Correspondence Hospital General de México and Universidad Nacional Autónoma de México, Dr Balmis 148, México DF 06720, México

Email burgosv@prodigy.net.mx

The case

A 14-year-old boy presented to a rheumatology clinic with persistent arthritis involving the knees, ankles, first and third metatarsophalangeal joints of the right foot and first metatarsophalangeal of the left foot, bilateral tarsitis, and severe pain in both feet at the plantar fascia and Achilles tendon attachments to the calcaneus. During the previous year he had been treated with NSAIDs, methotrexate 25 mg/week, intra-articular glucocorticoid injections (both knees, left ankle, and right sacroiliac joint; one injection in each joint in a time frame of 3 months), right knee casting for 4 weeks (ending 3 months before partial arthroscopic synovectomy), physiotherapy and rehabilitation. Of note, his father had mild psoriasis since the age of 30 years, but no joint disease.

The patient's symptoms had started at the age of 8 years with oligoarthritis involving the knees, left ankle and left tarsus; 8 months after onset of these symptoms he complained of bilateral talalgia. He had recurrent episodes of arthritis and enthesitis for several months, leaving him unable to attend school most days and causing him to stop playing sports. He was treated successfully with NSAIDs, antibiotics and intra-articular glucocorticoid injections, and returned to school after a few months.

Between the ages of 12 and 13 years, the patient's symptoms subsided and he did not require any treatment; however, he subsequently developed polyarthritis involving the knees, ankles, tarsi, metatarsophalangeal joints, wrists, and several metacarpophalangeal and proximal interphalangeal joints of the hands. He complained of spinal pain in the cervical, lower thoracic and upper lumbar areas, sacroiliac joint pain that alternated between the right and left sides, and pain in both feet at the plantar fascia attachment to the calcaneus. Although he rarely awoke during the night because of pain, he had constant spinal pain and early-morning stiffness. He usually felt better during the day, but the pain often appeared or worsened in the evening and at night with bed rest. Despite management with anti-inflammatory doses of diclofenac and naproxen, as well as prednisone 10 mg/day, his condition progressively worsened.

Physical examination at presentation revealed 14 active (tender and swollen) joints—all with reduced mobility—and 21 tender entheses (Box 1). The modified Schober's test (lumbar anterior flexion) result was 3 cm (normal range >5 cm), chest expansion was 6 cm (normal range >2.5 cm), the mean right and left cervical rotation was 65 ° and the mean right and left lateral spinal flexion was 18 cm. Outcome measures on patient-reported numerical rating scales were 2.7 for the Childhood Health Assessment Questionnaire (CHAQ; range 0–3), 7.5 and 7.0 for the Bath Ankylosing Spondylitis Disease Activity and Functional Indexes, respectively (BASDAI and BASFI; range 0–10 each), and 8 for pain (range 0–10). The patient's erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) values were 64 mm/h and 42 mg/l, respectively. The patient was HLA-B27-positive.

Radiographic studies revealed grade 3 bilateral sacroiliitis (Figure 1);¹ the patient's spine, hips, knees, and ankles appeared essentially normal. The tarsus showed generalized osteopenia and slight joint space reduction. A clinical diagnosis of juvenile-onset ankylosing spondylitis (AS) was made, on the basis of the modified New York criteria for AS.¹

Figure 1 X-ray of the patient at age 14 years, demonstrating grade 3 bilateral sacroiliitis.

The film (posteroanterior, 30 ° caudal angulated projection) shows subchondral sclerosis and irregularities of the joint surface, including erosions in both iliac bones. Permission obtained from Elsevier Ltd © Burgos-Vargas R (2006) The juvenile onset spondyloarthritides. In Ankylosing spondylitis and the spondyloarthropathies, 96–106 (Eds Weisman MH et al.) Philadelphia: Mosby Elsevier.⁵

Full figure and legend (14K)Figures & Tables indexDownload Power Point slide (109K)

The patient showed no improvement in symptoms following continued treatment with NSAIDs, sulfasalazine and methotrexate at recommended doses. After a chest X-ray and screening for tuberculosis, he received an intravenous infusion of infliximab 5 mg/kg. The same dosage was administered 2 and 6 weeks later, and then every 8 weeks thereafter. Remarkably, the number of active joints and tender entheses decreased by more than 50% within 2 weeks of the first infusion of infliximab. There was no sign of disease activity 6 weeks after the first infusion, and CRP and ESR values had returned to normal.

