Clinical spectrum and outcome of children with deficiency of adenosine deaminase 2 (DADA2): multicentric experience from India.

OBJECTIVES: Deficiency of adenosine deaminase-2 (DADA2) is a monogenic disorder closely resembling polyarteritis nodosa (PAN) and can present to physicians across various specialties. Through this case series, we aim to describe the clinical spectrum and outcome of Indian children with DADA2. We aimed to study the clinical spectrum and outcome of Indian children with DADA-2. METHODS: The deidentified data from all participating centres were entered in an excel sheet, and the coordinating centre (All India Institute of Medical Sciences, New Delhi) screened the data for accuracy and completeness. RESULTS: We enrolled 16 children (11 females) in the study; the mean (SD) age at the time of onset of symptoms for males and females was 46.2 (47) and 73.6 (50.4) months, respectively. The most common clinical feature in this cohort was fever and rash in 80% of patients. More than half of children n, (%) [8, (53%)] had a CNS stroke. The other clinical features were hypertension [5(33%)], anaemia [3 (20%)] and arthralgia/arthritis in 4 (26%). These children were managed with various immunomodulators: steroids [13, (86%)], anti-TNF agents [(12, (80%)], cyclophosphamide [2 (13%)] and mycophenolate mofetil [3 (20%)]. The median (IQR) duration of follow-up for this cohort was 17 (10, 29) months. Fourteen children achieved remission and none had recurrent strokes after the initiation of anti-TNF drugs. CONCLUSION: DADA-2 closely resembles PAN; early age of onset and CNS stroke are striking differentiating features from classic PAN. Most children respond well to anti-TNF agents without serious adverse events during short-term follow-up.

Prevalence and Clinical Implications of Autoantibodies in Juvenile Dermatomyositis: A Single-Center Experience From India.

OBJECTIVE: ​​This study aimed to characterize the profile of myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) in an Indian cohort of juvenile dermatomyositis (JDM) patients and correlate them with clinical features and outcomes. METHODS: Forty-three children diagnosed with JDM were enrolled for this observational study. Clinical details (presentation, course, and outcome) were noted in a predesigned proforma. Serum samples were tested for 16 MSAs/MAAs by line immunoassay. MSAs/MAAs were correlated with clinical features and outcome (defined as a complete clinical response [≥6 months' disease inactivity on medication] or complete remission [≥6 months' inactivity off all drugs]). RESULTS: Thirty-five subjects (81.4%) had at least 1 MSA/MAA detected. The most common antibodies were anti-NXP2 (n = 13, 30.2%), anti-TIF1γ (n = 10, 23.2%), and anti-MDA-5 (n = 8, 18.6%). No patient had anti-Ku, anti-Pm Scl-100, anti-PL-12, anti-EJ, anti-OJ, or anti-Ro52. Thirty-two patients (74.4%) attained a complete clinical response over a median follow-up duration of 14 months, among which 6 (13.9%) achieved complete remission over a median follow-up duration of 30 months. Anti-TIF1γ was associated with younger age at onset (≤3 years) (odds ratio [OR], 6.25; 95% confidence interval [CI], 1.15-34.12; p = 0.034) and disease flares after attaining complete response (OR, 10.18; 95% CI, 1.64-70.93; p = 0.013). Patients with anti-NXP2 had higher odds of severe muscular weakness (OR, 3.73; 95% CI, 0.95-14.59; p = 0.058) and truncal weakness (OR, 3.89; 95% CI, 0.97-15.64; p = 0.056). One child with anti-MDA-5 positivity had interstitial lung disease. We found no association between the MSA/MAA profile and the achievement of complete clinical response or remission. CONCLUSIONS: MSAs/MAAs were identified in 81% of children with JDM in our study, which is higher than most other studies. The most frequently observed antibodies displayed a pattern consistent with other studies. Anti-TIF1γ was associated with a younger age at onset and disease flares even after attaining a complete clinical response. Anti-NXP2 had higher odds of severe muscular weakness. These observations suggest consistency in certain phenotypic associations observed across geographic boundaries.

Case 316.

