Paediatric Rheumatology practice changing publications in 2020
Introduction - The lives of doctors changed across the world with the COVID-19 pandemic which swept across continents in 2020 and still appears to be unrelenting. This is not a year that we will be able to forget in a hurry. Doctors at all levels and all specialties faced unique challenges - the emergency, intensive care, infectious disease, and pulmonology staff were confronted with acute illness, death and acute concern for personal safety. Specialties such as ours grappled with trying to understand how best to serve our young clients: keep them safe and yet not place ourselves in the face of unknown danger and confront an unknown unseen and highly dangerous enemy.
We learnt. Online consultations became the norm. Patients began to be screened before hospital admissions. The teams that had digital record keeping perhaps are the ones who survived the best. We learnt how to use PPE. Masks became the norm. Webinars became commonplace and science marched on.
In spite of these challenges, landmark papers have been published in all areas of medicine in the year gone by. I present before you practice-changing papers that have been published in the arena of Paediatric Rheumatology in the year 2020. Much has been written about COVID-19 and its impact on Paediatric Rheumatology Services, and the presentation of patients with shock-like disease very similar to Kawasaki syndrome in some ways.
In this review, I have deliberately kept away from COVID-19 and Paediatric Rheumatology service impact and have focused my attention on new information that will impact our day-to-Day practice. The articles I have chosen are clinically oriented and as the number of publications exceeded 500, any omissions I make are an error and I accept full responsibility for that!
So, here it goes!
Tofacitinib in juvenile idiopathic arthritis
Background: Small molecule inhibition especially with Tofacitinib plays a very important role in the management of adult rheumatoid arthritis especially with the drug going off patent and the availability of the generic Tofacitinib in India effective November 2020. Thus far, no data was available for the use of this molecule for juvenile idiopathic arthritis. This has recently changed with the US FDA granting approval for the use of Tofacitinib in the polyarticular course of juvenile idiopathic arthritis in 2020.
The EULAR meeting was an online event in the summer of 2020
Abstract 0291: Presented data on the use of Tofacitinib in phase 3 randomized double-blind placebo-controlled withdrawal study in patients aged 2 to less than 18 years of age with polyarticular course, psoriatic or enthesitis-related arthritis. This was an 18-week open-label part 1 where all patients received Tofacitinib per the body weight. For the children who achieved the ACR 30 response at week 18, they were randomised 1:1 in the double-blind part 2 of the study which was 18-44 weeks where they either continued Tofacitinib or switched to Placebo. The primary endpoint was flare rate at week 44. A total of 225 patients were enrolled, 184 with polyarticular course juvenile arthritis, 20 with psoriatic arthritis, and 21 with enthesitis-related arthritis. The latter 2 sub-groups were excluded for efficacy analysis but safety was evaluated for all patients. In the polyarticular course juvenile idiopathic arthritis patients the disease flare rate was significantly lower with Tofacitinib versus placebo by week 44: tofacitinib (31 percent; n/N=27/88) was statistically significantly (p=0.0007) lower than patients treated with placebo (55 percent; n/N=47/85) at week 44.
2.4% of the patients had serious adverse events. Specifically, 2 patients developed herpes zoster. There was no thrombotic event in this cohort.
Tofacitinib has been granted approval by the US FDA for use in the child with polyarticular course of juvenile idiopathic arthritis.
10 kg to ≤ 20 kg body weight: 3.2 mg (3.2 mL oral solution) twice daily
20 kg to ≤ 40 kg body weight: 4 mg (4 mL oral solution) twice daily
Bodyweight ≥40 kg: 5 mg (one 5 mg tablet or 5 mL oral solution ) twice daily
My take:
It's early days yet. The exact place of Tofacitinib in the therapeutic pathway for children with Juvenile Arthritis is yet to be confirmed. It does appear to be a promising new agent for children impacted with arthritis and maybe the first step to get away from nasty needles. Postmarketing surveillance for the use of this drug is so important and we must not lose sight of that.
