THG14-001
A 16-month-old boy presented with fever for 2 months. Fever episodes are associated with evanescent rashes (as shown in images) and no joint symptoms. Child playful between fever spikes. Temperatures went as high as 104°F and as low as 96°F once a day. Fever persisted in spite of antibiotics, infectious causes ruled out. Hemoglobin (Hb) 7.6 g/dL, white blood cell (WBC) 18,000/mm3 (N 78, L 10), platelet 7.7 lakh/mm3, erythrocyte sedimentation rate (ESR) 100 mm/hour, C-reactive protein (CRP) 56 mg/dL, serum glutamic oxaloacetic transaminase (SGOT) 38 IU/L, serum glutamate pyruvate transaminase (SGPT) 43 IU/L, serum creatinine 0.6 mg/dL, chest X-ray was normal, ultrasonography (USG) abdomen mild hepatomegaly, and ascites present.
a. Identify the main diagnosis with likely complication described.
b. What are the International League of Associations for Rheumatology (ILAR) criteria for above condition and recent 2019 proposed criteria?
c. Is high CRP suggestive of sepsis in this disease?
d. What is the treatment of the disease?
Answer
| a. | Systemic-onset juvenile idiopathic arthritis (SOJIA) with macrophage activation syndrome |
| b. | ILAR criteria: Arthritis in any number of joints, together with a fever of at least 2 weeks of duration that is documented to be daily (quotidian) for at least 3 days and is accompanied by one or more of the following: Evanescent (nonfixed) rash, generalized lymphadenopathy, and enlargement of liver or spleen or serositis. |
Many children do not have arthritis at onset which makes it difficult to diagnose and often delays the diagnosis. Hence the 2019 proposed definition by PRINTO group: Daily fever documented for at least 3 consecutive days with quotidian pattern reoccurring over at least 2 weeks with two major criteria or one major criterion and two minor criteria.
| Major criteria: Evanescent rash and arthritis | |
| Minor criteria: |
| 1. | Generalized lymph node enlargement and/or hepatomegaly and/or splenomegaly |
| 2. | Serositis |
| 3. | Arthralgia lasting for 2 weeks or longer (in the absence of arthritis) |
| 4. | Leukocytosis (≥15,000/mm3) with neutrophilia |
| c. | Children with SOJIA often have high CRP with neutrophilic leukocytosis which leads to multiple courses of antibiotics with no response. Serum procalcitonin can be a helpful marker in differentiating a high CRP due to bacterial sepsis versus inflammatory etiology. |
| d. | Systemic juvenile idiopathic arthritis (JIA) treatment depends on the predominant manifestation—systemic features or arthritis. If systemic features are predominant then nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, interleukin-1 (IL-1) and IL-6 inhibitors work best whereas for arthritis methotrexate with bridging steroids works well. In a resource constraint setting like India, drugs like thalidomide, cyclosporine, leflunamide are also used for resistant cases. |
THG14-002
A 6-year-old boy with pain abdomen for 3 weeks extensively evaluated with all reports in normal range. Child was labelled as functional pain abdomen. After 4 weeks, he developed few purpuric lesions over lower limb and buttocks (as shown in images) with nonspecific joint pains. This was followed by scrotal swelling with one episode of blood in stool.
a. What is likely diagnosis and management?
b. Mention the classification criteria of this disease.
c. When are steroids indicated in this condition?
d. Which organ can be involved and needs monitoring after acute episode of this disease?
Answer
| a. | Immunoglobulin (IgA) vasculitis (formerly known as Henoch–Schönlein purpura) and needs supportive treatment in most cases. Some children need short course of corticosteroids (1–2 mg/kg/day oral prednisolone/prednisone) for disease resistant to supportive treatment. More severe or resistant cases may need high dose IV pulse steroids methylprednisolone (10–30 mg/kg/day for 3 days) with or without IV cyclophosphamide. Long-term disease-modifying antirheumatic drugs (DMARDs) such as mycophenolate mofetil or azathioprine maybe indicated in cases of nephritis. |
| b. | EULAR/PReS/PRINTO classification criteria—purpura or petechiae with lower limb predominance with one out of four of the following: Acute-onset diffuse colicky abdominal pain [may include intussusception or gastrointestinal (GI) bleeding], histology showing leukocytoclastic vasculitis or proliferative glomerulonephritis with predominant IgA deposition, acute onset arthralgia or arthritis, either proteinuria or hematuria. |
| c. | Steroids are indicated in IgA vasculitis when there is orchitis, cerebral vasculitis, pulmonary hemorrhage, severe GI involvement, skin bullae or concerning necrotic areas, and severe muscle or joint pains. |
| d. | Children with IgA vasculitis are at a risk of renal involvement in 20–80% of children and need renal monitoring—urine for protein and active sediments and blood pressure monitoring for the first 6–12 months of the disease. |
THG14-003
A 1-year-old girl presented with fever for 10 days with no focus. She developed edema of hands and feet with irritability. She was on intravenous antibiotics for the last 6 days but fevers persisted.
