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ARTHRITIS & RHEUMATISM Vol. 63, No. 10, October 2011, pp 3163–3168 DOI 10.1002/art.30502 © 2011, American College of Rheumatology BRIEF REPORT Clinical Outcomes After Withdrawal of Anti–Tumor Necrosis Factor Therapy in Patients With Juvenile Idiopathic Arthritis: A Twelve-Year Experience Kevin Baszis, Jane Garbutt, Dana Toib, Jingnan Mao, Allison King, Andrew White, and Anthony French Objective. To estimate the length of time to dis- ease flare and the likelihood of achieving clinical remis- sion after discontinuation of treatment with tumor necrosis factor (TNF) blockers in patients with juvenile idiopathic arthritis (JIA). Methods. We conducted a retrospective chart review in a cohort of patients with JIA treated with TNF inhibitors between January 1, 1998 and Novem- ber 1, 2009. Demographic information, laboratory data, and medication exposure were extracted using a stan- dardized tool. Outcomes of interest were based on preliminary criteria for remission in JIA. Results. One hundred seventy-one patients with 255 discrete episodes of anti-TNF treatment were reviewed. The median duration of patient observation was 59.7 months (range 5.8–211.2 months). Among patients in whom disease was inactive after discontinu- ation of anti-TNF therapy, 50% had persistently inac- tive disease at 6 months, and 33% had clinical remission at 12 months. The median duration of anti-TNF therapy after inactive disease was obtained was 6.1 months (range 0–67.9 months). No significant associa- tion was observed between the time to disease flare after cessation of treatment with TNF antagonists and the length of time from the diagnosis of JIA to the initiation of anti-TNF therapy, the duration of therapy following the onset of inactive disease, or the total duration of treatment with TNF antagonists prior to discontinua- tion. The category of JIA, sex, and age at diagnosis were not associated with the risk of relapse. Conclusion. One-third of patients with JIA can successfully undergo withdrawal of treatment with TNF antagonists and be spared the cost and potential morbidity of treatment for at least 12 months. Further studies are needed to identify factors to accurately identify these patients. Anti–tumor necrosis factor (anti-TNF) drugs, including etanercept, infliximab, and adalimumab, have revolutionized the treatment of juvenile idiopathic ar- thritis (JIA), and disease remission has become an attainable goal (1). To realize this goal, treatment providers must balance the potential of adverse effects from prolonged treatment with the risk of disease flare after withdrawal of therapy. The risk of immunosuppression and infections, particularly mycobacterial and fungal infections, associ- ated with TNF blockade is well established (2). A recent US Food and Drug Administration analysis of 10 years of postmarketing surveillance highlighted the po- tential risk of secondary malignancy, resulting in a boxed warning for these medications (3). That report induced anxiety in patients, parents, and healthcare providers and offered additional incentive to explore withdrawing patients from anti-TNF therapy once inactive disease is achieved. Minimizing exposure to TNF antagonists could lead to decreased adverse effects and costs. Currently, no guidelines exist to outline appro- priate withdrawal of TNF inhibitors once inactive disease status has been achieved. Treatment practices vary and remain provider-dependent, and many patients who experience disease remission are treated indefi- nitely, often for many years, unless adverse outcomes occur (4,5). Several studies have investigated factors for successful withdrawal of TNF inhibitors in adult pa- tients with rheumatoid arthritis (6,7), but the pediatric literature remains limited (8,9). The goal of the current study was to examine the effect of withdrawing TNF antagonists while continuing treatment with disease- modifying antirheumatic drugs (DMARDs) such as methotrexate, leflunomide, or sulfasalazine. The pri- Kevin Baszis, MD, Jane Garbutt, MB ChB, Dana Toib, MD, Jingnan Mao, MS, Allison King, MD, MPH, Andrew White, MD, Anthony French, MD, PhD: Washington University School of Medi- cine, St. Louis, Missouri. Address correspondence to Kevin Baszis, MD, Washington University School of Medicine, Department of Pediatrics, Division of Rheumatology, Campus Box 8116, One Children’s Place, St. Louis, MO 63110. E-mail: [email protected]. Submitted for publication September 29, 2010; accepted in revised form June 9, 2011. 3163

Clinical outcomes after withdrawal of anti–tumor necrosis factor α therapy in patients with juvenile idiopathic arthritis: A twelve-year experience

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ARTHRITIS & RHEUMATISMVol. 63, No. 10, October 2011, pp 3163–3168DOI 10.1002/art.30502© 2011, American College of Rheumatology

BRIEF REPORT

Clinical Outcomes After Withdrawal of Anti–Tumor Necrosis Factor � Therapy inPatients With Juvenile Idiopathic Arthritis: A Twelve-Year Experience

Kevin Baszis, Jane Garbutt, Dana Toib, Jingnan Mao, Allison King, Andrew White, and Anthony French

Objective. To estimate the length of time to dis-ease flare and the likelihood of achieving clinical remis-sion after discontinuation of treatment with tumornecrosis factor � (TNF�) blockers in patients withjuvenile idiopathic arthritis (JIA).