DOI: 10.1136/annrheumdis-2020-eular.396
Op0291?Tofacitinib for the treatment of polyarticular course juvenile idiopathic arthritis: results of a phase 3, randomised, double-blind, placebo-controlled withdrawal study
N. Ruperto1, O. Synoverska1, T. Ting2, C. Abud-Mendoza1, A. Spindler1, Y. Vyzhga1, K. Marzan2, V. Keltsev1, I. Tirosh1, L. Imundo2, R. Jerath2, D. Kingsbury2, B. Sözeri1, S. Vora2, S. Prahalad2, E. Zholobova1, Y. Butbul Aviel1, V. Chasnyk1, M. Lerman2, K. Nanda2, H. Schmeling2, H. Tory2, Y. Uziel1, D. O. Viola1, H. Posner3, K. Kanik4, A. Wouters3, C. Chang4, R. Zhang3, I. Lazariciu5, M. A. Hsu4, R. Suehiro6, A. Martini1, D. J. Lovell2, H. Brunner2 on behalf of PRINTO/PRCSG
Systemic juvenile idiopathic arthritis.
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My take - Thus far, systemic juvenile idiopathic arthritis is classified as a subtype of juvenile idiopathic arthritis by the International League against rheumatism. It is a unique condition that is seen much more commonly in children as compared to adults. For those of us who look after the child with systemic juvenile idiopathic arthritis, we are aware that these patients are in themselves a heterogeneous group - There are some children with difficult systemic features, there are others with very difficult to control polyarthritis and finally, there are some prone to macrophage activation syndrome. In addition to these troubling clinical problems that we already face, patients with early-onset systemic arthritis and interstitial lung disease are a newly described category of children. Interestingly, discussions about these patients suggest that the ones who developed this complication have often, not been given significant oral steroids and have been treated upfront with biologic agents. Thus, it is important for us to understand that long-term outcomes of patients on biologic medications are best studied by registries and not by short-term published phase 3 clinical trials with a maximum follow-up of one year or so.
Proceedings from the 2nd Next Gen Therapies for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome symposium held on October 3-4, 2019. Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53
IL- 18 and systemic juvenile idiopathic arthritis
Background: Systemic juvenile idiopathic arthritis is a fairly common disease category seen in India. The initial presentation and often the flares can mimic infections as fever is often a predominant feature. There is a lack of specific biomarkers for disease activity in systemic arthritis. Interleukin 18 has been previously studied and is thought to be responsive to change in clinical disease activity in patients with systemic arthritis.
Abstract: This study was carried out in Cincinnati in United States. In a longitudinal prospective study serial samples of interleukin 18, CXCL 9 and S100 protein was obtained from 30 systemic arthritis patients aged 1-19 years. Clinical data were also reviewed from the medical records. ILI 18 was found to be significantly higher with active disease (median 13279 pg per ml), in comparison to clinically inactive disease – (median 810 pg per mL). The median difference of 12469 pg per mL was highly statistically significant (p less than 0.0001). Additionally, IL18 correlated with S100 and CXCL 9. On further analysis, it was noted that patients who had significant systemic features or systemic features and arthritis had significantly higher IL-18 levels as compared to those children who had only an articular flare or were inactive.
What's new? This study has noted that IL-18 is significantly higher in patients with systemically active disease. This raises optimism about the use of IL18 as a biomarker in further studies. More work needs to be done to define the differences between IL 18 in systemic arthritis patients vs patients who have fever because of infections. Thus far, the study of the serum cytokine profile has not been useful in diagnosing patients who have inflammatory rheumatic diseases. Often what is looked at is the gene expression that is driven by the cytokines.
My take - If IL-18 cytokine estimation in the serum, a fairly simple test, can discriminate the child with active systemic juvenile idiopathic arthritis from infectious causes it would indeed be a landmark development.
IL-18: A Biomarker That Reflects Disease Activity, Could It Be the Next Disease Activity Measure in Systemic Juvenile Idiopathic Arthritis?
