Scand J Rheumatol 2011;40:101–107 101

© 2011 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation

DOI: 10.3109/03009742.2010.517546 www.scandjrheumatol.dk

SRHESafety and efficacy of adalimumab treatment in Greek children with juvenile idiopathic arthritis

M Trachana et alM Trachana1, P Pratsidou-Gertsi1, G Pardalos1, N Kozeis2, M Badouraki3, F Kanakoudi-Tsakalidou1

11st Department of Pediatrics, Pediatric Immunology and Rheumatology Referral Center, 2Department of Ophthalmology, and 3Departmentof Radiology, Hippokration General Hospital, Aristotle University, Thessaloniki, Greece

Objectives: To evaluate the safety and efficacy of adalimumab (AD) administration in patients with juvenile idiopathicarthritis (JIA).Methods: Twenty-six patients were enrolled from January 2004 to January 2008 in this prospective observationalstudy. Inclusion criteria were either unresponsiveness to disease-modifying anti-rheumatic drugs (DMARDs; n = 17) or toother anti-tumour necrosis factor (anti-TNF) agents (n = 9) or development of uveitis under other anti-TNFs (n = 2 of the 9).Efficacy was estimated using the American College of Rheumatology Pediatric (ACR Pedi) criteria.Results: After 1–5 years of AD exposure, nine different adverse events (AEs) were recorded (12.6 AEs/100 patient-years), mainly mild respiratory tract infections and injection site-related reactions. Serious AEs (SAEs, 2.8/100 patient-years) were the development of abscess at the site of injection (n = 1) and lethal sepsis (n = 1). The ACR Pedi ≥ 30responses for the first to the fifth year of treatment were 88.5, 57.7, 50.0, 34.6, and 11.5%, respectively. In total, 17 ofthe 26 (65.4%) patients responded to AD. Five of the 11 patients under steroids discontinued them 6 months post-treatment. Seven patients required weekly AD treatment to maintain remission and four of them benefited from thispolicy. Recurrent uveitis was hindered in three of the six patients, no new cases were recorded, and radiologicalregression was observed in two of the four patients with lesions.Conclusions: AD was safe and efficacious during the study period in the majority of patients. However, vigilance isrequired for the early detection of severe and potentially fatal infections. AD may control recurrent uveitis andradiological progression.

The advent of anti-tumour necrosis factor (anti-TNF)agents has opened a new era in the management ofpatients with juvenile idiopathic arthritis (JIA). How-ever, adequate data on the long-term safety and efficacyof the anti-TNFs are mainly for JIA patients with a pol-yarticular course and refer exclusively to etanercept(ET) (1–5). Publications on adalimumab (AD) (1)administration in JIA are sparse and mostly includesmall series of patients with exposure to the agent ofmore than 2 years (2, 6–8). This prospective observa-tional study was therefore designed to evaluate thesafety and efficacy of AD in patients with JIA of variousdisease types for a period of up to 5 years and to evalu-ate the efficacy of AD in non-responders to ET or toinfliximab (INFL).

Materials and methods

Study design and patient selection

Patients with refractory JIA attending the PaediatricImmunology and Rheumatology Referral Centre, Hip-pokration General Hospital, Greece were enrolled toreceive AD between January 2004 and January 2008.All met the following criteria of entry: (a) a confirmedJIA diagnosis according to International League AgainstRheumatism (ILAR) criteria (9); (b) fulfilment of theguidelines of the Greek Rheumatology Society’s Registryfor anti-TNF administration: JIA patients had to be non-responders to at least a 3-month duration of either onedisease-modifying anti-rheumatic drug (DMARD) withor without prednisolone or another anti-TNF agent. Thetype of previous regimen is shown in Table 1; (c) a parent’swritten consent for anti-TNF administration. After thefirst year of the study, two other inclusion criteria wereadded: development of uveitis under ET or INFL (10)and reluctance to start or non-adherence to the twiceweekly ET administration. The Scientific Committee ofthe hospital had previously approved anti-TNF studies inJIA patients (Approval no. 22/Year 2004).

Maria Trachana, 1st Department of Pediatrics, Pediatric Immunologyand Rheumatology Referral Center, Hippokration General Hospital,Aristotle University of Thessaloniki, 49 Konstantinoupoleos St,54642 Thessaloniki, Greece.E-mail: mtrachan@auth.gr

Accepted 18 August 2010

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Patients were followed-up at specific time points untilJanuary 2010.