HISTORY: A 10-year-old North Indian boy presented with swelling of multiple joints in his hands for the past 3 years. This swelling involved the small joints of his hands and some restriction of joint movement, without any associated tenderness or morning stiffness. No other joints were symptomatically involved. Prior to visiting our hospital, he had received disease-modifying antirheumatoid drugs for suspected juvenile idiopathic arthritis, without any clinical benefit. On examination, the metacarpophalangeal and interphalangeal joints were nontender but had swelling and flexion deformities. He also had a short stature (below the third centile) for his age. Inflammatory markers, including erythrocyte sedimentation rate (7 mm per hour; normal range, 0-22 mm per hour) and C-reactive protein level (1.5 mg/L; normal level, <10 mg/L), were normal, and the rheumatoid factor test result was negative. A skeletal survey of the patient was performed and is shown in Figures 1-6.

Case 316: Progressive Pseudorheumatoid Dysplasia.

HISTORY: A 10-year-old North Indian boy presented with swelling of multiple joints in his hands for the past 3 years. This swelling involved the small joints of his hands and some restriction of joint movement, without any associated tenderness or morning stiffness. No other joints were symptomatically involved. Prior to visiting our hospital, he had received disease-modifying antirheumatoid drugs for suspected juvenile idiopathic arthritis, without any clinical benefit. On examination, the metacarpophalangeal and interphalangeal joints were nontender but had swelling and flexion deformities. He also had a short stature (below the third centile) for his age. Inflammatory markers, including erythrocyte sedimentation rate (7 mm per hour; normal range, 0-22 mm per hour) and C-reactive protein level (1.5 mg/L; normal level, <10 mg/L), were normal, and the rheumatoid factor test result was negative. A skeletal survey of the patient was performed.

Kawasaki disease or polyarteritis nodosa: coronary involvement, a diagnostic conundrum.

Polyarteritis nodosa (PAN) is a medium-vessel vasculitis presenting with cutaneous and multisystem involvement with considerable morbidity. The necrotizing vasculitis in PAN typically involves renal, celiac, and mesenteric vascular beds. Coronary artery involvement is a characteristic feature of Kawasaki disease, another medium-vessel vasculitis; however, it has been rarely reported with PAN. Here, we present 2 cases with PAN involving coronaries mimicking Kawasaki disease. A 3.5-year-old boy with classical features of Kawasaki disease with giant coronary aneurysm refractory to IVIg, methylprednisolone, infliximab presented with persistent rise in inflammatory markers and gastrointestinal bleeding. Digital subtraction angiography (DSA) revealed celiac artery branches stenosis and beading suggestive of PAN. Another 2-year-old girl presented with persistent fever, abdominal pain, and distension. She had hypertension, hepatomegaly, and splenomegaly on examination. Echocardiography revealed multiple coronary aneurysms and DSA revealed numerous renal artery aneurysms. Coronary aneurysm although is a rare presentation of childhood PAN, and can mimic Kawasaki disease. Although both are medium-vessel vasculitis differentiation between these two entities is pivotal, as there are differences in treatment modalities, duration of immunomodulatory therapy, and the outcome. This manuscript describes the salient differences which can help differentiate PAN masquerading as Kawasaki disease at initial presentation.

Technical and Interpretive Pitfalls in Pediatric Musculoskeletal Ultrasound.

The use of musculoskeletal (MSK) ultrasound (US) in pediatric rheumatology has expanded rapidly with various diagnostic and therapeutic indications. Unlike magnetic resonance imaging (MRI), US allows real-time dynamic assessment, evaluation of multiple joints in a single session and comparison with contralateral limb. However, a long learning curve and lack of experience with MSK US in pediatric patients still precludes its routine use at many imaging centers. It is prudent for pediatric radiologists to be aware of normal US appearances of the growing MSK structures to avoid their misinterpretation as pathology. The normal MSK US findings in children which can be confused with pathology and create diagnostic difficulty can arise due to variable states of maturation of bones, cartilage and tendons, complex anatomical locations, accessory structures, and artifacts. Herein, we describe the various technical and interpretive challenges encountered with MSK US in pediatric patients.

Can Whole-Body Magnetic Resonance Imaging Predict Relapse in Juvenile Idiopathic Arthritis? A Longitudinal Pilot Study.