Shima Yasin1, Thuy Do2, Sanjeev Dhakal2, Elizabeth Baker2, Alexei Grom3 and Grant Schulert4, 1Cincinnati Children's Hospital Medical Center, Liberty twp, OH, 2Cincinnati Children's Hospital Medical Center, Cincinnati, 3Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 4PRCSG, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Meeting: ACR Convergence 2020
Belimumab and juvenile SLE
Background - Paediatric lupus is more aggressive than its adult counterpart with increased disease activity and high damage as the years progress. Many children with paediatric lupus are confined to high-dose steroids for prolonged periods of time because of non-response to conventional synthetic disease-modifying agents such as Mycophenolate and AZATHIOPRINE. There is no data on multi-targeted therapy for the child with lupus. RITUXIMAB is not licenced by the US FDA for use in Paediatric or adult lupus. Belimumab was granted US FDA approval for moderate lupus in 2011, but there was no data available for use in paediatric practice. This trial is an important landmark study following which Belimumab has been granted US FDA approval for use in Paediatric Lupus Patients.
The study: The PLUTO trial has been recently published. This studied the role of Belimumab in Paediatric patients with lupus aged between 5 and 17 years. The trial was not sufficiently powered to report p values for this drug. The SRI4 composite lupus responds index was used to judge the outcome and was the primary endpoint of this trial. Ninety- three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)).
The dose used was 10 mg/kg intravenously every four weeks. There were no additional safety concerns as compared to the adult trial for the drug. Specifically, there were no suicidal ideation behaviors in the patients given Belimumab. Interestingly, there was no reduction in the use of steroids in the arm given Belimumab, the authors report that this was because of a protocol-driven dosing for steroids and also that this study was not powered to look at this outcome measure.
Postscript The drug has been given approval by the US FDA for use in Paediatric lupus patients aged 5-17 in the year 2019.
My take -This biologic agent is not available in India. Its use has not met with significant enthusiasm in the Paediatric Rheumatology Community. More data is required about this drug before it can be used in a day to day Practice.
Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo- controlled trial. Ann Rheum Dis. 2020 Oct; 79(10): 1340–1348. Hermine I Brunner,#1 Carlos Abud-Mendoza,2 Diego O Viola,3 Inmaculada Calvo Penades,4 Deborah Levy,5 Jordi Anton,6 Julia E Calderon,7 Vyacheslav G Chasnyk,8 Manuel A Ferrandiz,9 Vladimir Keltsev,10 Maria E Paz Gastanaga,11 Michael Shishov,12 Alina Lucica Boteanu,13 Michael Henrickson,1 Damon Bass,14 Kenneth Clark,15 Anne Hammer,14 Beulah N Ji,15 Antonio Nino,14 David A Roth,14 Herbert Struemper,16 Mei-Lun Wang,14 Alberto Martini,17 Daniel Lovell,1 Nicolino Ruperto,#18 and in collaboration with the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)
SSC and ILD
Background :
Pulmonary function tests, specifically forced vital capacity, diffusion lung carbon monoxide, and FEV1/FV ratios are used as surrogate markers to screen for interstitial lung disease in adult patients with systemic sclerosis. The International Juvenile Systemic Sclerosis Cohort Data was reviewed to address the specific issue and review the sensitivity of these non-invasive investigations as compared to high-resolution computerized tomography of the chest.
Abstract: 86 patients with juvenile systemic sclerosis had both the high-resolution CT scan and pulmonary function tests done, results were thus available for comparison: sensitivity of FVC in detecting ILD was only 40%, specificity was 77%, and AUC was 0.58. Fifty-eight jSSc patients had both CT imaging and DLCO values for comparison. The sensitivity of DLCO in detecting ILD was 76%, the specificity was 70%, and AUC was 0.73.
What is new from this study?
Only doing the pulmonary function test in children with juvenile systemic sclerosis will miss 60% of patients with interstitial lung disease and therefore HRCT should remain the screening tool for ILD in juvenile systemic sclerosis.