Methods

Clinical assessment prior to and during the AD treat-ment. Twenty-six JIA patients (16 females, 10 males;age range 4.2–18 years) with various disease types ofonset and long-standing disease were enrolled. Of these26 patients, 19 had polyarthritis, either a polyarticular oran oligoarticular, or a systemic type of onset but a pol-yarticular course (defined for the study purpose as‘polyarthritis’) and seven had ‘oligoarthritis’, namelyoligopersistent JIA or a systemic type of onset and anoligoarticular course (Table 1).

The following information was obtained for eachpatient: diagnosis, patient demographics, disease dura-tion, previous regimen, reason for discontinuation ofother biologics, concurrent DMARDs, and AD adminis-tration (dose, frequency, and duration of treatment). Dis-ease activity prior to treatment was defined using theminimal disease activity definition for poly- and oli-goarthritis (11) and post-treatment remission or flarewas defined as suggested and performed by the Wallace

criteria (12, 13). Regarding safety, patients wereassessed periodically: monthly during the first 3 monthsand thereafter every 3 months (or earlier if necessary).Any adverse event (AE) reported by the parent orpatient was recorded in a preformatted diary [CaseReport Form (CRF)], including local and systemicreactions following the injection, infections, developmentof new symptoms/signs or change in mood. SeriousAEs (SAEs) were defined as events that were fatal orlife-threatening, required hospitalization or prolongedan existing hospitalization, resulted in a persistent orsignificant disability or incapability, or resulted in acongenital anomaly or birth defect (3). The post-treatment efficacy was assessed using Giannini’s criteriaor the American College of Rheumatology PediatricCriteria (ACR Pedi) 30, 50, and 70 and was recordedannually (14).

Laboratory assessment prior to and during the ADtreatment. Safety and efficacy assessments were alsobased on a laboratory work-up: haematology (completeblood count), erythrocyte sedimentation rate (ESR),C-reactive protein (CRP), serum chemistry (glucose levels,assessment of liver and kidney function), and urinalysis.The work-up was performed prior to AD administration

Table 1. Main demographics of the 26 patients of the study.

No. of patients naive to anti-TNF treatment/total no. of patients 17/26Sex of naive patients (F/M) 9/8No. of switchers from a previous anti-TNF* 9Sex of switchers (F/M) 5/4No. of anti-TNF sessions recorded in the 26 patients 27Age of JIA onset in years, mean ± SD 5.2 ± 3.6Age at AD treatment in years, mean ± SD 12.6 ± 4.7Disease duration prior to AD treatment in years, mean ± SD 7.1 ± 4.7Type of JIA, n (%)

Systemic 4 (15.4)Oligopersistent 4 (15.4)Oligoextended 7 (26.9)Polyarthritis RF negative 7 (26.9)Polyarthritis RF positive 1 (3.8)Psoriatic 0 (0)Enthesitis-related arthritis 2 (7.7)Unclassified 1 ( 3.8)

Patients with recurrent uveitis 6Previous treatment in the entire anti-TNF sessions administered to the 26 patients (27 sessions)

1 DMARD + PDN† 2/272 DMARDs ± PDN† 15/27INFL ± DMARD ± PDN† 6/27ΕΤ + DMARD 4/27

AD dosage (subcutaneously) 25 mg/m2/every 2 weeksConcomitant therapy administered in the 26 patients (27 sessions)

PDN (in combination with DMARDs)† 11/27MTX 24/27CSA‡ 3/27

F, Female; M, male; AD, adalimumab; RF, rheumatoid factor; DMARD, disease-modifying anti-rheumatic drug; ΕΤ, etanercept; PDN,prednisone; INFL, infliximab; MTX, methotrexate; CSA, cyclosporin Α.*One female patient received AD twice.†PDN dose < 0.5 mg/kg/day with a waning effect and discontinuation after 6–12 months.‡CSA administration due to MTX intolerance.

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and continued monthly for the first 6 months and at6-month intervals thereafter. In addition, the scheduledimmunological evaluation for patients under anti-TNFswas performed at baseline and at 6-month intervalsthereafter (15). It aimed to detect immunosuppressionand the development of new autoantibodies.

