Persistent inflammation refractory to standard antirheumatic therapy in children with juvenile spondylarthropathy (SpA) leads to morbidity and reduced quality of life. Tumor necrosis factor α (TNFα) plays an important role in the pathogenesis of synovitis and enthesitis. This study was undertaken to examine the impact of anti-TNFα agents on juvenile SpA that is refractory to nonsteroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs, and corticosteroids.
Ten juvenile SpA patients with a mean ± SEM age of 15.0 ± 0.7 years and disease duration of 4.4 ± 0.8 years, all of whom were HLA–B27 positive, were followed up for 1 year after initiation of either infliximab (n = 8) or etanercept (n = 2). Outcomes examined were within-subject differences in the tender entheseal count (TEC) and active joint count (AJC), markers of inflammation, functional assessments (Childhood Health Assessment Questionnaire [C-HAQ] score), and requirements for antirheumatic drugs.
At baseline, all patients exhibited active arthritis and enthesitis that were resistant to NSAIDs (n = 10), methotrexate (n = 6), sulfasalazine (n = 8), corticosteroids (oral n = 6, intravenous pulse n = 3, and intraarticular n = 6), and bisphosphonates (n = 2). In 2 patients, sulfasalazine (n = 2), corticosteroids (n = 1), and bisphosphonates (n = 1) were stopped after initiation of the anti-TNFα agent. In all patients, the arthritis and enthesitis significantly improved as evidenced by remission of the TEC and AJC by 6 months that was sustained during the 1-year followup, markers of inflammation and C-HAQ scores normalized, and there was a reduction in requirements for antirheumatic drugs (reduced dosage or discontinuation of NSAIDs n = 10, methotrexate n = 5, sulfasalazine n = 6, corticosteroids n = 4, and bisphosphonates n = 1).
Anti-TNFα therapy is a potential novel treatment for refractory juvenile SpA. Further prospective studies are required to examine the effectiveness and long-term outcomes of anti-TNFα therapy in this cohort.
The juvenile spondylarthropathies (SpA) comprise a group of HLA–B27–associated disorders with a disease onset in children younger than age 16 years. Under the International League of Associations for Rheumatology classification of juvenile idiopathic arthritis (JIA), the juvenile SpA population is referred to as those with enthesitis-related arthritis (ERA) (1). The disease is characterized by manifestations of arthritis and enthesitis, particularly with involvement of the lower limbs and, in some cases, the sacroiliac and spinal joints. Peripheral enthesitis, seen more frequently in children than in adults with SpA, can result in significant functional disability. Currently there are no effective remittive therapies for juvenile SpA. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) and corticosteroids may provide symptomatic improvement but do not alter disease progression. Sulfasalazine (SSZ) was found not to be significantly better than placebo in a randomized controlled trial (2). Methotrexate (MTX) has an uncertain effect and has not been demonstrated to modify the course of disease progression.
Children with juvenile SpA are potentially at significant risk of morbidity, impaired function, and reduced quality of life (3, 4). The presence of ongoing disease activity lasting more than 5 years is predictive of disability (5), and disease remission has been reported to occur in only 17% of patients after 5 years, with moderate to severe functional limitations found in up to 60% of patients at 10 years (6). Therefore, more efficacious therapies administered early in the disease course are required.
One promising treatment is directed against tumor necrosis factor α (TNFα). As demonstrated in adult-onset ankylosing spondylitis (AS), TNFα may play a pivotal role in the pathogenesis of juvenile SpA. At sites of synovitis and enthesitis in AS patients, as well as in the knees of children with juvenile SpA, there is evidence of T lymphocyte and macrophage infiltrates, activated CD8 cells, and expression of TNFα and TNFβ, as well as expression of interferon-γ, interleukin-2 (IL-2), IL-4, and IL-6 (7–12). This serves as a rationale for the use of TNFα antagonists. Improvement with such therapy has been noted both clinically and radiologically in AS and in undifferentiated SpA, in open and double-blind studies (13–19). Preliminary studies have shown promising results in juvenile SpA or ERA (20–24). To date, TNFα antagonists have been established as safe and tolerable in children receiving treatment for polyarticular juvenile rheumatoid arthritis/JIA (25–29) as well as inflammatory bowel disease (30, 31). Two anti-TNFα agents that have been used are etanercept, a fusion protein of the p75 TNF receptor and human Fc IgG1, and infliximab, a chimeric humanized monoclonal anti-TNF antibody.
In this open-label, pilot cohort study, we demonstrate that anti-TNFα agents are both tolerable and efficacious in children with juvenile SpA that is refractory to NSAIDs and disease-modifying antirheumatic drugs (DMARDs).