OBJECTIVE: To determine the utility of whole-body magnetic resonance imaging (WB MRI) to predict relapse in children with juvenile idiopathic arthritis (JIA) in clinical remission. METHODS: Consecutive patients with JIA who fulfilled the Wallace criteria for remission were recruited into this longitudinal pilot study and underwent WB MRI. A radiological score was devised, incorporating synovitis, bone marrow edema, sacroiliitis, enthesitis, and bone erosions. Two readers independently scored the MR data sets. The same score was calculated for both knee joints individually and correlated with outcome for that joint. Score-based models incorporating clinical and laboratory variables were generated. Logistic regression analysis was done to determine predictors for relapse. Receiver operating characteristic curve was drawn for significant variables. RESULTS: Twenty-two children (median age, 12 years; interquartile range, 9.5-14.25 years) were included in the final analysis. At 24 months' follow-up, 15 joints in 5 children relapsed; knee was the most common site. Seven knee joints had disease relapse. On univariate analysis, synovitis and total score on WB MRI were significant predictors of relapse at follow-up, with odds ratios of 9.46 (bias-corrected 95% confidence interval, 3.07-29.13) and 2.8 (bias-corrected 95% confidence interval, 1.23-6.39) respectively. Two models, which included a higher number of joints involved at presentation and abrupt drug withdrawal strategy as predictor variables, were also statistically significant (odds ratio, approximately 1.9). On multivariate analysis of the predictors variables in models where p < 0.6, it was found that only synovitis score and total score were near statistical significance ( p = 0.06); no clinical or laboratory variables were significant. The areas under the receiver operating characteristic curve for relapse prediction were approximately 0.82, 0.87, 0.79, and 0.81 for synovitis score, total MRI score, and both models, respectively. CONCLUSION: Synovitis on WB MRI is the strongest independent predictor for disease relapse in children with JIA in remission.

Efficacy of pulse dexamethasone in non-systemic juvenile idiopathic arthritis: a double-blind randomized controlled trial.

OBJECTIVE: Early aggressive therapy using biologicals is increasingly being used in JIA for early disease remission. Pulse steroids are used in induction regimes for rheumatic disorders such as SLE and systemic JIA; however, no controlled studies have demonstrated their use in non-systemic JIA. The objective of the present study was to evaluate the efficacy and safety of pulse dexamethasone therapy in children with treatment-naïve non-systemic JIA as early aggressive therapy in resource-limited settings. METHODS: Sixty treatment-naïve children with non-systemic JIA with an active joint count of ≥5 and/or involvement of hip or cervical joints were randomized to receive either pulse dexamethasone (3 mg/kg/day, max 100 mg/day) or placebo (normal saline) for three consecutive days during each visit at 0, 6 (±2) and 12 (±2) weeks; along with standard therapy (MTX and NSAIDs). The use of oral bridge steroids was permissible for persistent severe disease as per predefined criteria. The primary outcome was ACR-Pedi 70 response at 16 (±2) weeks after enrolment in the two groups. RESULTS: The proportion of children achieving ACR-Pedi 70 in the two groups at last follow-up was 11/30 (36.7%) in pulse dexamethasone arm vs 11/28 (39.3%) in the placebo arm (P-value 0.837, relative risk 0.93, 95% CI 0.48, 1.80). We did not observe any significant difference in the proportion of children requiring bridge steroids. Adverse events were comparable in the two groups. CONCLUSION: The addition of pulse dexamethasone to standard treatment may not add any advantage in improving ACR-Pedi 70 scores at medium-term follow-up. TRIAL REGISTRATION: Clinical Trial Registry-India; www.ctri.nic.in CTRI/2018/08/015151.

Sympathetic Blocks for Raynaud's Phenomena in Pediatric Rheumatological Disorders.

