Evolution of Understanding of Pediatric Rheumatologic Disease As Captured by Pediatrics Over 75 Years

Commentary From the Section on Rheumatology

The American Academy of Pediatrics (AAP) Section on Rheumatology (SORh) was established in 1981 to promote optimal care of patients with rheumatologic disorders, which include autoimmune, auto-inflammatory, and musculoskeletal conditions. To accomplish this mission, the section promotes collaborative, multidisciplinary education, advocacy, and quality healthcare.

For these commentaries, we performed a literature search for all related publications between 1948–2023 and identified papers that were instrumental in the identification and treatment of scleroderma, pediatric vasculitides, juvenile dermatomyositis, uveitis, systemic onset juvenile idiopathic arthritis, and juvenile idiopathic arthritis (then juvenile rheumatoid arthritis).

Evolution of Understanding of Pediatric Rheumatologic Disease As Captured by Pediatrics Over 75 Years

Scleroderma Publications in Pediatrics 1948 - 2023

Brandt Groh, MD, FAAP

Affiliation: Associate Professor of Pediatrics, Division of Rheumatology, Penn State Children’s Hospital, Hershey, PA

Highlighted Articles From Pediatrics

1. Hanson V, Drexler E, Kornreich H. Rheumatoid factor (anti-gamma-globulins) in children with focal scleroderma. Pediatrics. 1974;53(6):945-947
2. Flick JA, Boyle JT, Tuchman DN, Athreya BH, Doughty RA. Esophageal motor abnormalities in children and adolescents with scleroderma and mixed connective tissue disease. Pediatrics. 1988;82(1):107-111
3. Garty BZ, Athreya BH, Wilmott R, Scarpa N, Doughty R, Douglas SD. Pulmonary functions in children with progressive systemic sclerosis. Pediatrics. 1991;88(6):1161-1167
4. Holland KE, Steffes B, Nocton JJ, Schwabe MJ, Jacobson RD, Drolet BA. Linear scleroderma en coup de sabre with associated neurologic abnormalities. Pediatrics. 2006;117(1):e132-e136

The pathogenesis of localized scleroderma was unclear prior to observations of increased autoimmunity in family members of affected patients and the demonstration of autoimmune pathologic and serologic features. Perivascular lymphocytic infiltration was an early pathologic finding in biopsies of morphea and linear lesions. In 1974, Hanson et al at LA Children’s Hospital first demonstrated an autoantibody association in their report of IgM rheumatoid factor positivity in localized scleroderma.¹ In their review of 21 “focal” scleroderma patients, 1/3 were RF-positive, with the highest titers correlating with the most destructive linear lesions. They also noted an association with monoarticular synovitis in 2 of the 7 RF+ patients with typical inflammatory synovitis histology in one of these cases but no progression to polyarthritis in either case. Subsequent studies indicating the more consistent finding of anti-ssDNA positivity and its correlation with disease activity further bolstered the autoimmune argument. Although it has also been demonstrated that localized scleroderma is responsive to immune suppressive therapies, spontaneous remission of localized lesions can confound this assessment. Nonetheless, this 1974 study did open the door to trials of immune modulation to alter the course of potentially disfiguring and debilitating linear lesions.

Fortunately, systemic sclerosis (SSc) in children remains a relatively rare entity, even within the context of pediatric rheumatology clinics. The multisystem nature of this disease has long been apparent, but optimal strategies for early diagnosis and monitoring of these morbidities lacked literature support until 2 studies published in 1988 by investigators from Nemours Children’s Hospital and Children’s Hospital of Philadelphia who detailed the presence and progression of both pulmonary and gastrointestinal findings in their patients.^2,3 Flick et al noted a lack of published studies of esophageal function in pediatric scleroderma patients. They reviewed comprehensive esophageal studies in their mixed cohort of 13 scleroderma patients: 7 with SSc, 4 with mixed connective tissue disease (MCTD), and 2 with linear scleroderma.² Based on reports of abnormal peristalsis and reduced tone of the lower esophageal sphincter (LES) in adult patients who presented with GER, esophagitis, strictures, and dysphagia, they studied their cohort with barium esophagrams and manometry. Seven of 8 patients studied with esophagrams manifested abnormal peristalsis, and all patients complaining of dysphagia were in this group. Manometry indicated reduced LES tone and “feeble” distal esophageal pressure waves in 5 of 7 patients with SSc and in 2-3 of 4 patients with MCTD, whereas the 2 patients with linear scleroderma only manifested minor abnormalities of motility that did not progress and were not associated with symptoms. The authors concluded that these findings were comparable to those in adult patients. They recommended routine use of manometry, particularly for patients with dysphagia, but also for asymptomatic patients to help avoid outcomes such as esophageal stricture and aspiration.

