Spot Diagnosis

Multiple joint swellings - Consequences of the natural history course

Filipa Urbano1, Catarina Santiago Gonçalves1,2, Filipa Oliveira-Ramos3, Filipa Prata4
1Department of Pediatrics, Santa Maria Hospital, University Hospital Center of North Lisbon, Lisbon, Portugal, 2Pediatric Service, Department of Women's and Children's Health, Espírito Santo de Évora Hospital, Évora, Portugal, 3Pediatric Rheumatology Unit, Rheumatology Service of Santa Maria Hospital, University Hospital Center of North Lisbon, Lisbon, Portugal, 4Pediatric Infectious Disease Unit, Medical Pediatric Service of Santa Maria Hospital, University Hospital Center of North Lisbon, Lisbon, Portugal

Address for Correspondence: Filipa Urbano, Departamento de Pediatria do Hospital de Santa Maria - Avenida Professor Egas Moniz, 1649-035, Lisboa, Portugal.
Keywords : Pediatrics, juvenile idiopathic arthritis, rheumatic diseases, rehabilitation.
Question :
A 10-years-old girl, resident of Guinea-Bissau, presented to a Portuguese pediatric hospital with severe swelling of the knees, ankles, elbows, wrists, hands and feet interphalangeal (IPJ) joints for four years (Figure 1). She also had pain, joint stiffness and limited mobility of all joints, including the cervical spine, with flexion deformity of the elbows, IPJ and knees. She was not able to walk normally or perform daily activities. Family history was non-contributory. Throughout the four years of illness, she had episodes of anorexia, weight loss and intermittent episodes of fever. On investigations, she had microcytic hypo-chromic anemia (hemoglobin 9.4g/dL, mean corpuscular volume 54fL, mean corpuscular hemoglobin con-centration 30g/dL) and increased inflammatory markers (leukocytes 18.43x109/L, CRP 15.2mg/dL, ESR 120 mm, platelets 612x109/L). Rheumatoid factor (RF) was negative and complement and immunoglobu-lins were normal. Anti–citrullinated protein (CCP) and antinuclear antibodies (ANA), viral serologies and interferon-gamma release assay test (IGRA) for tuberculosis (TB) were negative (table 1). On radiological evaluation (Figure 1), there was a severe soft tissue edema with marked joint destruction and erosions on the radius, ulna and carpal bones, as well as several metacarpophalangeal and interphalangeal joints sclerosis, ankylosis and with signs of osteopenia. She had no other systems involvement.

Table 1. Investigations at the time of hospitalization.
Parameter Day 0 19th day of therapy 2 months of therapy
Complete blood count
Hemoglobin (g/dL) 9.4 9.3 10.3
Hematocrit (%) 31.4 31.8 34.6
Mean corpuscular volume (fL) 54.0 59.6 61.3
Mean corpuscular hemoglobin concentration (g/dL) 30.0 29.2 29.8
Red cell distribution width (CV%) 17.2 23.8 19.6
Leukocytes (x10^9/L) 18.43 24.28 14.5
Neutrophils (% / x10^9/L) 70.1 / 12.9 79.8 / 19.3 78.5 / 11.38
Eosinophils (% / x10^9/L) 2.2 / 0.41 0.3 / 0.07 0.5 / 0.07
Basophils (% / x10^9/L) 0.2 / 0.04 0.1 / 0.02 0.1 / 0.01
Lymphocytes (% / x10^9/L) 24.8 / 4.57 17.8 / 4.32 18.2 / 2.64
Monocytes (% / x10^9/L) 2.7 / 0.50 2.0 / 0.49 2.7 / 0.39
Platelets (x10^9/L) 612 440 380
Erythrocyte sedimentation rate (mm/hour) 120 100 77
Urea (mg/dL)   37 28
Creatinine (mg/dL) 0.34 0.30 0.36
Sodium (mmol/L) 137 138 140
Potassium (mmol/L) 4.6   4.1
Chloride (mmol/L) 94 96 98
C reactive protein (mg/dL) 15.2 4.93  
Glucose (mg/dL) 79   86
AST (U/L) 19 22 21
ALT (U/L) 7 16 12
GGT (U/L)   49 39
Total bilirubin (mg/dL)   <0.15  
Ferritin (ug/L) 773.0    
Proteins (g/dL) 8.3    
Albumin (g/dL) 4.1    
CK (U/L) 21    
LDH (U/L) 299 288  
Hereditary red cells alterations
Hb A2 (%) 2.2    
Hb F (%) 0.2    
HIV 1 and 2 Ab Negative    
HBsAg Negative    
HBsAb Negative    
HBcAb Negative    
VHC Ab Negative    
CMV IgG (UI/mL) 104    
CMV IgM Negative    
Parvovirus IgG index Negative    
Parvovirus IgM Negative    
Coxiella.burnetii IgG fase I and II Ab Negative    
Coxiella.burnetii IgM fase I and II Ab Negative    
EBV VCA IgG Positive    
EBV VCA IgM Negative    
EBV EBNA 1 IgG Positive    
VZV IgG 1.17    
IGRA for TB -    
Auto immunity
Antinuclear Ab Negative    
Anti-citrulline Ab Negative    
Anti-dsDNA Ab Negative    
ANA screening Negative    
Complement: C3 (mg/dL) 234    
Complement: C4 (mg/dL) 14    
Complement: CH50 (U/mL) 69.6    
Rheumatoid factor (UI/mL) 12.5    
TSH (uU/mL) 0.91    
fT4 (ng/dL) 1.49    
Vitamin D total (ng/mL) 21.6    