Imaging assessment prior to and during the AD treat-ment. Radiological assessment of all affected joints priorto treatment and on a 12-month basis thereafter was per-formed by the same radiologist. For the joints of thehands the modified paediatric Larsen score was used(16). The rest of the involved joints were evaluated quali-tatively as described in the study by van Rossum et al(17). These radiographs were compared sequentially todetect any progression of joint damage.

Safety and efficacy assessment in addition to jointevaluation. An eye examination (slit-lamp and fundos-copy) was performed prior to treatment and on a 3-monthbasis thereafter. Tuberculosis (TB) screening prior to ADadministration, including a tuberculin test (Mantoux),a chest radiograph and, in three patients, interferon(INF)-g-based assays (Quantiferon®), was performedduring the last 2 years of the study. Thereafter, Mantouxand chest radiographs were carried out annually.

Statistical analysis

The methodology used by Lovell et al (18) andLahdenne et al (19) was taken into consideration. Allindices of the ACR Pedi criteria 30, 50, and 70 (14) andserial measurements of CRP were analysed. Theassessed joint count for active joints was 73, for thosewith a limitation of movement with pain and/or tender-ness 71, and for swollen joints 66. The functional limita-tion was based on the Disability Index of the ChildhoodHealth Assessment Questionnaire (CHAQ).

Efficacy analyses were performed on an intention-to-treat population that was defined as all patients who hadreceived at least one dose of the drug during the study.For the purpose of the study, an excellent response wasdefined as an ACR Pedi 70, a satisfactory one as an ACRPedi 50, a marginal response as an ACR Pedi 30, while anon-response was an ACR Pedi < 30. Descriptive statistics

of the Disease Activity Indices were calculated usingthe JUMP 7.0 statistical package (SAS®). In addition,the relevant percentage improvement of these indicescompared to the baseline values was also calculated.Data with a normal distribution are given as means ± stand-ard deviation and the remaining ones as their median.A p-value < 0.05 is considered statistically significant.

Results

Patient characteristics

The mean age of the patients at the start of AD was12.6 years. Twenty-seven sessions were administered to26 patients for a period of 6–62 months (median 5.7 years)after JIA onset. These sessions account for 859 months(71.6 patient-years) of AD exposure. The mean expo-sure to AD of naive (n = 17) and switchers from otheranti-TNFs (n = 9) did not differ significantly (32.5 vs. 34.1months, respectively, p = 0.8). Of the 26 patients, ninecompleted 4 years and four completed 5 years of ADtreatment. In total, 13 completed at least 3 years of ADtreatment (Table 2).

Safety assessment

The majority (19/26, 73.1%) of patients tolerated ADwell (Table 3) and only two of the 26 (7.7%) patients dis-continued the medication due to an AE. In detail, nine dif-ferent AEs were recorded in seven patients (26.9%)during the study period. These correspond to 12.6 AEsper 100 patient-years. In three of the seven patients, AEswere associated with the route of AD administration. Themost common events were respiratory tract infections,which were either self-limiting or responded to antibiot-ics. Erythema and pruritus at the injection site wasreported by one patient, while two more patients mani-fested urticaria following the injection. Prolonged menses(15 days’ duration) was an annoying event for one patientand AD was discontinued after the third month due to adisease flare following a protracted respiratory infection.

SAEs were experienced by two patients (2.8/100patient-years). An adolescent manifested two episodesof severe staphylococcal skin infection (abscesses) atthe site of injection within a 2-month period due to

Table 2. Assessment of adalimumab (AD) efficacy in the 26 patients of the study.*

Year of treatment n (%) ACR Pedi 70 ACR Pedi 50 ACR Pedi 30 ACR Pedi < 30 Non-completers†

First 26 (100) 18/26 (69.2) 2/26 (7.7) 3/26 (11.5) 3/26 (11.5) 0 (0)Second 18 (69.2) 10/26 (38.5) 3/26 (11.5) 2/26 (7.7) 3/26 (11.5) 5 (19.2)Third 13 (50) 6/26 (23.7) 6/26 (23.7) 1/26 (3.84) 0/26 (0) 7 (26.9)Fourth 9 (34.6) 4 (15.4) 3/26 (11.5) 2/26 (7.7) 0/26 (0) 11 (42.3)Fifth 4 (15.38) 1/26 (3.84) 2/26 (7.7) 0/26 (0) 1/26 (3.84) 16 (69.5)

*Intention-to-treat analysis.†Non-completers of this year but still on AD treatment.