Gart et al compared pulmonary function studies in pediatric SSc patients with the adult experience.³ Their cohort of 13 patients with SSc closely resembled adult comparators with respect to a high rate (92%) of abnormalities on pulmonary functions tests (PFTs) yet a relative lack of correlating pulmonary symptoms or signs in 40% of patients. Chest radiographs were similarly insensitive in both pediatric and adult patients. The most common PFT abnormalities in this pediatric cohort were grouped into restrictive disease (54%), obstructive disease (15%), small airway disease (15%), and isolated depression of lung diffusion capacity (DLCO) (8%). Given the strong association with progression to pulmonary hypertension in adult SSc patients with declining DLCO values, this single pediatric patient was treated with D-penicillamine with normalization of the DLCO. Otherwise, PFTs in this pediatric cohort were stable on therapy (steroids, ASA, and D-penicillamine) over the mean follow-up interval of 6.2 years—again, similar to the adult experience. Two patients in the cohort expired from restrictive lung disease with associated fibrotic cardiomyopathy in one case and pulmonary HTN with right ventricular failure in the other. Thus, in spite of the authors’ reassurance that PFTs remain stable in most patients, their implied guidance was to follow serial PFTs in pediatric SSc patients to identify the minority of cases that do progress to significant morbidity and mortality.

Holland highlighted the pediatric preponderance and potential morbidity of linear scleroderma in their report of 3 cases with review of the localized scleroderma literature.⁴ The potential for joint contractures and atrophy of underlying structures in linear scleroderma is well known. Less appreciated is the potential central nervous system (CNS) morbidity associated with linear involvement of the scalp or “en coup de sabre”—particularly when CNS symptoms present in advance or concurrent with cutaneous findings. In the majority of cases, complex partial seizures are the harbinger of CNS involvement. In discussion of their 3 cases, the authors highlighted the potential for EEG and/or MRI and PET changes in the absence of recognized cutaneous changes. In 2 of these cases, they also highlighted the current therapy of high-dose corticosteroid in combination with subcutaneous methotrexate. The authors further clarified that the presence of hemifacial atrophy in the absence of cutaneous changes indicates the closely related (if not identical) disorder Parry Romberg syndrome. After a review of more typical cutaneous presentations and vascular pathology, they concluded with a review of other less conventional therapy options and the exhortation to perform careful skin exam in all patients with de novo neurologic presentations.

Vasculitis Publications in Pediatrics 1948 – 2023

Brandt Groh, MD, FAAP

Affiliation: Associate Professor of Pediatrics, Division of Rheumatology, Penn State Children’s Hospital, Hershey, PA

Highlighted Articles From Pediatrics

1. Wedgewood RJ, Klaus MH. Anaphylactoid purpura (Schönlein-Henoch syndrome): a long-term follow-up study with special reference to renal involvement. Pediatrics. 1955;16(2):196-206
2. Vernier RL, Worthen HG, Peterson RP et al. Anaphylactoid purpura: pathology of the skin and kidney and frequency of streptococcal infection. Pediatrics. 1961;27(2):181-193
3. Wagenvoort CA, Harris LE, Brown AL Jr, et al. Giant-cell arteritis with aneurysm formation in children. Pediatrics. 1963;32(5):861-867
4. Warshaw JB, Spach MS. Takayasu’s disease (primary aortitis) in childhood: case report with review of literature. Pediatrics. 1965;35(4):620-626
5. Kawasaki T, Kosaki F, Okawa S, et al. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54(3):271-276
6. Wooditch AC, Aronoff SC. Effect of initial corticosteroid therapy on coronary artery aneurysm formation in Kawasaki disease: a meta-analysis of 862 children. Pediatrics. 2005;116(4):989-995
7. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics. 2009;123(5):e783-789
8. Muise A, Tallett SE, Silverman ED. Are children with Kawasaki disease and prolonged fever at risk for macrophage activation syndrome? Pediatrics. 2003;112(6):e495-e497
9. Weiss PF, Feinstein JA, Xianqun L, et al. Effects of corticosteroids on Henoch Schönlein purpura: a systematic review. Pediatrics. 2007;120(5):1079-1087

Literature reports of vasculitis in children do appear in the 1948–1973 era of Pediatrics, predating the organization of pediatric rheumatology as a specialty in the mid-1970s.

Two studies in 1955 and 1961 furthered our understanding of the most common form of pediatric vasculitis across all 3 eras—anaphylactoid purpura (now known as Henoch-Schönlein syndrome or HSP).^1,2 Wedgewood et al in 1955 published a series of HSP cases seen at The Cleveland Clinic and reviewed disease features and predictors of significant nephritis.¹ In this series of 26 patients, 72% developed nephritis at a mean follow-up of 4 years. These authors did not identify any relationship between the severity of musculoskeletal, gastrointestinal, or cutaneous symptoms and the risk of nephritis. Nor did they find any relationship between early corticosteroid therapy and the rate of progression of nephritis. The authors speculated that childhood HSP might contribute to a risk of real disease later in life, foreshadowing the argument for more aggressive early treatment of HSP in our current era. While the focus of Pediatrics has been on the vastly more common small- and medium-size vessel diseases, 2 case reports of large vessel vasculitis with accompanying literature reviews were published in the journal between 1963 and 1965.^3,4