Note: Hb - hemoglobin; HIV - human immunodeficiency virus; Ab - antibody; Ag - antigen; HBsAg - Hepatitis B surface antigen; HBsAb - Hepatitis B surface antibody; HB Ag - Hepatitis B core antibody; HCV - Hepatitis C virus; CMV - cytomegalovirus; EBV - Epstein-Barr virus; VZV - varicella zoster virus; IGRA - interferon gamma release assay; TB – tuberculosis; dsDNA- double strain DNA; ANA - antinuclear antibody; TSH - thyroid-stimulating hormone; fT4 - unbound thyroxine

Figure 1a. Swelling and deformity of the knees; Figure 1b. Swelling and deformity of the hands; Figure 2a and 2b. Correspondence on x-ray.
<b>Figure 1a.</b> Swelling and deformity of the knees; <b>Figure 1b.</b> Swelling and deformity of the hands; <b>Figure 2a and 2b.</b> Correspondence on x-ray.

What is the diagnosis and how to treat this child?

Discussion :
When an arthritis persists for more than six weeks, especially in the absence of trauma or sepsis, juvenile idiopathic arthritis (JIA) should be considered.1,2 In this clinical case, the disease started around 6 years of age. However, it was not possible to determine exactly the number of joints affected in the first six months, thus it was not able to differentiate between oligoarticular and polyarticular arthritis. The patient also had an inconsistent history of fever, markedly increased acute phase reactants and no autoantibodies, but no other characteristics of systemic-onset JIA. However, it is not possible to guarantee that it is not a systemic arthritis with a later evolution to polyarticular. The patient also did not have characteristics of psoriatic or enthesitis-related arthritis.3 The hypothesis of being an infectious arthritis was also considered unlikely, due to the time of the disease's evolution and negative viral serologies and TB IGRA test. Thus, diagnostic hypothesis of polyarticular JIA (polyJIA) RF(-) ANA(-) with the following scores: JADAS 37, articular JADI 26 and extra articular JADI 2 was considered in our patient.
The therapy of polyJIA should be based on an early diagnosis and allocation to specialists in pediatrics rheumatology and a rapid and effective anti-inflammatory treatment with appropriate pain and disease control.4 None of these principles were possible to apply in our patient. Recent therapy algorithms support the initial treatment of patients with high risk polyJIA with methotrexate, non-steroidal anti-inflammatory drugs, oral prednisolone, intra-articular glucocorticoids and even biological treatment.4,5 Concerning biologics, there are currently six approved for use in JIA patients with different modes of action: three tumor necrosis factor inhibitors (adalimumab, etanercept and golimumab), one interleukin (IL)-1 inhibitor (canakinumab), one IL-6 inhibitor (tocilizumab) and one T-cell co-stimulation clocker (abatacept).6 In our patient, the initial therapy was prednisolone (starting 1 mg/kg/day and decreasing until ~0.25 mg/kg/day in ~4 weeks), parenteral methotrexate (starting with ~10 mg/m2/week and increasing until ~17.5 mg/m2/week in ~4 weeks) and ibuprofen, with cholecalciferol, calcium and folic acid supplementation. The wrists, elbows, knees and tibiotarsal joints were injected with triamcinolone hexacetonide. During hospitalization, there was a significant improvement in disease control and functional capacity, with less active joints, besides the extensive irreversible structural damages. The patient was then referred to an inpatient urgent rehabilitation program, maintaining the treatment with subcutaneous methotrexate in increasing doses (up to ~20 mg/m2/week), with a consequent reduction in the prednisolone dose. Despite the improvement in inflammatory analytical parameters (Table 2), she always presented with pain and disturbance of joint functionality. Six months later, therapy with tocilizumab (8 mg/kg/4 weeks) was started. A tocilizumab therapeutic failure was considered after 4 months (Figure 2A) and therapy was replaced by etanercept (0.8 mg/kg/week). There was an improvement in the number of painful and swollen joints (Figure 2B), and it was possible to suspend therapy with prednisolone (after one year). However, she still had increased inflammatory analytical parameters (Table 2). MRI of the knees showed moderate effusion and extensive synovitis on the right side after 4 months of etanercept, so a synovectomy was performed. After 8 months, ultrasounds still presented significant alteration of the wrists and ankles architecture, mild to moderate intra-articular effusion bilaterally in the elbows and tibiotarsic synovitis. Synovectomy was again planned for the knees and elbows. Currently, under etanercept for 10 months (~1 mg/kg/week) and methotrexate (~16 mg/m2/week), she is able to walk, although limping, and run, despite irreversible joint structural damage.

