining to intramuscular arteries (rather than to capillaries) was significantly associated with the outcome of chronic ulcerative disease. Nine of the 13 children with chronic ulcerative disease had DIF-arterial staining on muscle biopsy (69%), significantly greater than DIF-arterial staining in children with limited disease (32% had DIF-arterial staining) (p = 0.04), chronic non-ulcerative disease (8% had DIF-arterial staining) (p = 0.0002), and non-ulcerative disease overall (limited + chronic non-ulcerative disease groups combined) (20% had DIF-arterial staining), with p = 0.001. Additionally, lack of DIF-arterial staining on biopsy was significantly correlated with patients not having gastrointestinal ulceration (p = 0.002), cutaneous ulceration (p = 0.004) and/or death (p = 0.02) as disease-related complications. Infarct on muscle biopsy was significantly associated with the development of chronic ulcerative disease (p = 0.02), being present on biopsy in 23% of children with chronic ulcerative disease compared with none of the patients with chronic non-ulcerative disease and 4% of those with limited disease. Infarct on muscle biopsy correlated with the outcomes of death (p = 0.01) and gastrointestinal ulceration (p = 0.03), but not with the development of cutaneous ulceration (p = 0.18). CONCLUSION: DIF-arterial staining and infarct on muscle biopsy are significantly associated with the development of chronic ulcerative disease in JDM and JPM, while perifascicular myopathy and loss of the intramuscular capillary network are not associated with disease course. The presence of DIF-arterial staining and infarct on biopsy should suggest early use of second-line therapeutic agents to more quickly bring disease activity under control.

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. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group.

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 physician's 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 (Kendall's 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.

Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. II. Early predictors of outcome.

OBJECTIVE: To determine whether demographic, clinical, and immunogenetic variables measurable during the first 6 months of illness long-term health outcomes and quality of life in patients with juvenile rheumatoid arthritis (JRA). METHODS: Patient eligibility criteria: (1) first examined in our units between 1958 and 1990 within 6 months of onset of symptoms; (2) diagnosis of JRA by American College of Rheumatology criteria; (3) disease duration of at least 5 years at the time of assessment of outcome. Instruments used: (1) the Health Assessment Questionnaire (HAQ, short form), or Childhood HAQ (CHAQ) to measure disability (0-3 scale), (2) pain, and (3) parental assessment of overall well being, each scored on a 15 cm visual analog scale; (4) the Quality of Life Scales (QOLS) (adults only). Independent variables that showed significant results using univariate tests underwent multiple logistic regression analysis. RESULTS: 227 patients were available for analysis. Mean duration of disease at time of assessment of outcome was 15 years (range 5.3-36.1). Univariate tests allowed 11 variables for disability, 9 for pain, 7 for overall well being, and 4 for QOL into the multivariate analysis. The best predictor of higher disability was the articular severity score (odds ratio, OR, 5.69) while antinuclear antibody positivity foretold less disability (OR 0.29). HLA-DR5 positivity conferred the greatest risk for pain (OR 3.34), while HLA-B5, DR3, and C3 were protective (OR 0.25, 0.28, 0.33, respectively). Early hand involvement was the strongest predictor of poorer overall well being (OR 8.75). Only the erythrocyte sedimentation rate was predictive of future QOL, but the model yielded a low C statistic (< 70%) and the OR 95% confidence limits were extreme (OR 9.77; 95% confidence interval, 1.22-77.8). CONCLUSION: Clinical and immunogenetic variables measurable within 6 months of onset of JRA can be used to predict future disability, pain, and well being. QOL appears more difficult to forecast, perhaps due to the multiple domains that make up this outcome. Further study is needed to identify other genetic and laboratory factors that predict outcome in JRA with greater precision.

Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. I. Outcome status.

OBJECTIVE: To assess the long-term health outcomes and quality of life of patients with juvenile rheumatoid arthritis (JRA) using health and functional assessment questionnaires in 2 populations, one from the USA and one from Italy. METHODS: Patient eligibility criteria: (1) first examined in our units between 1958 and 1990 during the first 6 months after onset of symptoms, (2) diagnosis of JRA by the American College of Rheumatology criteria, (3) disease duration of at least 5 years at the time of assessment of outcome. Instruments used: (1) the Health Assessment Questionnaire (HAQ, short form, or childhood HAQ (CHAQ), and (2) Quality of Life Scales (QOLS, adults only). Eligible patients were identified by computer search and chart review and were then mailed a packet containing a consent/assent form and the assessment instruments. RESULTS: Of 346 patients who met the eligibility criteria were able to locate 301, and 290 verbally agreed to participate and were mailed packets. Signed consent and complete information were received from 227 of the 290 (78%), 178 from the USA and 49 from Italy. Mean duration of disease at the time of outcome assessment was 15 yrs. 127 had pauciarticular, 55 polyarticular, and 45 systemic onset disease. Mean and (median) scores of the outcomes are shown in the table. [table: see text] CONCLUSION: Long-term outcome, as assessed by the instruments used, is very favorable in most patients with JRA 5 years or more after onset of symptoms.