Methods. We conducted a retrospective chartreview in a cohort of patients with JIA treated withTNF� inhibitors between January 1, 1998 and Novem-ber 1, 2009. Demographic information, laboratory data,and medication exposure were extracted using a stan-dardized tool. Outcomes of interest were based onpreliminary criteria for remission in JIA.

Results. One hundred seventy-one patients with255 discrete episodes of anti-TNF� treatment werereviewed. The median duration of patient observationwas 59.7 months (range 5.8–211.2 months). Amongpatients in whom disease was inactive after discontinu-ation of anti-TNF� therapy, 50% had persistently inac-tive disease at 6 months, and 33% had clinical remissionat 12 months. The median duration of anti-TNF�therapy after inactive disease was obtained was 6.1months (range 0–67.9 months). No significant associa-tion was observed between the time to disease flare aftercessation of treatment with TNF� antagonists and thelength of time from the diagnosis of JIA to the initiationof anti-TNF� therapy, the duration of therapy followingthe onset of inactive disease, or the total duration oftreatment with TNF� antagonists prior to discontinua-tion. The category of JIA, sex, and age at diagnosis werenot associated with the risk of relapse.

Conclusion. One-third of patients with JIA can

successfully undergo withdrawal of treatment withTNF� antagonists and be spared the cost and potentialmorbidity of treatment for at least 12 months. Furtherstudies are needed to identify factors to accuratelyidentify these patients.

Anti–tumor necrosis factor � (anti-TNF�) drugs,including etanercept, infliximab, and adalimumab, haverevolutionized the treatment of juvenile idiopathic ar-thritis (JIA), and disease remission has become anattainable goal (1). To realize this goal, treatmentproviders must balance the potential of adverse effectsfrom prolonged treatment with the risk of disease flareafter withdrawal of therapy.

The risk of immunosuppression and infections,particularly mycobacterial and fungal infections, associ-ated with TNF� blockade is well established (2). Arecent US Food and Drug Administration analysis of 10years of postmarketing surveillance highlighted the po-tential risk of secondary malignancy, resulting in a boxedwarning for these medications (3). That report inducedanxiety in patients, parents, and healthcare providersand offered additional incentive to explore withdrawingpatients from anti-TNF� therapy once inactive disease isachieved. Minimizing exposure to TNF� antagonistscould lead to decreased adverse effects and costs.

Currently, no guidelines exist to outline appro-priate withdrawal of TNF� inhibitors once inactivedisease status has been achieved. Treatment practicesvary and remain provider-dependent, and many patientswho experience disease remission are treated indefi-nitely, often for many years, unless adverse outcomesoccur (4,5). Several studies have investigated factors forsuccessful withdrawal of TNF� inhibitors in adult pa-tients with rheumatoid arthritis (6,7), but the pediatricliterature remains limited (8,9). The goal of the currentstudy was to examine the effect of withdrawing TNF�antagonists while continuing treatment with disease-modifying antirheumatic drugs (DMARDs) such asmethotrexate, leflunomide, or sulfasalazine. The pri-

Kevin Baszis, MD, Jane Garbutt, MB ChB, Dana Toib, MD,Jingnan Mao, MS, Allison King, MD, MPH, Andrew White, MD,Anthony French, MD, PhD: Washington University School of Medi-cine, St. Louis, Missouri.

Address correspondence to Kevin Baszis, MD, WashingtonUniversity School of Medicine, Department of Pediatrics, Division ofRheumatology, Campus Box 8116, One Children’s Place, St. Louis,MO 63110. E-mail: [email protected].

Submitted for publication September 29, 2010; accepted inrevised form June 9, 2011.

3163

mary objective was to inform the clinical management ofpatients with JIA receiving anti-TNF� therapy. Specifi-cally, we sought to determine the length of time todisease flare and the likelihood of clinical remissionafter discontinuation of TNF� blockers in patients withJIA.