My take - The prevalence of systemic sclerosis is very low in children, much lower than what our adult counterparts see. It would be important for Paediatric Rheumatologists to protocolize how they manage children with systemic sclerosis and learn from our adult colleagues. Internal organ screening is very important and should include evaluation of the heart, the lungs, and the kidneys. This is all the more important in pediatric practice as the children with systemic sclerosis carry the burden of the disease for many more years than do their adult counterparts. Additionally, a majority of children with systemic sclerosis suffer from the diffuse variety of the disease; very few patients are reported to have limited systemic sclerosis in the childhood years.
Under detection of interstitial lung disease in juvenile systemic sclerosis (jSSc). Ivan Foeldvari 1, Jens Klotsche 2, Bernd Hinrichs 3, Nicola Helmus 1, Ozgur Kasapcopur 4, Amra Adrovic 4, Flavio Sztajnbok 5, et al. Arthritis Care Res (Hoboken). 2020 Nov 3.
JIA relapse after MTX discontinuation
Background: METHOTREXATE is the most widely used conventional synthetic disease-modifying anti-rheumatic drug in the management of a child with idiopathic arthritis. There is much debate with the weaning of METHOTREXATE once the child has gone into clinical remission. Most centers would wean medication 1 year after the patient has remained in a consistent state of inactive disease, some reports do recommend stopping the medication 6 months after the patient achieved inactive disease. This Portuguese JIA database has evaluated the predictive factors for juvenile idiopathic arthritis relapse after METHOTREXATE discontinuation.
Abstract: The Portuguese National data base on juvenile idiopathic arthritis was evaluated for this question. 1470 patients had been registered, of which 563 were under 18 years of age at the time of evaluation. 265 patients were treated with conventional synthetic disease-modifying agents and were biologic naive. Of these 119 patients discontinued METHOTREXATE due to inactive disease. 70% of these patients were female and 60% had oligoarticular juvenile idiopathic arthritis. Relapse occurred in 32% of the patients. In a Univariate analysis relapse was associated with 2 factors - first with the use of NSAID at the time of METHOTREXATE (p=0.027) and second if the patient had been in inactive disease for less than 2 years (p=0.040) No other association was defined as being statistically significant.
What's new: From a management paradigm point of view, if the child requires to take daily non-steroidal anti-inflammatory along with METHOTREXATE, it suggests that the disease in fact is active and the dose of the background disease-modifying agent either conventional or biologic needs a step up. Thus, it is important to discontinue non-steroidal anti-inflammatory drugs prior to reducing the METHOTREXATE. Prolonged periods of inactive disease even up to 2 years may be important before METHOTREXATE is tapered. With the current schedules up to 1/3rd of patients are likely to relapse on METHOTREXATE discontinuation.
My take -
Eular 2020: Fri0462?Predictive factors of relapse after methotrexate discontinuation in JIA patients with inactive disease. S. Azevedo1, J. Tavares-Costa1, A. T. Melo2, R. Freitas3, M. Cabral4, M. Conde5, F. Aguiar6, A. Neto7, A. F. Mourão7, F. Oliveira-Ramos2, M. J. Santos3, D. Peixoto1
Intra-articular injections in patients with juvenile idiopathic arthritis
Background: Intraarticular steroid injections are used very often in the child with juvenile arthritis. This can be used as a primary modality of therapy for oligoarticular patients or can be used to tackle 1 or more difficult joints in patients who have a polyarticular disease course. 2 drugs are available: TRIAMCINOLONE Hexacetonide and TRIAMCINOLONE Acetonide. Is there any difference between the 2? TRIAMCINOLONE Hexacetonide is not available in India.
Abstract: This was a retrospective review from Israel. Chart review of juvenile idiopathic arthritis patients who were treated with either TRIAMCINOLONE Acetonide (TA), or TRIAMCINOLONE Hexacetonide (TH), over a 10 year period was studied. Primary efficacy was defined as full recovery of arthritis 1 month after intraarticular steroid injection. Recurrence of arthritis was defined as joint swelling 3 months after the intraarticular joint injection.