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intramuscular drug administration. The patient respondedto the systemic administration of antibiotics combinedwith surgical drainage and continued AD thereafter.

The most important AE was occurrence of lethalsepsis in an 18-year-old female patient, 2 months afterAD readministration. She had previously received ADfor 2 years and then, because of a waning response, ETfor 9 months. The development of persistent uveitis 16years after the JIA onset prompted the switching againto AD (10, 20). Two months later she experienced a‘febrile illness’ following a journey abroad. At the timeof the late admission she was already in a pre-shockcondition associated with central nervous system (CNS)involvement followed by severe renal failure. Anautopsy was not performed.

No immunosuppression or development of persistentnew autoantibodies (more than 6 months of serum

presence) was found in the sequential immunologywork-up of any patient, no other laboratory abnormali-ties, and no TB cases were recorded.

Efficacy assessment

As shown in Table 2, the AD efficacy was performedon an annual basis. The treatment of the patient whohad twice received AD has not been included twice.The annual mean values of the indices included in theACR Pedi (CHAQ, laboratory tests, indices of jointactivity) are shown in Table 4. Of the 26 patients,23 (88.5%), 15 (57.7%), 13 (50%), nine (34.6%), andthree (11.5%) benefited from a 12–60-month ADtreatment, respectively, as having achieved an ACRPedi ≥ 30 response.

The seven (26.9%) non-responders to AD (ACR Pedi< 30) were all patients with polyarthritis. Conversely,among the 19 (73.1%) responders, 12 patients had poly-arthritis. Four of the nine switchers responded to AD.Moreover, two of the 19 patients achieved completeremission and discontinued AD, 3 and 4 years post-treatment. Both were patients with an oligoarthritiscourse but flared 9–12 months later with milder clinicalmanifestations.

In total, 17 of the 26 (65.4%) patients completed thestudy. The reasons for discontinuation in the remainingnine patients were either SAEs (n = 2) or inefficacy (n = 7).Apart from the patient who died, the remaining eightpatients were switched either to methotrexate (MTX) +leflunomide (n = 1) or to cyclosporin A (CSA) + pred-nisolone (n = 1) or to ET (n = 6). Six months later, thepatients under non-biologics had an ACR Pedi of 30,while the six patients under ET had an ACR Pedi ≥ 50.

Table 3. Adverse events during the adalimumab (AD) treatment(27 sessions).

Type of adverse event (AE) n = 26

Common infections of the upper respiratory system 7Erythema and pruritus at the site of injections

(local reaction)1

Urticaria, arthralgias following the injection (systemic reaction)

2

Severe skin infection (abscess) 1Prolonged menses 1Loss of hair 1Febrile episode with a non-detected reason and death

within a week* (attributed to a severe infection)1*

*Two months after AD administration; this patient had previouslyreceived AD for 2 years and then etanercept for 9 months(see text for details).

Table 4. Changes from baseline in disease activity variables during the 5-year adalimumab treatment in the 26 patients.

Baseline*

n = 27Month 12

n = 18Month 24

n = 13Month 36

n = 9Month 48

n = 4Month 60

a* b* a b a b a b a b

Physician’s global assessment†

3.75 −2.51 −66.97 −1.78 −47.41 −3.05 −81.33 −2.42 −64.44 −2.75 −73.33

Parents’ assessment of disease activity†

3.77 −2.62 −69.32 −2.19 −58.04 −3.50 −92.77 −3 −79.39 −2.77 −73.50

No. of active joints‡ 8.12 −4.73 −58.29 −3.41 −42.01 −7 −85.44 −6 −78.44 −7 −84No. of joints with LOM‡ 7.88 −5.12 −64.88 −3.47 −44.05 −6.88 −87.32 −6.13 −77.80 −6.38 −80.98CHAQ§ 0.5 −0.39 −79.18 −0.21 −42.45 −0.47 −94.91 −0.21 −42.53 −0.42 −83.46ESR¶ 43.92 −30.50 −69.32 −26 −59.09 −30.5 −65.51 −24 −54.55 −27 −61.36CRP¶ 44.71 −21.38 −83.82 −21.45 −84.12 −24.54 −96.24 −22.50 −88.24 −23.70 −92.94No. of swollen joints† 5.62 −4.35 −77.40 −2.62 −46.58 −5.07 −90.29 −3.62 −64.38 −4.12 −73.29