PATIENTS AND METHODS

This retrospective cohort study was approved by theWashington University Institutional Review Board. The studypopulation included all patients with JIA who were treated atthe Washington University division of Pediatric Rheumatology(2 clinical sites) between January 1, 1998 and November 1,2009.

Our general practice is to initiate treatment with TNF�antagonists in JIA patients in whom disease is refractory to atleast 3 months of therapy with methotrexate and nonsteroidalantiinflammatory drugs and who are not candidates for treat-ment with intraarticular steroids. Patients in whom diseaseremained inactive for 6–12 months while they were receivinganti-TNF� therapy are considered candidates for discontinu-ation of TNF� antagonists. These agents are typically stoppedabruptly rather than by decreasing the dose or dosing interval,and the majority continue to receive DMARDs.

A total of 241 patients who were treated with TNF�antagonists were screened for inclusion in this retrospectivestudy. Exclusion criteria were as follows: noncompliance withtherapy, limited followup or observation deemed inadequatefor extraction of the appropriate data, and concomitant treat-ment with other biologic agents during anti-TNF� therapy.Noncompliance was defined as cessation of therapy beforephysician-recommended cessation (i.e., before an adequatetherapeutic trial [2–3 months in most cases]) or cessation oftherapy during active disease. Limited followup was defined asan insufficient number of encounters deemed necessary forobservation of disease activity and response to therapy (en-counters less often than every 3–4 months or transfer toanother center). The percentage of missing data in the in-cluded patient records was minimal.

Seventy patients were excluded due to incompletemedical records (the diagnosis was made at another center orthe patient’s care was transferred to another site, with noopportunity for followup [n � 42]), diagnosis/symptom onsetafter the patient’s sixteenth birthday (n � 13), noncompliancelimiting adequate data points (n � 11), development ofmacrophage activation syndrome (n � 2), ambiguity in diag-nosis (n � 1), and limited drug exposure due to parentalconcerns (n � 1).

Inclusion criteria were the following: fulfillment of the2001 International League of Associations for Rheumatologycriteria for the classification of JIA (10), treatment with TNF�antagonists (etanercept, infliximab, adalimumab) during thestudy period, and onset of arthritis symptoms before age 16years. Patients continuing treatment with methotrexate, le-flunomide, sulfasalazine, or other DMARDs after cessation ofTNF� antagonists were included. After stopping anti-TNF�therapy during inactive disease, no patient received cortico-

steroids or biologic therapies. Chart review was performed bya pediatric rheumatologist, using a standardized tool.

Data extracted by chart review included demographicinformation, baseline serology and acute-phase reactant levels,concurrent medication use, and dates of diagnosis, therapy,and remission/flare. The category of JIA was recorded asoligoarticular, extended oligoarticular, rheumatoid factor(RF)–negative polyarticular, RF-positive polyarticular, system-ic, psoriatic, enthesitis-related, or undifferentiated. To verifythe reproducibility of data extraction, 10% of the charts werereviewed by a second pediatric rheumatologist.

The criteria described by Wallace et al were used forthe study definitions (11). Inactive disease was defined as noactive arthritis or uveitis; a physician’s global assessmentindicating no disease activity; no fever, rash, serositis, spleno-megaly, or lymphadenopathy; and no elevated erythrocytesedimentation rate or C-reactive protein level attributable toJIA. Clinical remission on medication was defined as 6 contin-uous months of inactive disease on anti-TNF� therapy. Forthis study, clinical remission off medication was defined as

Table 1. Characteristics of the 171 JIA patients treated with anti-TNF� therapy*

CharacteristicFemale sex 24 (14)Age at disease onset, median (range) years 7.1 (0.8–18.5)JIA category

Persistent oligoarticular 20 (12)Extended oligoarticular 19 (11)RF-negative polyarticular 56 (33)RF-positive polyarticular 24 (14)Systemic-onset 21 (12)Psoriatic 6 (4)Enthesitis-related 21 (12)Undifferentiated 4 (2)

ANA statusPositive 77 (45)Negative 86 (50)Not determined 8 (5)

Uveitis present 27 (16)ESR at diagnosis, median (range) mm/hour 42 (3–111)CRP at diagnosis, median (range) mg/liter 18.3 (0.1–250)Anti-TNF� agent used during treatment course

Etanercept 129 (75)Infliximab 68 (40)Adalimumab 13 (8)