The most impactful report of the 1974–1997 era in Pediatrics is clearly that of Kawasaki who described the mucocutaneous lymph node syndrome.⁵ This English language report of 2 national surveys in Japan included more than 6,000 case reports that summarized the disease demographics, clinical characteristics, and pathology (including multiple images of disease features) of this newly describe disease, later renamed Kawasaki disease (KD). This publication facilitated the development of diagnostic criteria that have enabled subsequent international collaborative studies. The authors pointed out that antibiotic treatment had no effect on disease progression. They also opined that corticosteroids, while antipyretic, seemed unlikely to impact the longer term morbidity of this disease—namely coronary artery aneurysms with attendant risk of thrombosis. This bias against steroid treatment persisted until subsequent studies by Wooditch et al and others demonstrated the efficacy of early steroid therapy for both high-risk and IVIG-refractory patients.⁶

In the 1998–2023 era of Pediatrics, KD articles continue to dominate numerically. The recognition of KD shock syndrome by Kanegaye et al⁷ and macrophage activation syndrome in the setting of KD by Muise et al⁸ broadened our recognition of disease variants and serendipitously prepared rheumatologists for MIS-C during the Covid-19 pandemic era. To come full circle in this historical tour, we continue to learn about the efficacy of corticosteroids in the treatment of HSP. Weiss et al in their 2007 systemic review and meta-analysis of HSP literature published between 1956 and 2007 questioned the prevailing wisdom that corticosteroids had no benefit in the mitigation or prevention of longer-term complications of this disease.⁹ As with the rehabilitation of corticosteroid treatment for KD, they pointed out that there is little reason, based on the experience with all other childhood vasculitides, to think that this treatment would lack any efficacy or prove harmful. Indeed, their analysis of 3 qualifying prospective studies with minimal heterogeneity (P = 0.341) clearly indicated benefit in the prevention of chronic renal disease with an odds ratio of 0.43 (0.19–0.96). Less robust results of this analysis also indicated a significant decrease in the mean time to resolution of abdominal pain and reduced (without statistical significance) odds of surgical intervention and disease relapse. It remains unclear if the lack of statistical significance for these other outcomes relates to underpowered studies or true lack of a corticosteroid effect. Using sensitivity analyses, the authors were not able to identify a significant dose-response effect, again possibly related to a statistical power issue and/or the differing steroid treatment regimens reported in these studies. They concluded by observing that it would require inclusion of a much larger prospective study (n > 400 and combined pooled OR > 2.25) to demonstrate a significant deleterious corticosteroid effect and thereby reverse their meta-analysis finding of significant corticosteroid benefit toward the prevention of chronic renal disease.

Juvenile Dermatomyositis From 1953 to the Present

Suzanne C. Li, MD, PhD, FAAP

Affiliation: Professor of Pediatrics, Division of Pediatric Rheumatology, Hackensack Meridian School of Medicine, Hackensack, NJ

Highlighted Articles From Pediatrics

• Wedgwood RJ, Cook CD, Cohen J. Special reviews: dermatomyositis. Pediatrics. 1953;12(4):447-466
• Silver RM, Maricq HR. Childhood dermatomyositis: serial microvascular studies. Pediatrics. 1989;83(2):278-283
• Eisenstein DM, Paller AS, Pachman LM. Juvenile dermatomyositis presenting with rash alone. Pediatrics. 1997;100(3):391-392
• Niewold TB, Wu SC, Smith M, Morgan GA, Pachman LM. Familial aggregation of autoimmune disease in juvenile dermatomyositis. Pediatrics. 2011;127(5):e1239-e1246

Juvenile dermatomyositis (DM) is the most common form of immune-mediated myopathies in children. Children classically present with symmetrical proximal muscle weakness and characteristic rashes, and they are at risk for severe morbidity and mortality. Pediatrics has published several noteworthy papers about DM. The first was a 1953 case series by Wedgwood, Cook, and Cohen.¹ At the time of their report, fewer than 100 children with juvenile DM had been described. Disease pathophysiology and etiology were not known; proposed mechanisms included infections, nutritional disturbances, scleroderma-like process, and immune problems. Wedgwood et al’s article succinctly described the clinical and histological features of DM and the authors’ experience with treatment. Most patients presented insidiously with weakness, fatiguability, and muscle stiffness. Rashes were common and included violaceous or erythematous discoloration of the upper eyelids (heliotrope rash) with periorbital edema as well as erythematous, atrophic, or scaly lesions on the extensor surfaces of the joints, especially on the knuckles, elbows, and knees (Gottron papules). Skin over the extremities often appeared tight, indurated, shiny, or scaly and had a thickened, leathery, or brawny feeling. Wedgwood et al described finding foci of lymphocytes and monocytes in biopsies of skin and muscle tissues that demonstrated skin atrophy and loss of skin appendages or muscle necrosis and loss of muscle fibers, respectively. Muscular arterioles had findings consistent with vasculopathy rather than vasculitis.

