Please select the eligibility criteria that correspond to the clinical trial below.
Title: Comparison of Anti-TNF Therapy Plus Methotrexate, Combination Therapy of DMARDs, and Methotrexate Alone in Very Early Polyarticular Juvenile Idiopathic Arthritis. A National Randomized Multicenter Clinical Trial.
Brief Summary: The objective of this study is to compare in very early polyarticular juvenile idiopathic arthritis (JIA) the efficacy, safety, and cost-benefit-ratio of three treatment strategies: biologic combination, combination of conventional disease-modifying drugs (DMARDs), and methotrexate alone.


Options:
A: Inclusion Criteria:

* Subjects must have a diagnosis of polyarticular juvenile idiopathic arthritis (JIA) age 4 to 17 by the American College of Rheumatology (ACR) criteria. Disease onset may have been systemic, polyarticular, or pauciarticular. If the disease was systemic onset, then the subjects must be free of any systemic JIA manifestations for at least 3 months before the time of qualification.
* At the time of study screening, the subject must have continuing active disease defined as \>= 5 swollen joints and \>= 3 joints with limitation of motion (LOM). These joints are not mutually exclusive.
* Subjects may be either naïve to MTX, inadequate responders to MTX, or intolerant to MTX. Intolerance to MTX will be defined by the subject's physician. The MTX must be maintained at a dose of at least 10 mg/m2 body surface area/week for a minimum of 3 months, prior to screening.
* Duration of disease is not limited, but must have been long enough for a subject to have been given an adequate trial of nonsteroidal anti-inflammatory drugs (NSAIDs).
* Have not received other disease-modifying anti-rheumatic drugs (DMARDs) including penicillamine, hydroxychloroquine, sulfasalazine, oral or injectable gold, cyclosporin; or intravenous immunoglobulin (IV Ig); or cytotoxic agents, for at least 4 weeks prior to receiving 1st dose of study drug. Subjects currently on one or more of these DMARDs must demonstrate active disease (defined above) prior to a minimum 4 weeks (28 days) washout of all DMARDs.
* Subjects who are refractory to MTX after 3 months of treatment must demonstrate active disease (defined above) prior to enrollment in the open-label part of the trial.
* Have not received an intra-articular glucocorticoid injection within 4 weeks (28 days) prior to enrollment into the study.
* Have good venous access and stable hematocrit \>= 24%.
* All sexually active male and female study participants must be practicing adequate contraception. Post-pubertal females must have a negative serum pregnancy test no greater than 10 days prior to the first dose of study drug.
* Parent or guardian has voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), after the nature of the study has been explained and the subject's parent or legal guardian has had the opportunity to ask questions.

Exclusion Criteria:

* Pregnant or nursing female.
* Functional class IV by ACR criteria.
* Laboratory parameters outside limits established in the protocol.
* Medical history, medical condition, or previous treatment not allowed by the protocol.
B: Inclusion Criteria (must meet all of the following to qualify):

* Stated willingness to comply with all study procedures and availability for the duration of the study period
* ≥ 2 years of age
* History of JIA or CAU diagnosed prior to 16 years of age (patient may be older than 16 at time of enrollment)
* Formal diagnosis of JIA-associated uveitis or CAU with no other suspected etiology
* ≥12 consecutive months of controlled ocular inflammation (≤0.5+ anterior chamber cell, ≤0.5+ vitreous haze, no active retinal/choroidal lesions in either eye)
* ≥ 12 consecutive months of controlled arthritis verified by a pediatric rheumatologist, if defined as JIA-associated uveitis
* ≥12 consecutive months of treatment with adalimumab or a biosimilar of adalimumab
* ≥180 days on a stable dose of adalimumab or a biosimilar; must be biweekly dose of either 20mg (if\<30kg) or 40mg (if ≥30kg)
* If on a biosimilar of adalimumab, ≥90 days on the biosimilar
* If on concomitant antimetabolite (injectable or oral methotrexate, mycophenolate mofetil, azathioprine, or leflunomide), dose must be ≤25 mg weekly for methotrexate, ≤3 g daily for mycophenolate mofetil, ≤250 mg daily for azathioprine, or ≤20 mg daily for leflunomide; dose and route of administration must be stable for ≥90 days
* If on topical corticosteroids, dose must be ≤2 drops prednisolone acetate 1% or equivalent per day and stable for ≥90 days
* Willingness to limit consumption of alcohol during the study period
* Agreement to avoid live attenuated vaccinations
* Agreement to use highly effective contraception for ≥28 days prior to screening and throughout study period (for males and females of reproductive age)
* Suitable, in the opinion of the Investigator, to continue treatment with adalimumab or placebo per regional labeling
* No contraindications to receive adalimumab as per the local Summary of Product Characteristics (SmPC)

Exclusion Criteria (any one of these excludes the patient):