Discussion of diagnosis

The sequence of clinical events in this patient included 8 months of oligoarthritis isolated to the lower limbs, followed by the combination of active arthritis and enthesitis for 10 months, and improvement for nearly a year. The patient then had a severe relapse, which consisted of peripheral arthritis and enthesitis, spinal and sacroiliac joint pain, and radiographic evidence of sacroiliitis. The clinical picture of this patient can be classified according to three different sets of criteria.

The International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis (JIA) are primarily intended to delineate, for research purposes, relatively homogeneous, mutually exclusive categories of idiopathic childhood arthritis on the basis of predominant clinical and laboratory features.² Although the patient in this Case Study fulfills four out of six inclusion criteria for the JIA subgroup of enthesitis-related arthritis (ERA), the fact that his father has psoriasis precludes this classification (Table 1). Instead, the patient falls into the category of "undifferentiated arthritis". In contrast to the spondyloarthritis (SpA) concept, which considers psoriatic arthritis (PsA) an important part of the disease group, ERA and PsA are mutually exclusive according to the ILAR classification.

Table 1 Classification of the patient's disorder according to three different sets of criteria.

Full tableFigures & Tables indexDownload Power Point slide (156K)

By contrast, the European Spondyloarthropathy Study Group (ESSG) criteria³ are intended to cover the whole spectrum of SpA, including early undifferentiated cases, PsA, reactive arthritis and the arthropathies associated with inflammatory bowel disease. Relevant family history includes the incidence of AS, psoriasis, acute uveitis, reactive arthritis and arthropathies related to inflammatory bowel disease. Despite the fact that the item "inflammatory back pain" has a low sensitivity for the diagnosis of SpA, the performance of ESSG criteria as a diagnostic tool for children is adequate.⁴ The current patient fulfills six out of nine ESSG criteria for SpA and would, therefore, be classified as having SpA (Table 1).

The patient fulfilled the modified New York criteria¹ for definite AS on the basis of radiographic evidence of grade 3 bilateral sacroiliitis and at least two of the relevant clinical criteria (Table 1). The latter include "low back pain and stiffness for at least 3 months, which improves with exercise, but is not relieved by rest" and "limited lumbar spinal motion in sagittal (sideways) and frontal (forward and backwards) planes". The clinical criterion not fulfilled by the patient was "limitation of chest expansion relative to normal values for age and sex". Overall, AS is rarely diagnosed in children. Most patients with juvenile-onset SpA fulfill AS criteria 5–10 years after onset; very few do so within 3 years.⁵ This patient was diagnosed 6 years after onset of symptoms.

As illustrated by this Case Study, juvenile patients fulfilling the ESSG classification criteria for SpA and the ILAR inclusion criteria for ERA should, if they have a first-degree relative with psoriasis, instead be diagnosed as having "undifferentiated arthritis" according to the ILAR classification system.^{6, 7, 8} In a study of 139 patients with juvenile PsA according to the Vancouver criteria,⁹ 36 (26%) patients excluded from this diagnosis by ILAR classification criteria were reclassified as having "undifferentiated arthritis" under those same criteria, owing to the presence of enthesitis or the combination of HLA-B27 positivity, male sex, and onset of arthritis after the age of 6 years.¹⁰ Although the patient in this Case Study fulfills the modified New York criteria for definite AS,¹ he has "undifferentiated arthritis" according to ILAR criteria.²

Inflammatory and structural changes to peripheral joints and entheses in juvenile-onset SpA yield impaired functioning long before the appearance of axial symptoms. Foot involvement, particularly tarsitis (Figure 2), and hip disease are the most severe problems. The recognition of enthesitis and tarsitis, as well as a family history of SpA, male sex, age at onset, and HLA-B27 positivity, therefore, is important to differentiate early juvenile-onset SpA from other types of JIA.¹¹ In contrast to treatment trends in adult-onset AS, there is no need to demonstrate spinal or sacroiliac joint involvement in juvenile patients before prescribing tumour necrosis factor (TNF) blockers, as the severity of peripheral disease justifies their use.