The outcome for most of these patients was grim, especially for those who had acute febrile onset with extensive involvement. Ten of 26 (38.5%) patients died within 4 to 26 months of onset, mostly due to respiratory or palato-respiratory muscle involvement. Among the 16 survivors, 4 (25%) had persistently active disease, 13 had contractures (described as crippling in 4), and 4 had calcinosis.

The authors tried several previously reported therapies, including for nutritional disturbances and hormonal therapy. No benefit was found with nutrition-focused therapies, but cortisone and adrenocorticotropic hormone treatment rapidly improved symptoms of patients with active disease. Based on their experience, the authors suggested early treatment of patients with DM with adrenocorticotropic hormones or corticosteroids, which still today is a cornerstone of initial treatment. Current recommendations are administering methotrexate, a steroid-sparing agent, with prednisone to allow more rapid reduction and discontinuation of steroids.²

Between November 1973 and October 1998, 2 DM publications in Pediatrics improved our understanding of disease pattern and treatment. By this time, the etiology was recognized to be related to the immune system, and treatment with immunomodulators was commonly used. Despite these advances, severe morbidity and mortality remained major concerns. Most patients had a chronic course with remissions and exacerbations, and clinical features identifying patients at risk for a more severe course had not yet been identified. Silver and Maricq reported on their prospective examination of nailfold capillary (NFC) patterns in 9 juvenile DM patients in 1989.³ All study patients had NFC abnormalities. Five had been examined in the first week of disease, and the earliest NFC pattern was thrombosis and hemorrhages. This was followed by extensive capillary loss along the edge of the nailfold, then giant capillary loop and bushy capillary formation, the latter postulated to reflect neovascularization.

NFC abnormalities correlated with the overall clinical state. Patients with more severe disease had more severe NFC changes, while those that had clinical improvement had normalization of their NFC changes. These findings supported using NFC examination as a tool to assess and monitor disease state. Several other studies have supported the utility of this observation, including a 2011 study that found a loss of capillary NFC pattern to be associated with elevated muscle enzyme levels and global scores of muscle and disease activity, and NFC hemorrhages to be associated with skin disease activity.⁴ Vasculopathy has been identified as a key pathological process in juvenile DM, with the most severe manifestations related to this abnormality.⁵ NFC examination continues to be an important tool in current practice, with visualization of the NFC possible in the office with use of an ophthalmoscope or other magnifying device.

In 1997, Eisenstein, Paller, and Pachman described 5 patients with amyopathic DM, an uncommon DM pattern in which patients exhibit typical cutaneous features but normal muscle strength and function.⁶ Only 7 pediatric patients had been previously described. In one of those articles, which included both adult and pediatric amyopathic DM patients, the authors had withheld steroid treatment because there was no muscle weakness. The adult patients were reported to be stable, but the one pediatric patient developed calcinosis. A prior article had described withholding steroid treatment if there was no muscle weakness, which was tolerated by the adult patients but which led to calcinosis in the juvenile DM patient. Eisenstein et al advocated for treatment of juvenile amyopathic DM, arguing that although juvenile and adult DM had different patterns of disease, juvenile DM more commonly was associated with calcinosis (67% vs 27% in 1 study). A recent gene expression profiling study identified different patterns in the blood and muscles of juvenile versus adult DM,⁷ supporting Eisenstein’s position. Eisenstein advised careful longitudinal follow-up because all 5 of their patients later developed myositis (6 months to 2 years later). All 5 patients were treated and had good outcome, so they argued amyopathic DM patients should also be treated. This remains the current recommendation because prevention of any form of disease activity increases the likelihood of remission and offers the best long-term outcome.²

Intravenous immunoglobulin G (IVIg) therapy started to be used to treat juvenile DM in the early 1990s because it improved skin and muscle disease and reduced the need for corticosteroid therapy.⁸ While generally well tolerated, some patients had adverse events including headaches, fever, arthralgia/myalgia, lethargy, and nausea or vomiting. Manlhiot et al looked for factors associated with adverse events (AE) in their 2008 article.⁹ AEs were not associated with dose, sugar or glycine content, osmolality, or patient’s age. A high IgA content in the IVIG preparation, which they defined as >15 µg/mL, was associated with fever, lethargy or malaise, and nausea or vomiting. The authors recommended selecting low-IgA content products for treatment with premedication to reduce AE.