Table 2. Serial direct and indirect inflammatory parameters.
Parameter Months after hospital discharge without therapy with biologicals
1 2.5 4
Leukocytes (x10^9/L) 14500 12540 16410
Neutrophils (% / x10^9/L) 11380 9960 13030
Eosinophils (% / x10^9/L) 70 30 50
Basophils (% / x10^9/L) 10 0 20
Lymphocytes (% / x10^9/L) 2640 2280 2920
Monocytes (% / x10^9/L) 390 280 390
Platelets (x10^9/L) 380000 624000 567000
C reactive protein (mg/dL)   3.82 4.02
Erythrocyte sedimentation rate (mm/hour) 77 77 87
Parameter Months after hospital discharge, under tocilizumab
6 7.5 8 8.5 9
Leukocytes (x10^9/L)       7860  
Neutrophils (% / x10^9/L)       2990  
Eosinophils (% / x10^9/L)       540  
Basophils (% / x10^9/L)       20  
Lymphocytes (% / x10^9/L)       3600  
Monocytes (% / x10^9/L)       700  
Platelets (x10^9/L)       254000  
C reactive protein (mg/dL) 3.4 0.1 0.1 0.03 0.1
Erythrocyte sedimentation rate (mm/hour) 28.7 4 3 2 4
Parameter Months after hospital discharge, under etanercept
10 11 12 14 18 20
Leukocytes (x10^9/L)     6240   6130 7590
Neutrophils (% / x10^9/L)     3730   3680 4010
Eosinophils (% / x10^9/L)     170   200 270
Basophils (% / x10^9/L)     10   10 20
Lymphocytes (% / x10^9/L)     1820   1820 2690
Monocytes (% / x10^9/L)     510   420 610
Platelets (x10^9/L)     483000   419000 365000
C reactive protein (mg/dL) 0.1 1 3.65 5.18 2.54 1.58
Erythrocyte sedimentation rate (mm/hour) 3 13 47   52 40

Figure 2. Evolution under tocilizumab (A) and under etanercept (B)

Note: x axis: months after hospital discharge
Abbreviations: VAS - visual analogue scale; CHAQ - The Child Health Assessment Questionnaire; JADAS: Juvenile Arthritis Disease Activity Score


Note: x axis: months after hospitalar discharge
Abbreviations: VAS - visual analogue scale; JADAS: Juvenile Arthritis Disease Activity Score

What we intend to alert with this case is that JIA is the most frequent cause of inflammatory arthritis in children and an early diagnosis and appropriate therapy are decisive for prognosis.2,3,8 This clinical case is special not because of the disease itself, but for the fact that it was diagnosed at a very advanced stage, rarely seen nowadays, having exceeded all possible therapeutic windows. We will probably never be able to achieve clinical remission, but the fact that low to moderate disease activity has been achieved is very positive for the patient.

References :
  1. Eisenstein EM, Berkun Y. Diagnosis and classification of juvenile idiopathic arthritis. J Autoimmun. 2014;48-49:31-33.
  2. Aoust L, Rossi-Semerano L, Koné-Paut I, Dusser P. Time to diagnosis in juvenile idiopathic arthritis: a french perspective. Orphanet J Rare Dis. 2017;12(43). doi: 10.1186/s13023-017-0586-4
  3. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet [Internet]. 2011;377:2138-2149.
  4. Horneff G, Klein A, Ganser G, Sailer-Höck M, Günther A, Foeldvari I, et al. Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND): results of the working group Polyarticular juvenile idiopathic arthritis. Pediatr Rheumatol. 2017;15(78). doi: 10.1186/s12969-017-0206-9
  5. Ringold S, Angeleshan ST, Beukelman T, Lovell D, Cuello CA, Becker ML, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis. Am Coll Rheumatol. 2019;71:717-734.
  6. Santos M, Conde M, Mourão A, Ramos FO, Cabral M, Brito I, et al. 2016 update of the Portuguese recommendations for the use of biological therapies in children and adolescents with Juvenile Idiopathic Arthritis. Acta Reumatol Port. 2016;41:194-212.
  7. Weiss PF. Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications [retrieved October 2019] Available at: polyarticular-juvenile-idiopathic-arthritis-clinical-manifestations-diagnosis-and-complications? search=polyarticularjuvenileidiopathicarthritis& source=search_result&selectedTitle=1~38& usage_type=default&display_rank=1. Accessed on 22nd April 2021
  8. Marcdante KJ, Kliegman RM. Juvenile Idiopathic Arthritis. In: Marcdante KJ, Kliegman RM. eds. Nelson Essentials of Pediatrics. Elsevier. Philadelphia. 7th ed. 2015:305-308.

Correct Answers : yes  100%

Last Shown : Feb 2022
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