a. What is the likely diagnosis with pointers toward the diagnosis?
b. What is the next most important investigation?
c. Is this investigation needed to confirm the diagnosis?
d. Mention the diagnostic criteria for this disease.
e. What is the treatment for this condition?
Answer
| a. | This is likely to be Kawasaki disease as in infants it is often incomplete not fulfilling the diagnostic criteria. The pointers toward this diagnosis are: fever without focus not responding to antibiotics, irritability with edema of hands and feet, BCG site erythema with rising platelet count, and CRP not improving in spite of antibiotics. |
| b. | Next most important investigation is a 2D echocardiogram to look for myocarditis and coronary aneurysms. Myocarditis is more common in the acute phase of the disease whereas coronary aneurysms are more common in the subacute phase of the disease. |
| c. | 2D echocardiogram is not mandatory for confirmation of diagnosis of Kawasaki disease as it is primarily a clinical diagnosis. |
| d. | Kawasaki disease criteria—fever for at least 5 days with four out five of the following: Conjunctivitis (bilateral bulbar nonsuppurative), lymphadenopathy (unilateral cervical often >1.5 cm), rash (polymorphous with no vesicles or crusts), changes in lips and oral mucosa (red cracked lips, strawberry tongue, or diffuse erythema of oropharynx), changes of extremities (initially—erythema and edema of palms and soles, convalescent stage—peeling of skin from fingertips. |
Important to mention that Kawasaki disease maybe diagnosed with fewer than four clinical features in case of presence of coronary aneurysm. As per the recent American Heart Association (AHA) 2017 guidelines, the diagnosis of Kawasaki disease in infants may be considered in: (1) Infants <6 months old with prolonged fever and irritability; (2) infants with prolonged fever and unexplained aseptic meningitis; (3) infants or children with prolonged fever and unexplained or culture-negative shock; (4) infants or children with prolonged fever and cervical lymphadenitis unresponsive to antibiotic therapy; and (5) infants or children with prolonged fever and retropharyngeal or parapharyngeal phlegmon unresponsive to antibiotic therapy.
| e. | The standard treatment protocol for Kawasaki disease includes intravenous immunoglobulin (IVIg) 2 g/kg along with moderate dose Aspirin (30–50 mg/kg/day in 3–4 divided doses). Aspirin is reduced to the anti-platelet dose (i.e. 3–5 mg/kg/day) 48 hours after defervescence of fever. Low dose Aspirin is continued for 6–8 weeks from disease onset and can be stopped if the echocardiography done at 6–8 weeks is normal. Kawasaki disease in infants often presents with incomplete phenotype of the disease and has a higher risk of coronary aneurysm formation. Such children need more agressive managment with additional medications such as steroids, cyclosporine, and/or infliximab (TNF inhibitor). |
THG14-004
A 10-year-old girl presented with prolonged fever, fatigue, and malar rash (as shown in image).
a. What goes against the diagnosis of active systemic lupus erythematosus (SLE)? Explain the reason to select your answer (multiple options can be selected).
b. Mention the 2019 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria of SLE.