PATIENTS AND METHODS
Ten patients with juvenile SpA, whose diagnosis was in accordance with the European Spondylarthropathy Study Group classification criteria (32) and who also fulfilled the diagnostic criteria for the JIA subgroup of ERA (1), were selected from The Hospital for Sick Children, Toronto, Canada and Hospital General de Mexico, Mexico City, Mexico for inclusion in this observational study. All patients had persistent arthritis and enthesitis despite treatment with maximum doses of NSAIDs and other drugs (corticosteroids, MTX, and SSZ), and were initiating anti-TNFα therapy. The choice of anti-TNF agent administered was based on drug availability and coverage from each patient's medical insurance plan. Patients received either infliximab (infusions of 5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks) or etanercept (0.4 mg/kg subcutaneously [SC] twice weekly to a maximum dose of 25 mg). This study was approved by the Research Ethics Board of The Hospital for Sick Children.
Data compiled from a retrospective chart review of all study patients were extracted through the use of specially prepared data forms at baseline, 6 weeks, 6 months, and 1 year. The information extracted, where available, included demographic data, medication history, active joint count, tender entheseal count, markers of inflammation, and functional assessment by the Childhood Health Assessment Questionnaire (C-HAQ) (33). Active joints were defined by the presence of a joint effusion, or at least 2 of the following signs/symptoms: warmth, pain/tenderness, or limited range of movement. Enthesitis was defined by the patients' response, elicited as pain, wincing, or withdrawal upon firm palpation over the entheses.
The data are expressed as the mean ± SEM as appropriate. Differences in characteristics and outcomes pre- and posttreatment with anti-TNFα therapy were analyzed by Student's t-test, utilizing SPSS statistical software (SPSS, Chicago, IL). Statistical significance was defined as a P value of less than 0.05.
The demographic characteristics of the patients at baseline are summarized in Table 1. The 10 juvenile SpA patients had a mean ± SEM age of 15.0 ± 0.7 years at the initiation of anti-TNFα therapy. There were 8 boys and 2 girls. All patients were HLA–B27 positive and had a mean ± SEM disease duration of 4.4 ± 0.8 years at the time of starting anti-TNF treatment. In 5 of the patients, there was a positive family history of HLA–B27–related disease. All patients had active disease (arthritis and/or enthesitis) that persisted despite treatment with NSAIDs (n = 10), MTX (up to 1 mg/kg to a maximum of 25 mg SC) (n = 6), SSZ (n = 8), corticosteroids (oral n = 6, intravenous pulse n = 3, intraarticular n = 6), and bisphosphonates (n = 2). At baseline, 4 patients had sacroiliac and axial involvement. In total, 8 patients were treated with infliximab and 2 patients received etanercept. In addition to the anti-TNFα agents, concomitant therapy reported in these patients included NSAIDs (n = 10), MTX (n = 4), SSZ (n = 4), combination of MTX and SSZ (n = 2), oral corticosteroids (n = 5), and bisphosphonates (n = 1).
Table 1. Demographic and clinical characteristics of the study patients (n = 10)*
Except where indicated otherwise, values are the mean ± SEM. TNF = tumor necrosis factor (antagonist); ANA = antinuclear antibody; RF = rheumatoid factor; NSAIDs = nonsteroidal antiinflammatory drugs; IV = intravenous; C-HAQ = Childhood Health Assessment Questionnaire.
Sex, no. male/no. female
Age at TNF initiation, years
15.0 ± 0.7
Disease duration, years
4.4 ± 0.8
HLA–B27 positive, no.
ANA positive, no.
RF positive, no.
Family history of HLA–B27–related disease, no.
Previous treatment, no.
Corticosteroids, oral/IV pulse/intraarticular
Active joint count
5.5 ± 1.8
Active entheseal count
4.8 ± 1.6
0.84 ± 0.2
Erythrocyte sedimentation rate, mm/hour
42.3 ± 8.1
The arthritis in all patients showed improvement (Figure 1) in terms of a significant reduction in the active joint count as early as 6 weeks posttreatment (P < 0.02) and absence of all signs and symptoms of disease activity by 6 months. This improvement was sustained in all patients during their followup over 1 year. Enthesitis was present in 9 patients at baseline, and after treatment with anti-TNFα agents, the enthesitis improved significantly (P < 0.02) and subsequently resolved in all patients (Figure 1). In addition, there was a similar reduction in the patients' C-HAQ scores and markers of inflammation during the course of treatment (Table 2).
Table 2. Outcomes and antirheumatic drug requirements after treatment with anti–tumor necrosis factor α agents*
ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; ND = not done; Y = yes; D = discontinued; R = reduced; NC = no change; N = no (see Table 1 for other definitions).
P < 0.02, baseline versus 3 followup time points.
P = 0.001, baseline versus 3 followup time points.