In the period from November 1998 to the present, we have learned more about the pathophysiology of DM. In 2011, Niewold et al identified a higher familial frequency of systemic lupus erythematosus (OR >5) with juvenile DM. This suggested a shared pathophysiology and shared causal genes.¹⁰ Possible shared causal genes include those in the interferon-α (IFN-α) pathway because higher serum IFN-α levels had been identified in both SLE and juvenile DM. The authors were able to examine serum samples from 18 of their patients and found higher serum IFN-α activity in juvenile DM patients that had a family history of SLE, which supports the shared causal gene hypothesis. Many other studies have supported the importance of both type 1 and type 2 interferons in DM pathophysiology.^2,11

In conclusion, articles in Pediatrics over the last 70 years have identified several important features of juvenile DM and served to improve its treatment. Fortunately, mortality has fallen greatly since Wedgwood et al’s initial report but morbidity remains prevalent. Half of patients with DM suffer musculoskeletal damage, including joint contractures, and demonstrate reduced endurance. A high proportion (8%-40%) exhibit growth delays.² Further advances are therefore needed to improve the long-term outcome for these children.

References

1. Wedgwood RJ, Cook CD, Cohen J. Special reviews: dermatomyositis. Pediatrics. 1953;12(4):447-466
2. Kim H, Huber AM, Kim S. Updates on juvenile dermatomyositis from the last decade: classification to outcomes. Rheum Dis Clin North Am. 2021;47:669-690
3. Silver RM, Maricq HR. Childhood dermatomyositis: serial microvascular studies. 1989;83(2):278-283
4. Mugii N, Hasegawa M, Matsushita T, et al. Association between nail-fold capillary findings and disease activity in dermatomyositis. Rheumatology (Oxford). 2011;50:1091-1098
5. Gitiaux C, De Antonio M, Aouizerate J, et al. Vasculopathy-related clinical and pathological features are associated with severe juvenile dermatomyositis. Rheumatology (Oxford). 2016;55:470-479
6. Eisenstein DM, Paller AS, Pachman LM. Juvenile dermatomyositis presenting with rash alone. Pediatrics. 1997;100(3):391-392
7. Lopez De Padilla CM, Crowson CS, Hein MS, et al. Gene expression profiling in blood and affected muscle tissues reveals differential activation pathways in patients with new-onset juvenile and adult dermatomyositis. J Rheumatol 2017;44:117-124
8. Lang BA, Laxer RM, Murphy G, Silverman ED, Roifman CM. Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med. 1991;91:169-172
9. Manlhiot C, Tyrrell PN, Liang L, Atkinson AR, Lau W, Feldman BM. Safety of intravenous immunoglobulin in the treatment of juvenile dermatomyositis: adverse reactions are associated with immunoglobulin A content. Pediatrics. 2008;121:e626-e630
10. Niewold TB, Wu SC, Smith M, Morgan GA, Pachman LM. Familial aggregation of autoimmune disease in juvenile dermatomyositis. Pediatrics. 2011;127(5):e1239-e1246
11. Rider LG, Nistala K. The juvenile idiopathic inflammatory myopathies: pathogenesis, clinical and autoantibody phenotypes, and outcomes. J Intern Med. 2016;280:24-38

Uveitis in Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis Pediatrics 1948-2023

Karen Marzan, MD, FAAP

Affiliation: Children’s Hospital Los Angeles, Associate Professor of Pediatrics, Chief, Division of Rheumatology, Keck School of Medicine of University of Southern California, Los Angeles, CA

Highlighted Articles From Pediatrics

1. Schaller J, Kupfer C, Wedgwood RJ. Iridocyclitis in juvenile rheumatoid arthritis. Pediatrics. 1969;44(1):92-100
2. Yancey C, White P, Magilavy D, et al. Guidelines for ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 1993;92(2):295-296
3. Cassidy J, Kivlin J, Lindsley C, Nocton J, Section on Rheumatology, Section on Ophthalmology. Ophthalmologic examinations in children with juvenile rheumatoid arthritis. Pediatrics. 2006;117(5):1843-1845

As the field of pediatric rheumatology was developing, descriptions of iridocyclitis (or anterior uveitis) as an extra-articular manifestation of juvenile rheumatoid arthritis (JRA) were noted to be a potential serious complication of the disease that could lead to visual loss. The first publication in Pediatrics was in 1969 when J. Schaller and colleagues published their review of 70 children with JRA who over a 4-year period underwent regular ophthalmologic evaluations that included slit lamp examination.¹ Their diagnostic criteria at that time for JRA was the presence of arthritis involving 2 or more joints for 6 or more months with exclusion of other connective tissue diseases, although they included patients with monoarthritis if a synovial biopsy done confirmed chronic synovitis. In their study, 11% of the entire group developed iridocyclitis; however, what was most striking was that in the group of patients with pauciarticular or monoarthritis, a much larger proportion (29%) of patients developed iridocyclitis. Several of their findings remain true to this day. Iridocyclitis was not seen in patients with systemic manifestations of JRA. Iridocyclitis occurred at unpredictable times during the course of JRA, and there was no correlation between joint disease activity and active iridocyclitis. It was typically not associated with elevated inflammatory markers. Monoarticular or pauciarticular forms were seen most often in association with iridocyclitis. The frequency of antinuclear factor was also higher in this subgroup of patients with iridocyclitis, the significance of which was uncertain at that time. This was felt to be in stark contrast to adult-onset rheumatoid arthritis where iridocyclitis occurred no more commonly than in the general population. Slit-lamp examinations by ophthalmology were recommended at least twice a year as it was already recognized that the eye manifestations were not usually associated with acute eye symptoms and that active iridocyclitis could result in significant complications that included keratic precipitates, posterior synechiae, secondary glaucoma, band keratopathy, cataract formation, and visual loss. Treatment included atropine as well as steroid topical drops. When these therapies were not effective, subconjunctival steroid injections and systemic corticosteroids were utilized.