Figure 2 Composite images of ankylosing tarsitis in a second patient, a 16-year-old boy with 9 years' disease duration and complete ankylosis of the tarsal bones and grade 2 bilateral sacroiliitis.

(A) Flat foot and swelling around the ankle. (B) Complete ankylosis of the tarsal bones and enthesophytes at the plantar fascia attachment. (C) T₂-weighted fat-saturation MRI showing edema (white spots) in several tarsal bones, joint spaces, and surrounding fat. (D) Posterior and (E) coronal views showing the same changes in the bones and joint spaces seen in (C), but also demonstrating distorted architecture of the tarsus and, notably, edema around the tendons.

Full figure and legend (23K)Figures & Tables indexDownload Power Point slide (126K)

In regard to axial involvement in children with SpA, however, there are several important factors that should be considered. First, inflammatory back pain criteria^{12, 13} have not been validated in children. Second, radiographic sacroiliitis is rarely seen in children. Third, MRI might identify acute and chronic changes in the sacroiliac joints of children with undifferentiated and definite SpA (particularly those with back pain) that might not be evident on radiography (Figure 3).¹⁴ Finally, little information exists on the radiographic and MRI aspect of the spine in children.¹⁵ We can conclude, therefore, that appropriate studies are needed to characterize back symptoms in juvenile-onset SpA and to determine the role of imaging methods in diagnosis.

Figure 3 Coronal T₁-weighted MRI of the sacroiliac joints in a third patient with spondyloarthropathy, a 16-year-old boy with a 3-month history of gluteal pain and a 3-year history of peripheral arthritis and enthesitis.

The sacroiliac joints appeared normal on X-rays. (A) Intense edema is evident in the upper quadrant of the sacrum (right side), and extensive edema is apparent in the iliac bone. There are also irregularities of the joint surface and even erosions and cysts. (B) Follow-up image taken 14 weeks after starting treatment with infliximab. Although the intensity and extension of the edema changed a little, the erosions appear clearer than in (A).

Full figure and legend (35K)Figures & Tables indexDownload Power Point slide (142K)

Treatment and management

In cases of juvenile-onset SpA, treatment decisions are based on clinical experience rather than on evidence from clinical trials. Some information derived from adult-onset SpA, for example the Assessment of Spondyloarthritis International Society (formerly the Assessments in AS International Working Group) and the European League Against Rheumatism recommendations for the management of AS,¹⁶ would have to be adapted for pediatric use, but they could provide guidance for pediatric rheumatologists unfamiliar with SpA. Therapeutic modalities for other types of JIA might be useful in treating juvenile-onset SpA; in particular, NSAIDs and glucocorticoids—administered systemically or locally—reduce pain and inflammation. Sulfasalazine⁵ and methotrexate do not exert any significant effect on the disease. Finally, the role of physiotherapy and rehabilitation needs to be determined. Nevertheless, the proportion of patients who do not respond to standard treatment seems to be high.

Currently, the best treatment for juvenile-onset SpA is anti-TNF therapy. Case series of patients treated with TNF-blockers, such as infliximab and etanercept, have shown significant improvements in the number of active joints and tender entheses, ESR and CRP levels, and CHAQ scores.^{17, 18} In addition, the results of a 3-month, randomized, double-blind, placebo-controlled trial to assess the efficacy of infliximab showed that this treatment significantly improved most measures of disease activity compared to placebo, including the number of active joints and tender entheses, pain intensity, patient and/or parent assessment of well-being and physician assessments of disease activity, health status, CHAQ score and CRP level.¹⁹ There was no difference between groups in the frequency of adverse events. The impact of TNF blockers in juvenile-onset SpA is broader than that assessed by qualitative measures. In this Case Study, the patient returned to school and started playing sports again following treatment with infliximab.