The antirheumatic drug requirements at baseline and during the course of the study are summarized in Table 2. The clinical reduction in the active joint count and tender entheseal count in response to the anti-TNFα agents was sustained and prompted reductions in medication. All patients were able to completely discontinue their NSAIDs. Of the 6 patients receiving concomitant treatment with MTX, 5 were able to decrease the dosage, and ultimately, 2 discontinued the medication. All 6 patients receiving SSZ were fully tapered off their medication within 6 months. Four of 5 patients receiving corticosteroids and 1 patient receiving bisphosphonates were able to stop their medication within 6 weeks after the initiation of anti-TNFα therapy.
The majority of patients tolerated the anti-TNFα agents well. One patient experienced a flu-like reaction after the third infliximab infusion. Another patient had recurrent episodes of severe anterior uveitis while receiving infliximab and required concomitant use of corticosteroids and MTX; all known infectious causes of uveitis in this patient were investigated and excluded. No patients developed serious adverse events, including infections, abnormal results on laboratory tests, or autoimmune symptoms/serology (lupus-like).
The 10 study patients with juvenile SpA all demonstrated improvement with anti-TNFα therapy, as evidenced by a reduction in their active joint count, tender entheseal count, markers of inflammation, C-HAQ scores, and concomitant antirheumatic medications. The response was rapid, occurring as early as 6 weeks, and sustained in all cases. This is in keeping with the response seen in AS patients treated with anti-TNFα agents, and is consistent with preliminary data on 8 patients with juvenile AS treated with etanercept who showed improvements in the number of active joints, morning stiffness, and erythrocyte sedimentation rate (23). In contrast to the patients in the study by Henrickson and Reiff (23), our study cohort comprised patients who were all HLA–B27 positive, had active arthritis, and had a much higher reported frequency of enthesitis (90%). In addition, since patients with juvenile SpA or ERA have a propensity to have either a few joints/entheses or many joints/entheses involved, the data were reported as individual trends rather than as cumulative mean scores to better observe the response to anti-TNFα agents.
Although the American College of Rheumatology pediatric core criteria definition of improvement in juvenile arthritis (34) has currently not been validated for juvenile SpA or ERA, our study patients met the requirements for improvement. This response is significant, since the condition in all patients in this study was previously refractory to NSAIDs, combination DMARDs, and corticosteroids. Further studies need to be done to validate a measure of improvement or disease activity in this pediatric population. Improvement criteria for AS (i.e., the ASsessment in Ankylosing Spondylitis improvement criteria ) focus on spinal involvement, which is not a prevalent manifestation in juvenile SpA or ERA, and its use in children is therefore limited. Furthermore, all patients fulfilled the proposed JIA criteria for inactive disease and medication-induced clinical remission (36). The preliminary criteria for clinical remission in JIA were developed by consensus by pediatric rheumatologists and originally focused mainly on the oligoarticular (persistent, extended), polyarticular (rheumatoid factor–negative or –positive), and systemic JIA subtypes. Further studies will be required to standardize and validate these criteria to define remission and to be applicable to all subtypes of JIA.
This study also demonstrates promising results with the use of anti-TNFα agents in the treatment of enthesitis. Peripheral enthesitis, in contrast to that seen in adults, is a common manifestation in juvenile SpA or ERA. Enthesitis can be prolonged and persistent, leading to significant functional disability. Conventional treatments (NSAIDs, MTX, SSZ, and corticosteroids) used in the treatment of juvenile SpA may be helpful in the alleviation of arthritis but have been largely ineffective for the treatment of enthesitis. Preliminary results suggesting that anti-TNFα agents may be efficacious in the treatment of peripheral enthesitis were reported by D'Agostino et al (37), who noted clinical and radiologic improvement in 2 HLA–B27–positive adult patients with refractory, erosive, calcaneal enthesitis. No studies regarding this approach in children have been reported.
Although more patients in this study received infliximab compared with etanercept, both anti-TNFα agents seemed to be equally efficacious. The medications were well tolerated in all cases and no severe adverse events were reported. There were no reports of serious infections with either anti-TNFα agent. All patients were prescreened to exclude the presence of tuberculosis prior to the initiation of anti-TNFα therapy.
Anti-TNFα appears to be safe and efficacious in the treatment of refractory synovitis and enthesitis. The response to anti-TNFα agents in juvenile SpA patients appears to be as efficacious as that seen in open and double-blind studies in AS patients. Our study highlights the improvements made in both arthritis and enthesitis in response to anti-TNFα agents in the largest cohort of juvenile SpA patients studied to date, who fulfilled the criteria for ERA and had previously exhibited an inadequate response to standard antirheumatic drug therapy. Further prospective studies are required to examine the long-term outcomes of anti-TNFα blockade in children with juvenile SpA.