In 1993, the Section on Rheumatology and Section on Ophthalmology of the AAP published “Guidelines for Ophthalmologic Examinations in Children With Juvenile Rheumatoid Arthritis.”² Much more was known by that time about iridocyclitis and JRA and, similarly to the study by Schaller et al,¹ it was noted that fewer than 2% of children with systemic onset JRA exhibited iridocyclitis. The majority of patients with iridocyclitis manifested pauciarticular disease. Seven percent to 37% of children with polyarticular disease had iridocyclitis and were felt to be at moderate risk. The majority of children at risk for developing iridocyclitis were young females with pauciarticular onset JRA. The significance of a positive antinuclear antibody was then known to be the serologic marker most strongly associated with iridocyclitis and was present in 65% to 88% of these children. HLA-DR 5 was also correlated with the presence of eye disease. Twenty-five percent of patients with iridocyclitis had a good prognosis while 25% responded poorly to therapy. The latter were patients at high risk for visual loss. Fifty percent of patients required prolonged treatment for moderate to severe inflammation, although the visual prognosis was generally good. The frequency of ophthalmologic visits for children with JRA without known iridocyclitis was recommended based on the JRA subtype and age at onset of disease. High-risk patients were those with pauciarticular and polyarticular disease who were less than 7 years of age and had a positive ANA. It was recommended that these patients receive ophthalmologic evaluations every 3 to 4 months. Those with pauciarticular disease and polyarticular disease who were ANA negative and had disease onset at less than 7 years of age or who were ANA positive or negative and had disease onset at greater than 7 years of age were assessed to be at medium risk, requiring ophthalmologic examinations every 6 months. Those with systemic JIA had low risk and only required examinations every 12 months.

Cassidy et al and the Section on Rheumatology and Section on Ophthalmology of the AAP updated the guidance for ophthalmologic examinations in children with juvenile rheumatoid arthritis in 2006.³ This statement noted that the children at greatest risk of developing uveitis were those who presented with oligoarticular onset JRA. The presence of antinuclear antibody was strongly associated with chronic uveitis and was found in 65% to 90% of those children. Although this statement quoted that prognosis was good and 25% of cases and 25% of children responded poorly to treatment, this article differed by stating that approximately 50% of patients required prolonged treatment for moderate to severe chronic inflammation and that the visual prognosis in these patients remained guarded rather than good. Early and aggressive therapy was recommended to reduce ocular morbidity. The guidelines identified patients with oligoarthritis or polyarthritis who were ANA positive, 6 years of age or younger at onset of disease, and with a disease duration less than 4 years to be in the high-risk category with a need for eye examinations every 3 months. Moderate-risk patients were those with oligoarthritis or polyarthritis and a positive ANA with age of onset at 6 years of age or younger and disease duration greater than 4 years; those with a positive ANA and an age of onset greater than 6 years of age and disease duration less than or equal to 4 years; and those who were ANA negative with age of onset at 6 years of age or younger and disease duration of less than or equal to 4 years of age. They recommended eye examinations for these moderate-risk patients every 6 months. All other patients with oligoarthritis or polyarthritis or those with systemic disease were felt to be at low risk, with a recommendation for eye examination every 12 months.

The most recent guidelines that were published in subspecialty journals in 2019 are now much more multifaceted and take into account the use of nonbiologic and biologic disease modifying anti-rheumatic drugs now available. The new guidance remains a collaboration between rheumatology and ophthalmology based on groundwork laid by the 3 previous guidelines published in Pediatrics.

Systemic Onset Juvenile Idiopathic Arthritis in 75 Years of Pediatrics

Sandy D. Hong, MD, FAAP

Affiliation: Associate Professor of Pediatrics, Division of Rheumatology, University of Iowa Health Care, Carver College of Medicine, Stead Family Children’s Hospital, Iowa City, IA

Highlighted Articles From Pediatrics

1. Manners PJ, Ansell BM. Slow-acting antirheumatic drug use in systemic onset juvenile chronic arthritis. Pediatrics. 1986;77(1):99-103
2. Huang Z, Lee PY, Yao X, Zheng S, Li T. Tofacitinib treatment of refractory systemic juvenile idiopathic arthritis. Pediatrics. 2019;143(5):e20182845
3. Bindstadt BA, Levine JC, Nigrovic PA, et al. Coronary artery dilation among patients presenting with systemic-onset juvenile idiopathic arthritis. Pediatrics. 2005;116(1):e89-e93