Antibodies to the 45 kDa DEK nuclear antigen in pauciarticular onset juvenile rheumatoid arthritis and iridocyclitis: selective association with MHC gene.

OBJECTIVE: To study the frequency of autoantibodies to the 45 kDa DEK nuclear antigen, a putative oncoprotein, in a sample of patients with juvenile rheumatoid arthritis (JRA), and to make correlations with disease subtype and complications such as iridocyclitis. Class I and Class II HLA associations with reactivity to the antigen were also sought. METHODS: Sera from 146 HLA typed patients with JRA representing all subtypes were analyzed for reactivity with the 45 kDa DEK protein by immunoblotting. The antigen was purified to near homogeneity from nuclei of HeLa cells. RESULTS: Antibodies to DEK were found in 57% of all patients with JRA compared to 3% of controls (p < 0.0001). Antibodies were detected more frequently in pauciarticular onset (78%) than in polyarticular onset patients (29%; p < 0.01) and controls (3%; p < 0.0001). 97% of patients with JRA (regardless of onset subtype) and iridocyclitis had anti-DEK antibodies compared to 47% of patients without eye disease (p < 0.0001). Anti-DEK antibodies were found more frequently in females compared to males in the pauciarticular onset disease group (84 vs 42%; p < 0.01). The occurrence of anti-DEK antibodies was closely associated with positive antinuclear antibody serology, and a strong association with the Class I gene HLA-A2 was also observed. CONCLUSION: Antibodies to the 45 kDa DEK protein are characteristic of the pauciarticular onset subtype of JRA, particularly in patients with a history of iridocyclitis. The occurrence of anti-DEK antibodies is significantly but paradoxically associated with the presence of the HLA-A2 allele in such patients.

VH4-34 (VH4.21) gene expression in the chronic arthritides of childhood: studies of associations with anti-lipid A antibodies, HLA antigens, and clinical features.

OBJECTIVE: To determine if the germ line gene VH4-34 (VH4.21) encodes the antimonophosphoryl lipid A (MPL) polyspecific antibodies found in oligoarticular arthritis of childhood. METHODS: Sera from a range of rheumatic diseases of childhood were assayed for VH4-34 derived antibodies by ELISA using the antiidiotype monoclonal antibody 9G4. Results were compared to assays for anti-MPL antibodies, C4d, and Bb, and for HLA type, joint count, and sedimentation rate. RESULTS: VH4-34 derived antibodies were elevated in all diseases studied except rheumatoid factor positive polyarticular disease. In oligoarticular arthritis, VH4-34 gene expression correlated with C4d concentration, and VH4-34 encoded globulins were more concentrated in synovial fluid than in blood. No association was found with HLA type. An association between VH4-34 expression and IgG anti-MPL was found in sera from patients from Cincinnati but not from Stanford. No other evidence supported a direct association between VH4-34 derived and anti-MPL antibodies in these children. CONCLUSION: The expression of VH4-34 is increased in several rheumatic diseases of childhood, but, as in adults, not in rheumatoid arthritis. VH4-34 expression is not associated with HLA type. The polyspecific autoantibody nature of some VH4-34 derived antibodies may explain the wide range of the unusual antibodies found in oligoarticular arthritis.

Human leukocyte antigen-DRB1*1104 in the chronic iridocyclitis of pauciarticular juvenile rheumatoid arthritis.

To determine whether genetic markers for chronic iridocyclitis could be identified, we used both serologic and oligonucleotide dot blot techniques to characterize immunogenetically 164 children with early-onset pauciarticular juvenile rheumatoid arthritis. Seventy-eight children (47.6%) had chronic iridocyclitis and 86 (52.4%) had not had evidence of eye disease during a mean follow-up period after the onset of arthritis of 15.8 years (minimum of 5.5 years). Control subjects were 218 healthy, unrelated individuals. The analysis was limited to alleles known to be associated with an increased or decreased risk of early-onset pauciarticular juvenile rheumatoid arthritis or of chronic iridocyclitis in this form of juvenile rheumatoid arthritis. Only one split of human leukocyte antigen (HLA)-DR5, HLA-DRB1* 1104, showed a statistically significant association with a risk of chronic iridocyclitis (chi-square value = 7.52; p = 0.036 adjusted; odds ratio 3.45); HLA-DQA1* 0501 and HLA-DQB1* 0301, both in linkage disequilibrium with HLA-DRB1* 1104, also were significantly associated with eye disease. Patients with both the DRB1* 1104 and DPB1* 0201 genes had a 7.7-fold increased risk for chronic iridocyclitis compared with that for other patients. The presence of HLA-DRB1* 1104 was about four times as specific, but only about one third as sensitive, as antinuclear antibodies in identifying patients at risk for eye disease. Although all children with early-onset pauciarticular juvenile rheumatoid arthritis should undergo periodic slit-lamp examinations, those with the HLA class II gene DRB1* 1104 are at particularly high risk for eye disease, and we recommend that they be monitored carefully for its evolution.

