Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

BACKGROUND: The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). METHODS: The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. RESULTS: One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. CONCLUSIONS: Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

Juvenile dermatomyositis at diagnosis: clinical characteristics of 79 children.

OBJECTIVE: To evaluate demographic and clinical characteristics, duration of time between disease onset (date of first rash and/or weakness), and diagnosis/therapy, as well as socioeconomic status, of children with newly diagnosed juvenile dermatomyositis (JDM). METHODS: Structured telephone interview of families of a cohort of 79 children with JDM: interval between onset of symptoms to diagnosis, median of 3 months (range 0.5-20.0). RESULTS: At diagnosis, all the children had rash (100%) and proximal muscle weakness (100%); 58 (73%) had muscle pain; 51 (65%) fever; 35 (44%) dysphagia; 34 (43%) hoarseness; 29 (37%) abdominal pain; 28 (35%) arthritis; 18 (23%) calcinosis, and 10 (13%) melena. Muscle derived enzymes were normal in 10% of the children. Of the 43 children who had an electromyogram (EMG), 8 (19%) had normal results. Fifty-one children had a muscle biopsy; the results were normal/nondiagnostic in 10 (20%). Median time from disease onset to diagnosis was different between racial groups: Caucasians (n=59) 2.0 months: for minorities (n=20), 6.5 months, (p=0.0008). The median time from disease onset to therapy was: Caucasians. 3.0 months; minorities, 7.2 months (p=0.002). Report of calcinosis was associated with increased time to diagnosis and therapy (p=0.04). In the 33 children whose first symptom occurred in June-September, rash preceded or accompanied onset of muscle weakness in 83% (n=27). Ninety-one percent of the children were given steroid therapy and 9% received methotrexate as well. CONCLUSION: The results of an undirected site for muscle biopsy or EMG may not be diagnostic. Minority children had a longer interval between first JDM symptom and diagnosis/therapy than Caucasian children. Delay in diagnosis/therapy was associated with calcinosis.

New-onset juvenile dermatomyositis: comparisons with a healthy cohort and children with juvenile rheumatoid arthritis.

OBJECTIVE: To determine, in a case-control study, if patients with new-onset juvenile dermatomyositis (juvenile DM) have increased symptoms prior to onset, exposure to certain environmental conditions, frequency of familial autoimmune diseases, or antibody titers, compared with 2 control groups. METHODS: A structured interview with the families of 80 children with juvenile DM, 40 children with juvenile rheumatoid arthritis (JRA), or 23 healthy children, from the same geographic area as the children with juvenile DM, was conducted. All children's sera were tested for antibody to Toxoplasma gondii, herpes simplex virus (HSV), or coxsackievirus B (CVB). RESULTS: A high proportion of children with juvenile DM had constitutional symptoms 3 months before the disease-onset date (P = 0.013 versus control children). Children with JRA had more relatives with rheumatoid arthritis (P = 0.0001) and pernicious anemia (P = 0.003) than did children with juvenile DM or healthy children. Among children < or =7 years of age, elevated enteroviral titers were more frequent in those with juvenile DM (81%) and in healthy controls (90%) than in those with JRA (64%), suggesting a common environmental exposure. Titers to T gondii, HSV, or CVB 1-6 were normal. CONCLUSION: Frequencies of familial autoimmune disease, exposure to environmental factors, or elevated antibody titers to T gondii, HSV, or CVB are not increased in juvenile DM. Children with juvenile DM do have symptoms of illness 3 months before the disease-onset date, and young patients have elevated enteroviral titers, as do young geographic controls.

Psychosocial effects of juvenile rheumatic disease. The family and peer systems as a context for coping.

The psychosocial effects of juvenile rheumatic diseases and disease activity were examined among 24 children and their families (12 children with a rheumatic disease and 12 children with no chronic illness). Each child with rheumatic illness was paired with a healthy control child nominated by their classroom teacher. Family and child functioning was assessed through measures of competence, coping, and adjustment and through direct observation of social functioning with peers at school. Multivariate and univariate analyses were performed to examine scores on the assessment measures, percentages of time spent in peer activities, and frequency scores for types of peer interactions. The results of these analyses indicated that juvenile rheumatic disease (JRD) is not associated with detrimental psychosocial outcomes. Instead, the results indicated that JRD children and their families actively utilize multiple coping strategies. These findings stress the importance of including and examining the family and peer systems as contexts for coping in future research.