*All values are means. a: mean change from baseline, b: mean percentage change from baseline.†A visual analogue scale was used for the assessment of disease activity by both the physician and the parent, measured as 0 = best,10 = worst.‡The total numbers of joints assessed was as follows: 73 for the total active joint count, 71 for the limitation of movement (LOM) withpain and/or tenderness, 66 for the swollen joint count.§The range for the Childhood Health Assessment Questionnaire (CHAQ) is 0–3 (0 = best, 3 = worst).¶The range of normal values for the ESR is 0–20 mm/h and for CRP 0–5 mg/dL.

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AD impact on systemic JIA

At the end of the first year, all four patients had a mini-mum ACR Pedi 50 in improving the systemic and articu-lar disease activity. At the end of the study, threepatients had benefited from the AD administration andthe patient who flared after the fourth year had mildersystemic manifestations compared to baseline.

AD impact on steroid withdrawal

Among the 11 patients who required steroid administrationat study entry, five achieved discontinuation of steroidswithin the first 6 months of the study. Alternatively, themajority of the patients (five of the six) who required ste-roids in a low dose to maintain remission were previousanti-TNF receivers with a long-standing JIA prior to ADadministration (median 4, range 2.5–14 years).

Impact of early AD administration with respect to disease duration

All three patients who received AD within the first2 years (17–22 months) of JIA onset benefited from theearly therapy, and all were still under AD during theirthird year of treatment, with an ACR Pedi 70.

Impact of shortening the interval between AD injections

Seven patients with polyarthritis were switched to aweekly administration of AD for 6–24 months post-treatment, in order to remain in remission. Four of thembenefited from this regime, one patient showed a mar-ginal improvement (ACR Pedi 30), and the remainingtwo discontinued AD due to non-response (ACR Pedi< 30). Among the improvers, a patient with polyarthritiswas able to return to the alternate week schedule6 months later, without deterioration of her indices.

AD impact on the development and course of uveitis

Six of the 26 patients had active uveitis at baseline. Intwo patients with oligoarthritis, AD was purposely cho-sen as the first choice of anti-TNF due to their history ofrecurrent uveitis (10). Three of the six patients did notexperience any further flares of uveitis under AD.Among the three non-responders, two were naive toanti-TNFs and one who had previously received INFL.The flares of these patients were controlled by the sup-plementation of local therapy (n = 2) whereas theremaining patient underwent an operation due to thedevelopment of cataract and glaucoma. No new cases ofuveitis were recorded during the AD administration. Ofnote, two of the three AD responders had previouslyreceived INFL and ET. No other eye disorders wereobserved during the study.

AD impact on radiological progression

At baseline, only four patients had abnormal radiologi-cal findings, namely a Larsen score >1 in the hands orpresent lesions apart from soft tissue swelling in allother affected joints. These were all patients with a long-standing disease (> 5 years). Their Larsen scores were3 (n = 1), 4 (n = 1), and 5 (n = 2). Two patients withLarsen scores of 3 and 5, respectively, also had erosionsin the ankles (n = 1) and hips (n = 1). The serial evalua-tion of the hand radiographs revealed that two patientsmanifested regression of their hand lesions from scores4 and 3 to 2 (Figure 1), after the fourth and fifth year ofAD exposure, while the other two failed to demonstrateany radiological improvement but remained stable. Asfor the erosions of the other joints, regression was evi-dent after the fourth year of AD, only in the patient withthe affected ankles.

Discussion

The present study is the first that has aimed to assess thesafety and efficacy of AD for a period up to 5 years, inGreek JIA patients who were resistant either toDMARDs (n = 17) or to other anti-TNFs (n = 9).Encouraging data regarding AD administration inrefractory RA prompted the design of this study in 2003(6, 21) whereas the first publications on JIA patientsemerged during the last 2 years of this study (7, 8, 22–24).