Of the 292 joints of 102 juvenile arthritis patients, 138 were given TRIAMCINOLONE Acetonide and 154 TRIAMCINOLONE Hexacetonide. Complete recovery after 1 month was documented in 69.6% of patients (107) of TA-treated joints and 96 (69.69%) of TH-treated joints. P value=0.232. Thus, the efficacy of both the molecules was the same. However, the rate of relapse after 3 months was significantly higher in patients treated with TA joint injection 27(20.1%) versus TH 13 (8.8%) (p less than 0.01). No adverse events were documented except for a minor scar at joint injection sites.
What is new? Although arthritis recovery was similar, approximating 70% for both molecules, the relapse rate was more than double in the patients treated with TRIAMCINOLONE Acetonide.
My take -Curiously, we do not have TRIAMCINOLONE Hexacetonide in our country and are totally reliant upon TRIAMCINOLONE Acetonide. Multiple conversations and suggestions to the pharmaceutical industry over the last two decades have not yet yielded any results and in the year 2021, we are still reliant only upon TRIAMCINOLONE Acetonide in India.
Long Term Efficacy and Safety of Triamcinolone Hexacetonide versus Triamcinolone Acetonide Intraarticular Injection for Juvenile Idiopathic Arthritis. Shiri Rubin1, Orly Ohana1, Ori Goldberg2, Yulia Gendler1, Zohar Habot-Wilner3, et al
Meeting: ABSTRACT NUMBER: 0720, ACR Convergence 2020
Switching from Reference to Biosimilars for Children with juvenile idiopathic arthritis
Background - Anti-TNF agents are the mainstay of therapy for a child with juvenile arthritis who fails to respond completely to subcutaneous METHOTREXATE. Both reference and biosimilar molecules are available in our country. There has been much debate about the decision to use a reference molecule or a biosimilar, and while the patient is being treated there has been discussion about the safety of switching from 1 Brand to the other. What does the current data tell us?
Abstract -A retrospective study was conducted in Italy. Medical Charts of children with juvenile arthritis who have switched from Etanercept or Adalimumab originator to biosimilars were reviewed. Outcome Measures were juvenile arthritis disease activity score (JA DA s - 10), a number of inflamed joints, ESR, c reactive protein, visual analogue scale and childhood health assessment questionnaire. The occurrence of adverse events was also evaluated.
43 children were evaluated. 14 had received upfront Etanercept originator and 29 had received Adalimumab originator molecule as first-line anti-TNF therapy for refractory juvenile arthritis. Due to health care policies, predominantly cost saving, patients were switched to several biosimilars both for Etanercept and for Adalimumab. Median time at which the biologic was switched was 40.5 months after originator therapy had been initiated. At the time of the switch 10 of the 14 patients on Etanercept and 19 of the 29 on Adalimumab were in complete disease remission. No difference of any of the evaluated parameters was found at 3, 6 and 12 months of follow up. The number of patients who experienced adverse effects was also no different from the originator to the biosimilar molecule.
What’s new
Biosimilars are now being used widely all across the world. This paper gives us more confidence to be able to switch from originator to biosimilars in our country as well. This is keeping in mind that the brands available in Europe are different from what is available in India where we have more intended copies and not biosimilars as technically defined by the WHO.
My take – We tend to familiarize ourselves with a few biosimilars and have shown in an abstract presented at the ACR a few years ago that the biosimilars in the Anti TNF arena work as well as the originator. We try not to switch brands for individual patients and persist with the same agent as long as needed for each patient.
Abstract 0712: Switching from reference to biosimilars does not reduce efficacy and safety in juvenile idiopathic arthritis. Maccora I, Simonini G, Bettiol A,
ACR Convergence meeting 2020 ( Virtual ) Https://acrabstracts.org/abstract/ /. Accessed March 15, 2021.
Glucocorticoid-induced osteopenia in juvenile rheumatic disease:
Background - Significant inflammatory rheumatic diseases are usually treated with upfront high dose steroids with the associated problems of glucocorticoid induced osteopenia or osteoporosis. Several guidelines exist for the management of adult glucocorticoid-induced osteoporosis, but thus far children with high dose steroid intake have only been given vitamin D and calcium unless they develop a fragility fracture.