Other therapies used during disease courseMethotrexate 155 (91)Sulfasalazine 25 (15)Leflunomide 24 (14)Intraarticular steroid injection 73 (43)

No. of injections per patient, median(range)

3 (1–36)

Time from diagnosis to initiation of anti-TNF�therapy, median (range) months

9.8 (0–175.9)

Time from diagnosis to last recorded visit,median (range) months

59.7 (5.8–211.2)

* Except where indicated otherwise, values are the number (%) ofpatients. JIA � juvenile idiopathic arthritis; anti-TNF� � anti–tumornecrosis factor �; RF � rheumatoid factor; ANA � antinuclearantibody; ESR � erythrocyte sedimentation rate; CRP � C-reactiveprotein.

3164 BASZIS ET AL

inactive disease for 12 months while off anti-TNF� therapy.Other anti-arthritis or anti-uveitis medications, excluding cor-ticosteroids and biologic agents, could be used.

The primary outcome was the proportion of patientsachieving clinical remission after discontinuation of anti-TNF�therapy. We analyzed the initial course of treatment in patientsnaive to TNF� antagonists in addition to the total number ofepisodes across patients, because some patients underwentmultiple courses of anti-TNF� therapy. Categorical data weresummarized using percentages, and continuous variables arereported as medians and ranges. A Kaplan-Meier survivalcurve was plotted to estimate the length of time to flare. Aproportional hazards model was used to estimate the associa-tion of risk factors with the remission survival rate. Hazardratios (HRs) and 95% confidence intervals (95% CIs) for eachJIA category were calculated. Statistical analyses were per-formed using SAS version 9.1 software.

RESULTS

A total of 697 patients with JIA were treatedduring the 12-year study period. Of these, 241 patients(35%) received �1 dose of anti-TNF� medication.Seventy of the 241 patients were excluded, and theremaining 171 patients were included in the analysis.

The characteristics of the 171 patients are shownin Table 1. The median duration of followup was 59.7months (range 5.8–211.2 months). All JIA categorieswere represented: 23% of the patients had oligoarticulardisease (12% had persistent JIA and 11% had anextended course), 47% had polyarticular disease, 12%had systemic-onset arthritis, 12% had enthesitis-relatedarthritis, 4% had psoriatic arthritis, and 2% had undif-ferentiated arthritis. Ninety-one percent of the patientswere treated with methotrexate at some point in theirdisease course. Etanercept was the most commonlyprescribed TNF� antagonist (75% of patients), followedby infliximab (40%) and adalimumab (8%).

Table 2 details 255 episodes of TNF� antagonistexposure among 171 patients. The percentages of pa-tients in the various JIA categories and the medicationexposure rates were similar to the patient data shown inTable 1. The median length of exposure to TNF�antagonists was 13.9 months (range 1.2–106.2 months).The duration of anti-TNF� therapy had no significanteffect on the time to flare after cessation of TNF�antagonist (HR 0.98, 95% CI 0.94–1.03).

Among the patients exposed to 255 episodes ofTNF� antagonist treatment, 84% achieved inactive dis-ease at least once; the median duration was 3.6 months(range 0.3–45.3 months) from the initiation of treatmentto the onset of inactive disease. One hundred twenty-seven of these patients (50%) attained clinical remission

(6 months of inactive disease) on medication. Themedian length of treatment after inactive disease wasachieved was 6.1 months (range 0–67.9 months). Amongthe 182 patients in whom exposure ended in the cessa-tion of treatment with TNF� antagonists, 136 (75%) hadinactive disease at the time of drug discontinuation andwere analyzed for survival data.

Of the 136 patients with inactive disease at thetime of cessation of TNF� treatment, 25% experienceda disease flare within 3 months of the withdrawal ofanti-TNF� therapy. An additional 25% experienced aflare by 6 months, leaving 50% of the patients withsustained inactive disease off TNF� antagonist therapyat 6 months. Thirty-two percent of the 136 patientsachieved clinical remission (12 months of inactive dis-ease) off anti-TNF� therapy. The median duration of an

Table 2. Characteristics during 255 episodes of TNF� antagonistexposure among 171 JIA patients*

Female sex 193 (76)JIA category

Persistent oligoarticular 36 (14)Extended oligoarticular 30 (12)RF-negative polyarticular 84 (33)RF-positive polyarticular 30 (12)Systemic-onset 27 (11)Psoriatic 11 (4)Enthesitis-related 30 (12)Undifferentiated 7 (3)