Dismantling the pyramid.

The suggestion is heard, with increasing frequency, that the therapeutic pyramid be dismantled and that medical management be reordered to treat juvenile rheumatoid arthritis as early and as decisively as possible to induce prompt remission of disease, thereby preserving function and the quality of life. We scrutinize paradigms that guide our treatment strategies, review current practices, update data derived from those practices, and propose reassessment for treatment in the 1990s.

The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients.

In a cohort of 72 patients with iridocyclitis (iritis) and early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) the course of the eye disease was matched with ocular outcome. Chronicity of inflammation (greater than 6 months/episode) was correlated with complications of eye disease that caused impairment of vision. HLA antigens in these patients were compared with the HLA antigens in a cohort of 77 patients with EOPA-JRA in whom iridocyclitis had failed to develop over a followup of 5 years or longer. HLA-DR5 (11) was correlated with the presence of eye disease, and HLA-DR1 with its absence; HLA-DRw8, which strongly predisposes to EOPA-JRA, was neutral with respect to eye disease.

Juvenile rheumatoid arthritis: outcome and treatment for the 1990s.

There has been much discontent with the hazards and the uncertain responses of patients with juvenile rheumatoid arthritis (JRA) to time-honored modalities of management. The treatment of JRA is often thought of as a pyramid with the base formed by nonsteroidal anti-inflammatory drugs, patient and family education, physical therapy, occupational therapy, and family support. Mechanisms of human disease have begun to open the gates to understanding the why and when of connective tissue diseases; they also offer the prospect of direct therapeutic intervention. In this article, the authors scrutinize the paradigms that guide our treatment strategies, review current practices, update data derived from those practices, and propose reassessment of therapy in the 1990s.

Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis.

The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA.

Arthropathy of Down syndrome.

A juvenile rheumatoid arthritis-like arthropathy has previously been documented in 12 patients with Down syndrome. An additional 9 patients are described and the literature is reviewed. It is unknown whether these patients have juvenile rheumatoid arthritis or a unique arthropathy in light of the genetic and immunologic abnormalities associated with Down syndrome. Most of the patients had a progressive course with polyarticular disease complicated by subluxations and a long lag time to diagnosis. The purpose of reporting these children is to increase awareness of this association and facilitate more appropriate and timely diagnosis of arthritis in Down syndrome patients.

Summer camps for juveniles with rheumatic disease: do they make a difference?

Summer camps for juveniles with rheumatic disease are being offered increasingly as components of comprehensive treatment approaches, but the therapeutic value of these sessions is largely undetermined. This study attempted to judge the impact of a summer camping experience on two aspects of participants' psychosocial functioning, self-concept, and locus of control. Both of these constructs have been related to effective disease management. On both measures, the mean scores of 36 campers improved significantly following a week-long camp session, and these positive effects were maintained over a 6-month follow-up period. Campers who had attended previous camping sessions appeared to obtain maximal benefit, and male campers with rheumatic disease were identified as needing special attention. The study's limitations are discussed, and future research directions are outlined.

HLA and altered sex ratios in juvenile rheumatoid arthritis sibships.

Analysis of sex ratio in 301 siblings of 150 patients with early-onset pauciarticular juvenile rheumatoid arthritis revealed a male-to-female ratio of 1:2.00 in sibships with an HLA-B44+ proband, compared with a ratio of 1:1.05 in other sibships (G2 = 6.07, df = 1, p = 0.014). The siblings had a sex ratio of 1:0.8, when the HLA-B44 antigen was present in either parent but not transmitted to the proband. The capacity to distort the sex ratio was limited therefore to disease-associated HLA-B44 haplotypes.

Reflections of a pediatric rheumatologist.

Pediatric rheumatology has come of age and has made significant contributions through interdisciplinary care to the health of patients, families, and communities. Our patients have also achieved greater career education than their peers in the general population. Basic research in the rheumatic diseases of childhood is beginning to coexist with strong patient care and clinical research programs.

Community programs for children with rheumatic diseases.

There is an evident need for both qualitative and quantitative expansion of services to children with rheumatic or connective tissue diseases. These are necessary for diagnosis, amelioration, rehabilitation and reconstruction at the physical level. They are equally important for the development of appropriate and gratifying career and other biopsychosocial goals and for the achievement of them. Two model programs have been described. Such programs should be designed to accommodate local and regional conditions within the broad context of comprehensive care. Numerous governmental and private agencies are available to assist in this process, but it is still dynamic and evolutionary.

A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis.

Criteria for the classification of juvenile rheumatoid arthritis were analyzed in a detailed database of 250 children in order to assess the accuracy of diagnosis and validity of onset types and course subtypes. A number of conclusions have been derived from this study: All definitions of the 1973 criteria for classification of juvenile rheumatoid arthritis should be retained. The addition of onset types to the 1976 revision of the criteria has been validated. The course of the disease after the onset period of 6 months is as important to the outcome of a group of children as is the onset type. The current classification should be broadened to include the course subtypes.