The study - patients with inflammatory rheumatic diseases who had been started on high dose steroids were recruited into a double-dummy placebo-controlled trial in a ratio of 1: 1: 1 for Placebo, 1-ALFACALCIDOL, and weekly Risedronate. The primary endpoint was lumbar spine change in z score via bone densitometry measured at 1 year. A secondary endpoint was a reduction in the fracture rate.
Risedronate 1 mg/kg/week for body weight< 30kgs, or 35 mg/wk. for body weight > 30 kgs.
The risedronate and risedronate placebo were identical as were the alfacalcidol and placebo. All children received a supplement of 500 mg calcium and 400 IU vitamin D daily.
270 patients were recruited for this study. The primary endpoint that is the lumbar spine change in z score was highly statistically significantly in favour of Risendronate versus placebo and 1 ALFACALCIDOL: the placebo and risedronate groups; 0.274, 95% CI (0.061, 0.487) (p b 0.001) and between the risedronate and the alfacalcidol groups; 0.326 95% CI (0.109, 0.543) (p b 0.001).
What this study adds - Use of risedronate in children and young people with in?ammatory conditions receiving steroids, especially those considered at higher risk for fracture should be standard of care. Hopefully, with the publication of this report paediatric rheumatologists will now have the confidence to use a Bisphosphonate up front when they begin to use steroids in Systemic Rheumatic Diseases such as class IV lupus nephritis, new-onset juvenile dermatomyositis, a sick systemic juvenile idiopathic arthritis patient or the newly diagnosed child with a severe systemic vasculitis such as polyarteritis nodosa. It is interesting that the author used Risedronate not Alendronate which appears to have a better impact on improving the bone mineral density.
My take - In our unit, we often begin the patient on Alendronate and we have only a couple of children with fragility fractures. In fact, we conducted the Denosumab trial for children with rheumatic diseases on steroids and had difficulty in recruiting children as many children we screened were screen failures as the Genant lumbar spine score was often 0!
The prevention and treatment of glucocorticoid-induced osteopenia in juvenile rheumatic disease: A randomised double-blind controlled trial? Madeleine Rooney a, ?, Nick Bishop b , Joyce Davidson c , Michael W. Beresford d , Clarissa Pilkington e , Janet McDonagh f , Sue Wyatt g , Janet Gardner-Medwin h , Rangaraj Satyapal i , Jacqui Clinch j , Helen Foster k , Mark Elliott l , Rejina Verghis m, on behalf of theBritish Society for Paediatric and Adolescent Rheumatology UK . EClinicalMedicine. 2019 Jul 3;12:79-87. doi: 10.1016/j.eclinm.2019.06.004. eCollection 2019 Jul.
Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children. Rocío Galindo-Zavala, Rosa Bou-Torrent,2 Berta Magallares-López,3 et al. Pediatr Rheumatol Online J. 2020; 18: 20.
Kawasaki disease
Background - The recognition and perhaps incidence of Kawasaki disease is increasing all across the world. It is today, the most common cause of acquired heart disease in the developed world. With appropriate diagnosis and early management, specifically if IVIG is given to the patient within 10 days of disease onset, the incidence of the development of coronary artery lesions can be reduced from 25% to just under 5%.
It is now well established that the coronary artery Z score at diagnosis is highly predictive of the coronary arteries size at 4-6 weeks after initial diagnosis. However, the American Heart Association guidelines of 2017 have not specifically addressed the issue of management of the patient that presents to the clinic for the first time with a coronary artery lesion. Of note, risk scores for non-response to IVIG have been validated within Japan only. Application of these criteria for example the Kobayachi score has poor sensitivity in the diverse North American Population.
The study -Using the demographic and clinical characteristics yielded by the logistic regression, a simple scoring model was constructed to define risk factors that predicted persistence of coronary artery lesions 2-8 weeks after disease onset.