Anti-TNF� agent used during treatment courseEtanercept 184 (72)Infliximab 104 (40)Adalimumab 21 (8)

Other therapies used during disease courseMethotrexate 216 (85)Leflunomide 38 (15)Sulfasalazine 27 (11)

ESR at anti-TNF� initiation, median (range)mm/hour

24 (0–92)

CRP at anti-TNF� initiation, median (range)mg/liter

6.0 (0.2–318)

Inactive disease achieved during course oftreatment

213 (84)

Time from anti-TNF� initiation to inactivedisease, median (range) months

3.6 (0.3–45.3)

Clinical remission on medication achievedduring course of treatment

127 (50)

Anti-TNF� treatment discontinued 182 (71)Length of treatment after achievement of

inactive disease, median (range) months6.1 (0–67.9)

Patients with inactive disease when anti-TNF�therapy was discontinued

136 (53)

Duration of anti-TNF� treatment, median(range) months

13.9 (1.2–106.2)

* Except where indicated otherwise, values are the number (%) ofepisodes. JIA � juvenile idiopathic arthritis; anti-TNF� � anti–tumornecrosis factor �; RF � rheumatoid factor; ANA � antinuclearantibody; ESR � erythrocyte sedimentation rate; CRP � C-reactiveprotein.

WITHDRAWAL OF ANTI-TNF� THERAPY IN JIA 3165

episode of clinical remission was 4.2 months (range0.2–42.1 months). This duration is underestimated, be-cause we were unable to complete 12-month followup on40 (29%) of 136 episodes. Of 100 episodes ending inflare, 60% occurred when the patient was off all drugtherapy, and 40% occurred when methotrexate wascontinued. Of 36 patients who continued to experienceclinical remission at the last followup, 42% remained onmethotrexate, and 58% were off all drug therapy.

To remove the potential bias of individual pa-tients or poor responders contributing more than oneepisode of anti-TNF� treatment to our analysis, weexamined each patient’s initial course of therapy, ensur-ing that each of the patients was naive to anti-TNF�therapy. The median duration from the time of diagnosisof JIA to the initiation of anti-TNF� therapy was 9.8months, and this had no significant effect on the time toflare (HR 1.004, 95% CI 0.997–1.010). Twenty-fivepercent of patients with inactive disease experienced adisease flare by 3 months after TNF� antagonist with-drawal, and 50% experienced a flare by 6 months afterthe withdrawal of treatment (Figure 1). Thirty-threepercent of patients achieved clinical remission 12months after TNF� antagonist cessation. The medianduration of clinical remission was 3.9 months (range0.2–35.6 months); this may be an underestimate due toincomplete followup. No patients with RF-positive poly-articular disease achieved clinical remission after with-drawal of anti-TNF� therapy.

The category of JIA, sex, and age at diagnosishad no statistically significant effect on the duration ofinactive disease after TNF� antagonist cessation. Each

category of JIA was compared with RF-positive polyar-ticular disease, which is generally accepted as the mostlikely category of JIA in which patients may experiencea disease flare after anti-TNF� therapy is discontinued(1). Hazard ratios ranged from 0.37 (95% CI 0.10–1.43)for systemic JIA to 1.81 (95% CI 0.63–5.18) forenthesitis-related arthritis, but none were statisticallysignificant. The small sample size precluded calculationof an HR for undifferentiated arthritis.

The median length of treatment after inactivedisease was achieved was 6.1 months (range 0–67.9months). The duration of anti-TNF� therapy after inac-tive disease was achieved had no significant effect on thetime to flare after cessation of therapy (HR 1.01, 95% CI0.96–1.07).

In this cohort of 171 patients, with an averagefollowup period of 3.8 years after initiation of anti-TNF� therapy (658 patient-years), only one seriousadverse event occurred (osteomyelitis requiring hospi-talization). No malignancies were observed. There wasone case each of mononucleosis, varicella zoster infec-tion, and recurrent urinary tract infection. Among 104exposures to infliximab, there were a total of 10 infusionreactions leading to drug cessation.