The findings of this study indicate that AD was safeand well tolerated by the majority of patients (73.1%)during the 71.6 patient-years of exposure and AEs werethe reason of AD discontinuation for a minority of them(8%). The recorded rate for AEs was 12.6/100 patient-years, and the rate for SAEs was 2.8/100 patient-years.Mild AEs not requiring hospitalization or leading todisability in both adults and children have also been

Figure 1. Radiological regression under adalimumab (AD) treatment.(A) Pretreatment: hand bone loss (black arrow), narrowing of the intra-articular spacing of carpi and all metacarpophalangeal joints, withjoint haziness and the presence of microcystic lesions most prominentin the schaphoid bone (white arrow). (B) Four years post-treatment:improvement of the hand bone loss and regression of the microcysticlesions, while the intra-joint spacing remained unchanged.

A B

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reported by other investigators at a rate similar to thepresent study (25, 26). Infections were the most com-mon AEs (27%) in the present study, as have beenreported primarily in adults (21, 22, 25–28). Severeinfections occurred in two (7.7%) patients, namely a softtissue abscess at the site of injection and a lethal sepsis,which raised the mortality rate to 4%. Skin and softtissue infections have also been observed as frequentAEs in RA patients under AD (25, 26). The fatal eventcannot be associated directly with the AD exposure dueto the vague history prior to the late admission and theabsence of autopsy.

In this study, the observed SAEs per 100 patient-yearswere significantly lower than those of the Lovell et almulticentre study, which is the largest series of JIApatients published so far (3.1 vs. 46.6). However, thestudy design, the type of JIA enrolled, and the diseaseduration (mean 7.1 vs. 4 years) differed significantlybetween the present and the Lovell et al study (7).

Although recent publications emphasize the policy ofperiodical TB screening in patients under anti-TNFtreatment, no TB cases were reported during the study(25–28).

The development of new autoantibodies related to awide spectrum of autoimmune entities was negative inthis study, in contrast to those experienced with otheranti-TNFs (15). Other investigators, despite havingtested a narrower spectrum of autoantibodies, reportedsimilar findings (24, 28).

The intention-to-treat analysis showed that ADproved to be efficacious in 50% of this study populationafter 3 years of continuous exposure, with most patientssustaining their disease inactivity over 4 (n = 9) and5 (n = 3) years, respectively. Importantly, two patientsafter 3 and 4 years of treatment were able to discontinuethe medication due to sustained remission (12, 13). Mostof the patients had a 6-year disease duration prior to ADinitiation and 34.6% of them a previously recorded lackor loss of response to ET or INFL. The response ratewas 63% for patients with polyarthritis. With respect topatients with polyarthritis, the beneficial impact of ADafter the first and third years were comparable to theLovell et al study (7) and to other publications of a2-year AD administration (8, 22, 23).

Switching from another anti-TNF to AD based on theexperience from RA patients was a successful policy inhalf of the switchers (6, 27). AD administration also hada beneficial impact on the disease control in three (75%)patients with systemic JIA and is concordant with arecently published South American study (8). Thesteroid-sparing effect of AD administration was feasiblein about 50% of the patients of this study. As reportedpreviously, patients who continued to need a low dose ofsteroids were all switchers from other anti-TNFs andwith a long-standing refractory disease (29). Theimportance of early anti-TNF administration in achiev-ing remission and preventing joint damage has beenshown in all three patients of this study who started AD

within the first 2 years of their disease onset (30, 31).Shortening the interval of two consecutive AD injec-tions to maintain remission (12, 22) was effective inabout half of these patients. Half of the patients withrecurrent and recalcitrant uveitis benefited from the ADadministration. This favourable impact is comparable toprevious publications reporting 35–50% uveitis controlunder AD (22, 23, 32). Thus, AD may be a potentialtreatment option for JIA-associated uveitis, even in non-responders to previous anti-TNF treatment (32, 33). ADhindered the radiological progression in half of theaffected hands of this study (n = 2), as observed previ-ously in RA adults (34, 35).

The policy regarding the ‘optimal’ time of AD dis-continuation following disease remission remains unde-fined. In this study, the two patients who achievedremission and discontinued AD flared with milder fea-tures 9–12 months later, as reported previously (36).

One limitation of this study was the small numbers inall the above subgroups studied. However, these find-ings provide some evidence that needs to be confirmedin larger series of patients.

The findings of this study show that, in our JIA popu-lation, AD administration was safe and efficacious inachieving remission. However, vigilance is required forthe early detection of severe and potentially fatal infec-tions. It is worth trying to administer AD in patients witha waning efficacy or ineffectiveness to other anti-TNFs,or in patients with recurrent uveitis and established radio-logical joint damage.

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