Conclusions

This Case Study illustrates the clinical events and consequences of AS in children. The patient's symptoms progressed from inflammation in the peripheral joints to structural changes in the sacroiliac joints. This Case Study also highlights certain problems in classifying and making a clinical diagnosis, which, in this instance, ultimately corresponded to AS. The patient received inappropriate treatment for some time with NSAIDs, glucocorticoids and methotrexate. Eventually, however, he started on TNF blockers, and his symptoms improved remarkably.

Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

References

1. van der Linden S et al. (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27: 361–368 | Article | PubMed | ChemPort |
2. Petty RE et al. (2004) International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31: 390–392 | PubMed | ISI |
3. Dougados M et al. (1991) The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 34: 1218–1227 | Article | PubMed | ISI | ChemPort |
4. Prieur AM et al. (1992) Evaluation of four sets of criteria for spondyloarthropathy in children: a multicenter cross-sectional European study [abstract]. Arthritis Rheum 35 (Suppl): S190 | Article |
5. Burgos-Vargas R (2006) The juvenile onset spondyloarthritides. In Ankylosing spondylitis and the spondyloarthropathies, 96–106 (Eds Weisman MH. et al.) Philadelphia: Mosby Elsevier
6. Burgos-Vargas R et al. (2002) The place of juvenile onset spondyloarthropathies in the Durban 1997 ILAR classification criteria of juvenile idiopathic arthritis. International League of Associations for Rheumatology. J Rheumatol 29: 869–874 | PubMed |
7. Berntson L et al. (2002) The influence of heredity for psoriasis on the ILAR classification of juvenile idiopathic arthritis. J Rheumatol 29: 2454–2458 | PubMed |
8. Merino R et al. (2005) Evaluation of revised International League of Associations for Rheumatology classification criteria for juvenile idiopathic arthritis in Spanish children (Edmonton 2001). J Rheumatol 32: 559–561 | PubMed |
9. Southwood TR et al. (1989) Psoriatic arthritis in children. Arthritis Rheum 32: 1007–1013 | Article | PubMed | ChemPort |
10. Stoll ML et al. (2008) Comparison of Vancouver and International League of Associations for rheumatology classification criteria for juvenile psoriatic arthritis. Arthritis Rheum 59: 51–58 | Article | PubMed |
11. Burgos-Vargas R and Vázquez-Mellado J (1995) The early clinical recognition of juvenile-onset ankylosing spondylitis and its differentiation from juvenile rheumatoid arthritis. Arthritis Rheum 38: 835–844 | Article | PubMed | ChemPort |
12. Calin A et al. (1977) Clinical history as a screening test for ankylosing spondylitis. JAMA 237: 2613–2614 | Article | PubMed | ChemPort |
13. Rudwaleit M et al. (2006) Inflammatory back pain in ankylosing spondylitis: a reassessment of the clinical history for application as classification and diagnostic criteria. Arthritis Rheum 54: 569–578 | Article | PubMed |
14. Bollow M et al. (1998) Use of dynamic magnetic resonance imaging to detect sacroiliitis in HLA-B27 positive and negative children with juvenile arthritides. J Rheumatol 25: 556–564 | PubMed | ChemPort |
15. Riley MJ et al. (1971) Radiological manifestations of ankylosing spondylitis according to age at onset. Ann Rheum Dis 30: 138–148 | Article | PubMed | ChemPort |
16. Zochling J et al. (2006) ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65: 442–452 | Article | PubMed | ISI | ChemPort |
17. Henrickson M and Reiff A (2004) Prolonged efficacy of etanercept in refractory enthesitis-related arthritis. J Rheumatol 31: 2055–2061 | PubMed | ChemPort |
18. Tse SM et al. (2005) Anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondylarthropathy. Arthritis Rheum 52: 2103–2108 | Article | PubMed | ChemPort |
19. Burgos-Vargas R et al. (2007) Efficacy, safety, and tolerability of infliximab in juvenile-onset spondyloarthropathies (JO-SpA): results of the three-month, randomized, double-blind, placebo-controlled trial phase. Arthritis Rheum 56 (Suppl): S319

Contact the journal about this article

Subject areas under which this article appears: Pediatric rheumatic disease | Spondylarthropathies