DISCUSSION

Among patients with JIA in whom TNF� inhib-itors were discontinued after inactive disease wasachieved, 50% had persistently inactive disease at 6months, and 33% had disease in clinical remission 12months after stopping anti-TNF� therapy. To ourknowledge, this is the largest pediatric study to datedescribing outcomes of flare/remission following with-drawal of anti-TNF� therapy. Two small previous stud-ies have addressed this issue. Prince et al described 19children with JIA in whom etanercept therapy waswithdrawn after 0–4.7 years of inactive disease (8). Tenpatients (53%) sustained inactive disease for a medianof 0.8 years, and successful withdrawal was associatedwith prolonged clinical remission on medication. Reme-sal and colleagues described 26 children in whom etan-ercept was discontinued during inactive disease (9). Themean duration of etanercept therapy was 19 months;treatment was continued for a mean of 14.7 months afterinactive disease was obtained. After cessation of etaner-cept therapy, 50% of patients continued to have inactivedisease at 6 months, and 39% had inactive disease at 12months. No association was observed between the dura-tion of inactive disease prior to etanercept cessation andthe time to disease relapse. The analysis of our larger

Figure 1. Survival analysis after the initial course of anti–tumornecrosis factor � (anti-TNF�) therapy was discontinued in 99 juvenileidiopathic arthritis patients with inactive disease. The survival timestarts when anti-TNF� therapy was stopped and represents theproportion of patients in whom disease continued to be inactive afterthe cessation of therapy. The end point of the curve representsattainment of clinical remission or persistent inactive disease 12months after cessation of TNF� antagonist treatment.

3166 BASZIS ET AL

cohort, which was studied over a longer period of time,confirmed similar periods of inactive disease after ces-sation of anti-TNF� therapy. In addition, we also ob-served no correlation between the risk of flare and thelength of anti-TNF� therapy after inactive disease wasachieved.

Our data can help inform the clinical practice ofJIA treatment. In our population, TNF� antagonistswere withdrawn a median of 6.1 months after inactivedisease was achieved. This duration had no correlationwith the duration of inactive disease/time to flare afteranti-TNF� therapy cessation, suggesting that prolongedtreatment with TNF� antagonists does not increase thelikelihood of sustained remission after withdrawal oftherapy. We propose that these findings are clinicallysignificant, suggesting the potential to spare the risksand costs of prolonged therapy. Also of interest is ourobservation that the median duration (9.8 months) fromthe diagnosis of JIA to the initiation of anti-TNF�therapy had no significant effect on the time to flareafter withdrawal of anti-TNF� therapy, suggesting that awindow of time exists during which therapy can beescalated without affecting the long-term prognosis.

Systemic JIA is distinct from other categories ofJIA in that a substantial proportion of patients respondpoorly to TNF� blockade. In our cohort, only 38% ofpatients with systemic JIA achieved inactive diseasewhile receiving anti-TNF� therapy; this proportion issimilar to that observed in previous studies (12). How-ever, 5 of 8 patients with systemic JIA (63%) whoachieved inactive disease status were able to achieveclinical remission 12 months after anti-TNF� therapywas stopped. Prince and colleagues reported a similarfinding in their study, in which 4 of 5 patients withsystemic JIA had persistent inactive disease after treat-ment with etanercept was stopped (8). Therefore, al-though the majority of patients with systemic JIA re-spond poorly to TNF� blockade, the subset of patientswho do experience a response appear to do well afterstopping therapy with TNF� antagonists.

Several limitations of our study should be noted.Although the study population was large, all of thepatients were treated by practitioners at a single divisionof pediatric rheumatology. As with any retrospectivestudy, data extraction was limited to information avail-able in the medical record. Although the category of JIAdid not significantly affect the time to disease flare, smallsample sizes may have precluded detection of a signifi-cant difference. Despite having clinically inactive dis-ease, some patients may have had evidence of radio-graphic or biologic disease activity. Imaging is not

typically performed before stopping therapy to assess forsubclinical inflammation, and no established laboratoryor biologic markers exist to define inactive disease.Patients with subclinical disease activity may be with-drawn from anti-TNF� therapy, followed by a subse-quent clinical disease flare.

Data from our nearly 12-year experience withanti-TNF� agents in the treatment of JIA suggest that50% of patients can be successfully withdrawn fromTNF� antagonists for 6 months, and 33% can be with-drawn for at least 12 months. The challenge remains ofpredicting which subset of patients will successfullyattain clinical remission after withdrawal of anti-TNF�therapy.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors approvedthe final version to be published. Dr. Baszis had full access to all of thedata in the study and takes responsibility for the integrity of the dataand the accuracy of the data analysis.Study conception and design. Baszis, Garbutt, King, White, French.Acquisition of data. Baszis, Toib, White.Analysis and interpretation of data. Baszis, Garbutt, Mao, White.

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