Systemic onset Juvenile Idiopathic arthritis (sJIA) was first recognized as “Still’s Disease” by George Frederic Still in the 1890s. It is now understood to be an autoinflammatory disorder. Treatment of sJIA reflects the breakthroughs of treatment for juvenile arthritis and other pediatric rheumatologic diseases. Prior to the development of protein-based anti-cytokine therapies of the biologic era of the early 2000s, treatment for autoimmune and autoinflammatory disorders consisted of steroids, gold, anti-malarials, and non-steroidal anti-inflammatory drugs. Next came the era of slow-acting anti-rheumatic therapies. Manners et al published an article on the use of anti-rheumatic drugs on the systemic (rash, fever, serositis) versus joint features of systemic JIA based on case reviews in 1986.¹ This paper highlights how we treated sJIA prior to the 1980s. It highlights that gold and D-penicillamine were not effective or well tolerated in patients with systemic disease and were only about 50% effective in patients with polyarticular or pauciarticular joint disease. They also highlighted the common adverse effects of chlorambucil. These modalities have since fallen out of use. The article is the first to highlight that anti-malarial therapy used for joint disease in juvenile arthritis is futile in patients who present with systemic disease. The use of azathioprine, steroids, and non-steroidal anti-inflammatory agents are discussed and are still options for sJIA treatment today, though not always as first-line therapies. This article is important as it highlighted the use of azathioprine for the joint features of sJIA, which paved the way for the use of other slow-acting anti-rheumatic drugs.

The adoption over the past 10 years of protein-based cytokine therapies that target interleukin 1 and interleukin 6 for treatment of sJIA has been extraordinary. Both new and chronic patients have achieved remission due to these novel biologic therapies that have minimized or eliminated corticosteroid exposure. However, these therapies are expensive, are not always available, require injection or infusion, and are not effective for all patients with sJIA. The use of new oral Jak kinase inhibitors for sJIA is highlighted in Huang’s case report, which features a child with steroid refractory disease treated in China, where anti-interleukin 1 therapy is not available and whose parents refused parenteral therapy with interleukin 6 inhibition. The use of oral Jak inhibition resulted in disease remission for this patient.²

For general pediatricians, Binstadt’s paper that highlighted the possibility of coronary artery dilation in patients with sJIA is important.³ The presentation of patients with JIA with systemic disease findings of fever, rash, adenopathy, arthritis, and serositis may closely mimic that of patients with Kawasaki disease. This paper demonstrated that the presence of coronary artery dilation does not exclude sJIA as a diagnostic consideration during the evaluation for Kawasaki disease.

Juvenile Rheumatoid Arthritis/Juvenile Idiopathic Arthritis in Pediatrics 1948-2023

Karen Marzan, MD, FAAP

Affiliation: Children’s Hospital Los Angeles, Associate Professor of Pediatrics, Chief, Division of Rheumatology, Keck School of Medicine of University of Southern California, Los Angeles, CA

Highlighted Articles From Pediatrics

1. Lockie LM, Norcross BM. Juvenile rheumatoid arthritis. Pediatrics. 1948;2(6):694-698
2. Gauchat RD, May CD. Early recognition of rheumatoid disease with comments on treatment. Pediatrics. 1957;19(4):672-679
3. Schaller J, Wedgwood RJ. Juvenile rheumatoid arthritis: a review. Pediatrics. 1972;50(6):940-953
4. Ilowite NT. Current treatment of juvenile rheumatoid arthritis. Pediatrics. 2002;109(1):109-115

What we know of and how we treat what was previously called juvenile rheumatoid arthritis (JRA) and is now termed juvenile idiopathic arthritis (JIA) has come a long way since Diamnat-Berger published the first account of 38 children with chronic arthritis in 1891 and George Frederick Still described 22 cases of children with acute and chronic arthritis in 1896. Pediatrics has been along for the ride. Some of these classic descriptions and distinctions remain true to this day and others after a more thorough understanding of the disease and research have been discredited.

In 1948, the inaugural year of Pediatrics, M. Lockie and B. Norcross from University of Buffalo Children’s Hospital¹ published an article describing their experience since 1934, in the follow-up of 28 patients with “typical juvenile rheumatoid arthritis which began before the age of 12.” Much of what they wrote no longer holds true. They began the article questioning Still’s separation of JRA into 2 types (chronic rheumatoid arthritis similar to the adult form and a less common type with systemic symptoms) by asserting there was no justification for that division. They opined that age was the factor responsible for modification of the disease, and that severe deformity was infrequent so that the poor prognosis attached to JRA was not warranted. Distinguishing JRA from rheumatic fever and tuberculosis were the differential diagnoses that proved most difficult. Classification was designated as mild, moderate, or severe based on disease duration, degree of joint involvement, and residual joint deformity as well as systemic symptoms. Complete bedrest was thought to be the most important part of treatment to be maintained during periods of active disease until the child had entered a quiescent phase of disease. Intensive physiotherapy was not felt to be necessary because the child would naturally increase the use of their joints as the disease improved. Other therapies at that time included small blood transfusions given at weekly intervals, salicylate therapy, and gold therapy.