* Intraocular surgery in the past 90 days or planned surgery in the next 12 months
* Severe cataract or opacity preventing view to the posterior pole in both eyes
* Chronic hypotony (\<5 mmHg for ≥90 days) in either eye
* Treatment with oral corticosteroids or intraocular corticosteroid injection within the last 12 months
* Use of NSAID eye drops within the last 90 days
* Acute anterior uveitis characterized by redness and symptoms, including but not limited to floaters, pain, and light sensitivity
* Pregnancy or lactation (a pregnancy test will be conducted at baseline and all follow-up visits for females of reproductive age)
* Presence of intraretinal or subretinal fluid in either eye
* Prior safety or tolerability issues with adalimumab
* History of cancer, active tuberculosis, or hepatitis B
* Other medical condition expected to dictate treatment course during the study
* Any of the following laboratory test results on their most recent tests within the past 90 days prior to screening/enrollment: leukocyte count \<2500, platelet count ≤75000, hemoglobin \<9.0, Aspartate Aminotransferase (AST) or Alanine Transferase (ALT) ≥ 2 times the upper limit of normal range, creatinine ≥1.5

There are no sex, race, or ethnicity restrictions for this study.
C: Inclusion Criteria:

* juvenile idiopathic arthritis
* arthritis lasting for at least 6 weeks but not more than 6 months
* polyarticular disease with at least 5 active joints with at least 3 joints with pain or tenderness and limitation of motion
* no previous treatment with DMARDs

Exclusion Criteria:

* systemic JIA
* any abnormality in the hematopoietic or lymphatic system
* any major concurrent medical condition
* inadequate psychosocial situation
* pregnancy
* a non-abstinent female with reproductive capacity without regular contraceptive use
D: Inclusion Criteria:

1. Active uveitis associated with juvenile idiopathic arthritis, with the exclusion of systemic JIA, juvenile-onset rheumatoid arthritis, and enthesitis-related JIA
2. Uveitis resistant to well conducted topical steroid therapy comprising either dexamethasone or rimexolone at a dose adapted to the patient's situation as validated by one of the investigating ophthalmologists.
3. Failure of systemic treatment with methotrexate at a dose of 0.3 to 0.6 mg.kg (without exceeding 25 mg) once a week for at least 3 months (except in the case of methotrexate intolerance).
4. Patient who can be evaluated by laser flare photometry.
5. Patient at least 4 years old on initiation of trial medication and weighing a minimum of 15 kg
6. Signed informed consent both parents and/or patient's agreement
7. Patient has a social security or similar

Exclusion Criteria:

1. Systemic JIA, juvenile-onset rheumatoid arthritis, enthesitis-related JIA (with a risk of red eye uveitis).
2. History of treatment with anti-TNF alpha monoclonal antibody (either adalimumab or infliximab).
3. Any contraindication to administration of immunosuppressive therapy (immune deficit, opportunistic infection, other severe chronic disease)

   * History of cancer or lymphoproliferative disease other than successfully and completely resected squamous cell or basal cell skin cancer,
   * Any uncontrolled disease: unstable diabetes with documented history of recurrent infections, unstable ischaemic heart disease, moderate to severe heart failure (NYHA stage III/IV), recent stroke and any other disease or condition inducing, in the investigator's opinion, a risk for the patient related to his/her participation in the trial,
   * Positive hepatitis B or C serology indicating active infection,
   * History of positive HIV serology,
   * Persistent infection or severe infections requiring hospitalisation or IV antibiotic therapy during the 30 days prior to inclusion in the trial or oral antibiotic therapy during the 14 days prior to inclusion in the trial,
   * History of clinically significant alcohol or other substance abuse during the previous year,
   * Previous diagnosis or signs of demyelinating disease of the central nervous system,
   * History of active tuberculosis, histoplasmosis or listeriosis,
   * Signs of latent tuberculosis (based on a history of nontreated contamination, or an opacity greater than 1 cm on chest x-ray, or a positive intradermal reaction to 5 IU of tuberculin ≥ 5 mm).
   * Negative urine pregnancy test in girls with childbearing potential
4. Chronic rupture of the blood-aqueous barrier with marked flare on the initial examination but not modified by one month of anti-inflammatory therapy.
5. Impossibility to monitor flare:

   * Children \< 4 years
   * False flare due to the presence of giant cells on the surface of an artificial lens or in an aphakic child.
6. Children presenting complications such as refractory glaucoma or cataract rapidly requiring surgery.
7. Phthisis bulbi with hypotonia and atrophy of the ciliary body.
8. Any other situation raising problems for maintenance of stable doses of steroids and immunosuppressive drugs during the period between 4 weeks before D0 and the M2 evaluation. Authorized immunosuppressive therapies that must be maintained at stable dose are steroid eye drops, systemic steroid therapy and once weekly oral or subcutaneous MTX at a dose of 0.3 to 0.6 mg (without exceeding 25 mg).
9. Any ophthalmologic contraindication
10. If female and childbearing potential should have an appropriate contraceptive method during all study period and 5 months after last adalimumab dose. Abstinence with no oral contraception can be considered.

Answer: C