OBJECTIVE: Sympathetic blocks are invaluable to prevent morbidity from Raynaud's phenomenon (RP). RP may occur in children with rheumatological disorders and causes severe pain, discoloration of digits, gangrene, and auto-amputation. We describe the planning and execution of sympathectomy blocks in children with rheumatological disorders presenting with RP. METHODS: With upper-limb involvement, ultrasound-guided stellate ganglion block (USGB) was given with ropivacaine and clonidine. When all four limbs were involved, intrathecal block with bupivacaine and clonidine was also given. RESULTS: A total of 68 sympathectomy blocks were performed: 28 bilateral USGBs, two unilateral USGBs, and 10 intrathecal injections. Multiple interventions in a single day were frequently required. For safety, all USGBs were performed with an ultrasound with strict adherence to local anaesthetic volume was maintained, with periprocedure monitoring of 2-3 hours. All blocks were performed by an experienced specialist. All children reported immediate pain relief with prevention of major amputation. CONCLUSION: With meticulous planning, monitoring, and precautions, sympathectomy of limbs in pediatric rheumatological disorders with RP can be safely undertaken. Bilateral stellate ganglion block with ultrasound is safe in children, and clonidine is a useful adjunct for vasodilation and prolongation of the effect of sympathectomies in children.

Monogenic lupus with homozygous C4A deficiency presenting as bronchiectasis and immune-mediated thrombocytopenia.

Monogenic lupus is a subset of lupus caused by single-gene disorders, integrating the paradoxical combination of autoimmunity and immunodeficiency. Pulmonary manifestations with recurrent pneumonia and bronchiectasis have rarely been described as the predominant presentation of juvenile lupus and may suggest an alternate differential like primary immunodeficiency, especially in early childhood. We describe a case of 10-year girl who presented with a history of recurrent pneumonia, arthritis, alopecia, and poor weight gain for the past 2 years. On examination, she had respiratory distress, bilateral diffuse crackles and arthritis of the small joints of hands. Lab investigations showed pancytopenia, low complement levels and high titers of ANA and anti-dsDNA antibodies. The patient was diagnosed with juvenile lupus. Imaging studies revealed evidence of multiple lobar collapse and consolidation with bronchiectasis. She was started on steroids, HCQ and supportive measures for bronchiectasis. The child reported relief in initial symptoms of lupus on follow-up but developed recurrent thrombocytopenia requiring IVIG and escalating the doses of oral steroids. The young age and atypical presentation prompted a screening for monogenic lupus, and clinical exome sequencing revealed a novel homozygous missense variation in exon 20 of the C4Agene with clinically reduced C4 levels, consistent with the diagnosis of C4A deficiency.

Outcomes of multisystem inflammatory syndrome in children temporally related to COVID-19: a longitudinal study.

To study the clinical, laboratory characteristics and outcomes of multisystem inflammatory syndrome in children (MIS-C) temporally related to coronavirus disease 2019 (COVID-19) in a resource-limited setting. All children meeting the World Health Organization case definition of MIS-C were prospectively enrolled. Baseline clinical and laboratory parameters were compared between survivors and non-survivors. Enrolled subjects were followed up for 4-6 weeks for evaluation of cardiac outcomes using echocardiography. The statistical data were analyzed using the stata-12 software. Thirty-one children with MIS-C were enrolled in an 11-month period. Twelve children had preexisting chronic systemic comorbidity. Fever was a universal finding; gastrointestinal and respiratory manifestations were noted in 70.9% and 64.3%, respectively, while 57.1% had a skin rash. Fifty-eight percent of children presented with shock, and 22.5% required mechanical ventilation. HSP like rash, gangrene and arthritis were uncommon clinical observations.The median duration of hospital stay was 9 (6.5-18.5) days: four children with preexisting comorbidities succumbed to the illness. The serum ferritin levels (ng/ml) [median (IQR)] were significantly higher in non-survivors as compared to survivors [1061 (581, 2750) vs 309.5 (140, 720.08), p value = 0.045]. Six patients had coronary artery involvement; five recovered during follow-up, while one was still admitted. Twenty-six children received immunomodulatory drugs, and five improved without immunomodulation. The choice of immunomodulation (steroids or intravenous immunoglobulin) did not affect the outcome. Most children with MIS-C present with acute hemodynamic and respiratory symptoms.The outcome is favorable in children without preexisting comorbidities.Raised ferritin level may be a poor prognostic marker. The coronary outcomes at follow-up were reassuring.