2 Large cohort of multi ethnic patients with Kawasaki disease in the United States were taken to developing a new scoring system to predict persistence of coronary artery aneurysms (CAA) at 6-8 weeks from disease onset.
From the development cohort of patients, for each patient, 2 points were assigned if the maximum Z score at baseline was ≥2.00 (proximal left anterior descending and proximal right coronary artery dimensions were used for this purpose), 1 point if age at fever onset was < 6 months and 1 point if baseline CRP was ≥13 mg/dL. A 3-tier scoring system was determined based on the sum of points per patient: 0 to 1 point (low risk), 2 points (moderate risk), and 3 to 5 points (high risk).
This scoring system was then tested on a validation cohort of children with Kawasaki disease.
The odds of CAAs were 16-fold greater in the high- versus the low-risk groups in the development cohort (odds ratio,16.4; 95% CI, 9.71–27.7 [P<0.001]), and >40-fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8–180 [P<0.001]).
My take- This study has presented a new scoring system in a Multi-Ethnic population from the USA to identify patients at high risk of persistence of coronary artery lesions 2-8 weeks after the diagnosis of KD. Asian origin, young age at disease onset, presentation with coronary artery aneurysms at first connect, and a high c reactive protein have all been shown to be highly predictive of ongoing coronary artery inflammation which is detectable by a 2D echo a few weeks after disease onset. This data is very important to help stratify patients such that the patient that requires upfront adjuvant therapy can be easily identified and more carefully followed up with serial echocardiograms.
Risk Model Development and Validation for Prediction of Coronary Artery Aneurysms in Kawasaki Disease in a North American Population. J Am Heart Assoc. . 2019 Jun 4;8(11). Mary Beth F Son , Kimberlee Gauvreau , Adriana H Tremoulet , Mindy Lo , Annette L Baker , Sarah de Ferranti , Fatma Dedeoglu, Robert P Sundel, Kevin G Friedman, Jane C Burns, Jane W Newburger.
Granulomatosis with polyangiitis
Background - Primary systemic vasculitis, especially the ANCA associated vasculitides are very rare in the Paediatric Age Group. The most common vasculitis seen in Paediatrics is Kawasaki disease, Henoch Schonlein purpura, and infection-associated vasculitis. Our adult counterparts are very experienced in ANCA associated vasculitis as compared to the Paediatric Rheumatologist. Very busy centres which have been established for decades across the world do not have more than half a dozen patients of ANCA associated vasculitis at most. Thus far, CYCLOPHOSPHAMIDE has been the standard of care for inducing remissions in the child with severe systemic vasculitis including GPA.
In the study – 25 patients were enrolled from 11 centers, 19 (76%) had GPA and 6 (24%) had MPA. The majority were female (20 patients [80%]), white (17 patients [68%]) and the median age was 14 years (range: 6-17 years). Most patients (18/25) had new-onset disease. Median baseline PVAS was 8 (IQR 5-15).
The protocol :
Three doses of pulsed intravenous (IV) methylprednisolone were administered during the screening period followed by four weekly IV rituximab infusions of 375 mg/m2 body surface area and concomitant oral glucocorticoid taper. After the 6-month remission induction phase, patients received standard of care treatment (including additional rituximab infusions if required) for disease control. Visits occurred at 1, 2, 4 and 6 months during the remission-induction phase and every 3 months thereafter for a minimum of 18 months. The pediatric vasculitis activity score (PVAS) was used for exploratory efficacy assessments. Remission was defined as a PVAS of 0 and oral prednisone or prednisolone equivalent dose of ≤ 0.2 mg/kg/day (max 10 mg/day).
The results
Safety: The median duration of follow-up was 24 months (range:16-54 months). All 25 patients completed the first 4 rituximab infusions and the 6-month remission induction phase; 24 of 25 completed ≥ 18 months of follow-up. All patients experienced ≥ 1 adverse event (AE) during the first 6 months, with infusion-related reactions (IRRs) being the most common AE.Overall, infections occurred in 68% of patients (with upper respiratory tract infection being the most frequent [16% of patients]). Ten serious AEs (SAEs) occurred in 7 patients during the 6-month remission induction phase, including 1 IRR. Over the entire study, 27 SAEs occurred in 12 patients, and no deaths were reported.