Dark skin discoloration of finger joints in juvenile arthritis.

We examined the frequency of a known but poorly described finding, darkened skin over the proximal interphalangeal joints in patients with polyarticular juvenile arthritis. Examining a consecutive group of patients we found that 77% showed this sign. It reflects the presence of or previous episodes of inflammation of these joints. The reason for this finding is unknown.

Physical maturity screening for participation in sports.

In an effort to develop screening criteria to allow nonphysicians to detect physically immature boys prior to interscholastic sports competition, 364 male adolescents were studied as part of their group preparticipation health evaluation. Handgrip and self-assessed Tanner stage were measured, in addition to the routine preparticipation health evaluation procedures. Of the 118 boys who were Tanner 3 or less (immature), 103 (87%) had weak grips (less than 55 lb [24.9 kg]), and 88 (75%) rated themselves as Tanner 3 or less. Of the 246 boys who were greater than Tanner 3 (mature), 223 (91%) had strong grips (greater than or equal to 55 [24.9 kg]), and 229 (93%) rated themselves as greater than Tanner 3. Six of the 118 immature boys (5%) had both a strong grip and mature self-assessed Tanner stage; three of the 246 mature boys (1%) had both a weak grip and an immature self-assessed Tanner stage. Only 67 of 364 (18%) boys had grips and self-assessed Tanner staging that were discordant. Use of grip strength and self-assessed Tanner staging may obviate the need for physician assessment of Tanner stage for the majority of adolescent boys prior to participation in collision sports.

Thiemann's disease.

Two cases of Thiemann's disease in children are reported for the first time from North America. A history of swollen, tender proximal interphalangeal joints with radiographic evidence of irregularities of the epiphyses leading to premature fusion and subsequent shortening of the middle phalanges resulted in this diagnosis. Recognition of these features should lead to its more frequent diagnosis.

The hypermobility syndrome.

The hypermobility syndrome has been recognized as a definitive diagnostic entity among children referred to a Pediatric Arthritis Clinic with musculoskeletal complaints. The diagnosis of hypermobility was made by the ability of the patients to perform at least three of the following maneuvers: (1) extension of the wrists and metacarpal phalanges so that the fingers are parallel to the dorsum of the forearm; (2) passive apposition of thumbs to the flexor aspect of the forearm; (3) hyperextension of elbows (greater than or equal to 10 degrees); (4) hyperextension of knees (greater than or equal to 10 degrees); (5) flexion of trunk with knees extended so palms rest on the floor. Of 262 patients, 15 (5.7%) referred to an arthritis clinic between January 1979 and July 1981 were subsequently determined to have hypermobility as the basis for their rheumatic complaints. Three of these 15 had concomitant juvenile arthritis. The presenting complaint of pain was most often localized to the knees, hands, and fingers. Arthritis and elevated ESRs were not seen except in the three patients who had concomitant juvenile arthritis. All patients responded to physical therapy and nonsteroidal analgesic anti-inflammatory drugs. This is an entity not sufficiently well recognized as a source of musculoskeletal complaints in the United States. It will usually respond well to reassurance and symptomatic therapy.

The prevalence of juvenile arthritis.

A secondary analysis of two new large practitioner surveys, one national and one local, showed the prevalence of juvenile arthritis to be between 0.16 and 0.43 cases per 1,000 children. These rates compare quite closely with the majority of reports both in the United States and the world. We believe the prevalence of juvenile arthritis is between 0.2 and 1 case per 1,000 children (13,000--63,000 children), with the best estimate being about 0.5 cases per 1,000 children. Based on the 1980 census data, this latter estimate means there are approximately 32,00 children with juvenile arthritis in the United States.