Role of Imaging in Childhood Arthritis.

ABSTRACT: Imaging plays a pivotal role in the management of various childhood arthritis. Conventional radiography is the most commonly ordered imaging modality for the evaluation of arthritis. Owing to their higher sensitivity for detecting synovitis, magnetic resonance imaging and ultrasonography are increasingly being used to guide clinical management of various forms of arthritis, especially juvenile idiopathic arthritis. Magnetic resonance imaging is a preferred modality for evaluating more complex sites such as the sacroiliac joint. In this review, we have discussed the rational use and the characteristic imaging features of common childhood arthritis.

Role of Serum MRP8/14 in Predicting Response to Methotrexate in Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: Nearly 40% of children with juvenile idiopathic arthritis (JIA) might not respond to first-line disease-modifying antirheumatic drugs (DMARDs) including methotrexate (MTX). Hence, there is a need for a biomarker that can predict MTX response and help in tailoring initial therapy. Our objective was to study the role of serum myeloid-related protein (MRP) 8/14, and other inflammatory cytokines, as predictors of response to MTX among children with JIA. METHODS: We did a longitudinal follow-up study among children diagnosed with JIA at our institute. All MTX-naive children with JIA requiring DMARDs were eligible for this study; those who either took corticosteroids or DMARDs for more than 6 weeks at time of presentation were excluded. The demographic and clinical information was collected using a pretested semistructured questionnaire, and selected biomarkers were collected at baseline and again at 3 months. Response at 3 months was assessed using the American College of Rheumatology (ACR) criteria; responders were children who achieved ACR50, whereas those failing to achieve ACR30 were classified as nonresponders. Multivariate binary logistic regression was done to assess determinants of being a responder. RESULTS: We enrolled 69 children (36 boys) with JIA, of which 48 (69.5%) were responders. The baseline value of serum MRP8/14 was significantly higher in responders (median, 144.34 [interquartile range, 88.54-188.34] ng/mL) compared with the nonresponders (median, 95.34 [interquartile range, 76.54-130.28] ng/mL), p = 0.047. Being a responder was significantly associated with baseline serum MRP8/14 with adjusted odds ratio of 1.01 (95% confidence interval, 1.00-1.02). CONCLUSIONS: The baseline levels of MRP8/14 were significantly raised in children meeting ACR50 at follow-up and suggest a prognostic value in predicting response to MTX.

Successful use of tocilizumab in amyloidosis secondary to systemic juvenile idiopathic arthritis.

Amyloidosis secondary to juvenile idiopathic arthritis is a known complication of poorly controlled systemic juvenile idiopathic arthritis (SJIA), occurring in 1-2% of the patients. The IL-6 inhibitor tocilizumab is effective in controlling systemic signs and symptoms of sJIA and may be of therapeutic benefit in secondary amyloidosis. Herein, we report the clinical timeline of a 10-year boy with sJIA and secondary amyloidosis, who showed a sustained improvement of systemic symptoms and a reduction in proteinuria with tocilizumab. Compared to the data on adult patients affected with the secondary amyloidosis, there are very few reports on therapeutic options for the children affected with SJIA and secondary amyloidosis in the paediatric population. While doing a systematic literature search for writing this review, we could only retrieve nine case reports and one case series of the children affected with SJIA and secondary amyloidosis, including five cases which were treated with tocilizumab. We also looked into the clinical and biochemical response to various agents that have been used in the previous cases, including tocilizumab. The available literature and the present case report suggest that tocilizumab may be considered as a safe and effective option to treat SJIA-related secondary amyloidosis.

Juvenile dermatomyositis with IgA nephropathy: case-based review.

Juvenile dermatomyositis (JDM) is the most common childhood idiopathic inflammatory myopathy (IIM). It is characterized by the classic skin rash in the form of Gottron papules and heliotrope rash, and symmetric proximal muscle weakness. Renal involvement in JDM is rare which includes acute kidney injury and glomerulonephritis. We report a 10-year-old boy with juvenile dermatomyositis and IgA nephropathy. Child responded dramatically to the conventional therapy with steroids and methotrexate for the primary disease, and did not require any additional treatment for his renal disease. Child's primary disease is in remission and has normal urinalysis with normal renal function at 6-month follow-up. We reviewed the literature and found 11 cases of IIMs with renal involvement. Four patients (one JDM, two polymyositis, and one dermatomyositis) had IgA nephropathy out of which three patients responded to the conventional therapy of primary disease and only one patient with polymyositis needed hiking immunosuppression targeted for renal condition. Therapy targeting the underlying disorder is usually sufficient in patients with JDM and secondary IgA nephropathy.