Efficacy: Exploratory efficacy assessment showed that 56% of patients achieved remission by month 6; 100% of patients achieved remission by month 18. The median duration of remission during the study was 56 (IQR, 38-83) weeks.
What's new -The US Food and Drug Administration (FDA) has approved add-on rituximab (Rituxan) injection for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children aged 2 years and older. This is a major new milestone in the management of the child with ANCA associated vasculitis.
My take-Of note, the very sick patient with ANCA associated vasculitis that required ventilatory support, had pulmonary haemorrhage, or significant renal impairment or needed plasmapheresis was excluded from this trial. Thus, though RITUXIMAB is likely to become the standard of care for the child with ANCA associated vasculitis both for induction and for maintenance of remission, clinical judgment and use of cyclophosphamide may continue to remain very important for the very sick patient with ANCA associated vasculitis.
ABSTRACT NUMBER: L04
Pediatric Open-Label Clinical Study of Rituximab for the Treatment of Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA). Paul Brogan, Gavin Cleary, Aimee O. Hersh, Ozgur Kasapcopur, Satyapal Rangaraj, Rae S.M. Yeung, Andrew Zeft et al.
Meeting: 2018 ACR/ARHP Annual Meeting
Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist. Lee JJY, Alsaleem A, Chiang GPK, Limenis E, Sontichai W, Yeung RSM, Akikusa J, Laxer RM. Pediatr Rheumatol Online J. 2019 Jun 26;17(1)
Ultrasound in Pediatric Rheumatology
Background - Clinical examination of the child with juvenile idiopathic arthritis or indeed any other systemic inflammatory rheumatic disease that has arthritis as its clinical component can be fraught with difficulties and challenges. Additionally, joints that appear to be clinically normal may in fact be afflicted with significant synovitis that is not picked up by our hands. This is very important for the shoulder and the hip joint which can be chronically inflamed and yet be relatively painless and have a normal range of motion. Ultrasound is an excellent tool to examine joints of children with arthritis. This procedure requires no sedation, is child-friendly, multiple joints can be evaluated at one time, and patients can be carefully followed up (with diligent note keeping!).
The review- This review article on the role of ultrasound in Paediatric Rheumatology is written by one of the world’s leading experts. It describes the benefits, the utility, common definitions, differentiation of normal from abnormal joints, and normative data on some joints such as the knee which have now been published. Paediatric Rheumatology and specifically ultrasound examination of the joints is very different to scanning the joints of adult patients. The 2 key differences are that the epiphysis is open in children and the bones are growing. This growth is done by hyaline cartilage which is an anechoic structure and can mimic fluid in the joint. Secondly, as the child grows, the secondary ossification centres at the end of bones get fused and therefore the cartilaginous long bones change to ossified bones and the appearance of the joint changes as the child gets older. This tool is also excellent for defining the site of inflammation: joint, tendon or enthesis and a prerequisite for precision injection placement. Finally, it is a practical and visual display of the site of inflammation for the parent and helps them to understand the disease better.
My take – Ultrasound is now used very frequently and is seen in every department of the hospital- emergency, intensive care, nephrology, hepatology, and rheumatology to name a few. It is indeed practice-changing and beautifully compliments, in fact, improves clinical skills. It is enormously useful in the clinic and a must have skill for the new genre of pediatric rheumatologists in the country. It has its challenges: A very steep learning curve, the need for a good mentor, and the upfront cost of the machine are some important roadblocks that need to be crossed. But, it's only with effort that there is progress and this is an effort worth the result.
Emergence of Musculoskeletal Ultrasound Use in Pediatric Rheumatology. Johannes Roth.
Curr Rheumatol Rep. 2020 Apr 14;22(5):14.
Dr Sujata Sawhney