Nearly 10 years later, in 1957, R. Gauchat and C. May from the University Hospital of the State University of Iowa published a review entitled, “Early Recognition of Rheumatoid Disease with Comments on Treatment”² and articulated a number of key points. They first raised concern that there was a lack of general pediatric interest in JRA, despite the fact that the available evidence at that time suggested that the incidence of new cases in the general population under 15 years of age was roughly the same as for diabetes mellitus and nephrosis, which garnered much more interest. The review sought to depict the classic features of JRA and emphasized the feasibility and importance of early diagnosis. They also opined that Still’s distinction of acute and chronic disease as separate entities of JRA was misleading. Instead, they agreed with using the term “rheumatoid disease” as proposed by Elman and Ball because arthritis only appeared to be a component of a generalized systemic disease. Their review described many of the features well-known today as typical of systemic juvenile idiopathic arthritis (sJIA). They also lamented the lack of a specific diagnostic test, a need that continues to this day. Their review agreed with the prevailing theory that spontaneous remission was characteristic of the disease, and that supportive therapy might be all that was needed. They acknowledged that in some patients the disease burns itself out but that it may remain active for 20 years or longer. Medications used at that time included acetylsalicylic acid, various forms of steroids, and phenylbutazone. They advised using prednisone due to its greater efficacy in controlling rheumatoid symptoms and its lower salt retention effect.

J. Schaller and R. Wedgewood from the University of Washington School of Medicine published a comprehensive review on JRA in 1972³ that summarized the course in 124 children who had a mean disease duration of 7.5 years. They described 3 distinct subgroups of disease, where the type of joint disease involvement was generally determined within the first 6 months. Systemic disease presented with classic spiking fevers of more than 2 weeks that would return to normal or subnormal, an evanescent rheumatoid rash, hepatosplenomegaly and/or generalized lymphadenopathy, pleuritis, and pericarditis. In these patients, arthritis was often overshadowed by the systemic symptoms early in the disease. This is now known as sJIA and recognized as a separate entity from the other types of arthritis, both with respect to pathophysiology and treatment. Polyarticular disease was described as most resembling that of adult-onset rheumatoid arthritis and typically affected multiple joints in a symmetric way, including the small joints. They described some systemic symptoms in these patients. Pauciarticular disease was limited to 5 or fewer joints. Although patients in this subgroup had few or no systemic signs or symptoms, iridocyclitis was an important feature. Prior to this article monoarticular disease was often considered as a separate subtype, which the authors felt was inaccurate. Apart from the redesignation of pauciarticular disease as fewer than 5 joints, these 3 subtypes were incorporated in the first criteria for the classification of JRA by the American Rheumatism Association in 1973. Similar to the study by Gauchat and May, they treated patients with salicylates, gold therapy, chloroquine, and non-steroidal anti-inflammatory drugs. Some patients received corticosteroid joint injections and others had synovectomy done. In contrast to Gauchat and May, these patients received physical therapy. Only 13% of their patients had severe disease, although the rest of the patients had some discomfort or limitation of motion. Visual loss secondary to iridocyclitis was a serious morbidity particularly noted in ANA+ patients with pauciarticular disease.

With the age of biologics and the current therapies now available, the goal of JRA treatment is to achieve remission. In 2002, Ilowite wrote a special article that discussed current therapies, including a pediatric clinical trial of the tumor necrosis factor inhibitor etanercept.⁴ Although the International League of Associations for Rheumatism criteria for JIA had been proposed in 1995 and revised in 2001, these were not yet widely being used in 2002. As such, this article still used the old nomenclature, gave a brief review of the subtypes of JRA, and emphasized that though the classifications were based on the type of onset, the course of disease was also important to the patient's prognosis. Eleven poor prognostic indicators were identified. These included, though were not limited to, continued active systemic disease at 6 months after onset, polyarticular onset or disease course, early involvement of small joints of the hands and feet, and the rapid appearance of erosions. Remission rates of 25% and 34% for polyarticular and pauciarticular onset disease were noted in contrast to previous literature that suggested these forms were self-limited. Those with systemic onset disease had a much higher rate of remission at 74%. This review suggested treatment with NSAIDs and intra-articular steroids as well as physical therapy and cognitive behavioral therapy. Goals of therapy included not only symptom control but also prevention of erosive disease. Methotrexate and sulfasalazine were the standard of therapy as disease-modifying antirheumatic drugs . Newer medications discussed included leflunomide, etanercept, infliximab, and Cox-2 inhibitors. The “Pediatric Rule” of the FDA was credited with encouraging the study of new agents for JRA. Since then, there has been an upsurge of new biologics that have targeted different pathways of the immune system. We now understand that children do not outgrow JIA. The treatment paradigm has shifted to initiating aggressive therapy early to achieve complete remission. Biologic medications and targeted small molecules have allowed us to treat patients with JIA to prevent or improve erosions, as well as to foster normal growth and development.