Efficacy of Oral Zinc Supplementation in Radiologically Confirmed Pneumonia: Secondary Analysis of a Randomized Controlled Trial.

Objective: To evaluate the effect of zinc as an adjuvant therapy in radiologically confirmed pneumonia in children 2-24 months of age. Patients and Methods: We analyzed data of 212 children with pneumonia for whom chest X-ray films were available at enrollment and at least two radiologists agreed on the diagnosis of pneumonia. We compared the time to recovery in the two groups (n = 121, zinc group and n = 91, placebo group) using a Cox proportional hazards regression model. Results: Time to recovery was similar in both groups [median interquartile range: zinc, 84 h (64, 140 h); placebo, 85 h (65, 140 h)]. The absolute risk reduction for treatment failure was 5.2% (95% confidence interval: -4.8, 15.1) with zinc supplementation. Conclusion: There was no significant beneficial effect of zinc on the duration of recovery or risk of treatment failure in children with radiologically confirmed pneumonia.

Juvenile systemic sclerosis: experience from a tertiary care center from India.

Juvenile systemic sclerosis (JSSc) is a rare disorder with paucity of information on its treatment and longterm  outcome. Herein, we are sharing our experience with this rare entity. Case records of children, diagnosed to have systemic sclerosis attending Pediatric Rheumatology Clinic at All India Institute of Medical Sciences, New Delhi from January 1998 to June 2016 were reviewed. The demographic, clinical, laboratory, treatment and outcome details were recorded. Disease outcome was classified arbitrarily as controlled, partly controlled or non-responsive/progressive based on: (A) ability to perform activities of daily life (ADL) and (B) presence or absence of musculoskeletal symptoms, skin changes (ulceration/progressive digital pitting/gangrene), and visceral organ involvement (dyspahgia, cardiopulmonary symptoms). Controlled: ability to perform ADL and absence of B features for at least 6 months. Partly controlled: inability to perform ADL or any of the B features. Non-responsive/progressive disease: presence of both A and any of B features. Thirty-two children (21, girls) diagnosed as systemic sclerosis for whom follow-up of more than 6 months was available were included for this retrospective analysis. Mean (SD) age at presentation was 112.79 (30.05) months, while the median (IQR) delay in diagnosis was 28.5 (9-47.25) months. Of the 32 children 17 (53.12%) had diffuse systemic sclerosis (dSSc), 5 (15.62%) had limited systemic sclerosis (lSSc) and 10 (31.25%) had sclerosis with overlap syndrome. The common clinical features apart from sclerosis/induration proximal to metacarpophalangeal joint were Raynauds phenomenon (n = 22, 68.7%), skin rash (n = 20, 62%), arthritis or arthralgia (n = 16, 50%), and muscular weakness (n = 10, 31.2%). Among those for whom data regarding investigations were available; ANA was positive in 50% (12/24), whereas Anti Scl70 was positive in one out three cases. Treatment regimen included naproxen, methotrexate, calcium channel blockers with or without steroids. HCQ was added in children with skin rash or in children with partial control. Median (IQR) follow-up period was 19.75 (12-31.75) months. With the above treatment protocol, 19 (59.3%) children achieved disease control on treatment, 8 (26.6%) had partial control while 5 (16.6%) showed no response or progressive disease. Esophageal dysmotility and intertitial lung disease (ILD) were documented in three children each. Complication (cataract and herpes zoster) related to immunosuppressive therapy were observed in two children. There was no mortality during the study period. Juvenile Sclerosis though rare is associated with significant morbidities and lacks a curative treatment but a reasonable quality of life to perform daily activities can be achieved using methotrexate and steroid-based immuosuppressive therapy.