Answer
| a. | Option 2 and 4 goes against SLE. Hematological manifestations of SLE classically have leukopenia with lymphopenia and low platelets on a complete blood count. Most cases of active SLE will have a high ESR with a low positive or a negative CRP. When CRP is high in SLE, coexisting infections and serositis need to be ruled out. |
| b. | Current classification criteria for SLE 2019 are the modification of the 2012 SLICC criteria. It includes an entry criterion of ANA ≥1:80 followed by a scoring system includes clinical and immunological domains and a score of ≥ 10 points. The clinical domains includes constitutional (fever), hematologic (leukopenia, thrombocytopenia, or autoimmune hemolysis), neuropsychiatric (delirium, psychosis, and seizure), mucocutaneous (nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus, and acute cutaneous lupus), serosal (pleural or pericardial effusion and acute pericarditis), musculoskeletal (joint involvement) and renal (proteinuria >0.5 g/24 hours, renal biopsy suggestive of lupus nephritis). The immunological domain includes antiphospholipid antibodies, low complements C3 or C4 or both, and SLE-specific antibodies anti-double-stranded deoxyribonucleic acid (anti-dsDNA) or Anti-Smith antibody. |
THG14-005
A 5-year-old child presented with rashes around knuckles (image A) and muscle weakness for the last 2 years. Bloods reports show raised inflammatory markers and muscle enzymes with a total creatine phosphokinase (CPK) of 5,600 U/L, antinuclear antibody (ANA) by immunofluorescence assay (IFA) 1:320, and extractable nuclear antigen (ENA) profile negative with few hard nodules palpable under the skin of bilateral cubital fossa (image B).
a. Name the disease and different type of rashes seen in this disease.
b. Mention the three commonest myositis antibodies seen in children with this disease and their clinical signifiance.
c. Is muscle biopsy indicated in all cases?
d. Name the complication shown in image B and the most common associated myositis antibody.
Answer
| a. | Juvenile dermatomyositis (JDM). Rashes seen in this disease are periorbital heliotrope rash over the upper eyelids as a violaceous, reddish-purple suffusion, Gottron papules over knuckles, and extensor surfaces of joints, malar rash over the nasal bridge. Others: V sign, shawl sign, and Holster sign—if seen over the posterior neck, upper back, shoulder, this erythema is known as the “shawl sign”, and anterior neck, upper chest, this erythema is known as the “V sign”. Violaceous rash over the lateral hip, called the “Holster sign”. Also described are inverse Gottron papules over the palmar surface of fingers and hands. |
| b. | Myositis antibodies [myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs)] are seen in 50–70% of children and can help prognosticate the disease. Three most common MSAs in JDM are MDA5, NXP2, and TIF 1 gamma. |
| i. | TIF 1 gamma—severe cutaneous disease, chronic course, and lipodystrophy |
| ii. | NXP-2 (or anti-MJ)—chronic course, risk of calcinosis, severe muscle disease, GI bleed, ulcers, and dysphagia |
| iii. | Anti-MDA5—rapidly progressive interstitial lung disease (ILD), high mortality rate, arthritis, and ulceration |
| c. | The original Bohan and Peter criteria of dermatomyositis (DM) (1975) included muscle biopsy as a criteria but with more advanced investigation modalities such as MRI and myositis antibodies, the need for muscle biopsies has reduced. The 2017 European league against rheumatism/American college of rheumatology (EULAR/ACR) classification criteria has a scoring system for patients with or without muscle biopsy for the probability of idiopathic inflammatory myopathies (IIM). Muscle MRI has also been incorporated in some recent criteria. |
| d. | Calcinosis is a well-known complication of JDM. The myositis antibody commonly associated with calcinosis is anti-NXP2. |
THG14-006
A 2-year-old girl with swelling left knee for last 6 months and stiffness early morning hours. ANA by IFA titer is 1:640 other blood reports in normal range.
a. What is the relevance of ANA titer in a child with oligoarthritis?
b. What are the types of childhood arthritis as per the ILAR criteria?
c. When would you start oral bridging steroids and methotrexate in this case?
Answer
| a. | Children with oligoarticular JIA and an ANA titer >1:80 have a higher risk of chronic silent uveitis. Eye screening is required every 3–12 months depending on risk categories. Based on the recommendations, if a child has oligoarticular JIA, rheumatoid factor (RF)-negative polyarticular JIA, psoriatic JIA, or undifferentiated JIA, and they have a positive ANA, age of onset <7 years old, and disease onset within the last 4 years, they are considered at higher risk for developing uveitis and should be screened every 3 months, compared to those that are ANA negative, which can be screened every 6–12 months. |
| b. | ILAR criteria classify JIA into seven types—oligoarticular JIA, RF-positive polyarticular JIA, RF-negative polyarticular JIA, enthesitis-related arthritis, systemic-onset JIA, psoriatic JIA, and undifferentiated JIA. |
| c. | Children with oligoarticular JIA, initial treatment includes NSAIDs or intra-articular steroid injections. If the disease progresses or recurs then stepping up to systemic therapy such as oral steroids and methotrexate maybe considered. |
Figure Sources
All the figures are from author’s personal collection.