Management of Juvenile Idiopathic Arthritis

Name

Etanercept

Infliximab

Adalimumab

Chemical content

Fully humanized

Mouse chimeric

Fully humanized

Chemical structure

P-75 soluble TNF receptor protein fused to human Fc region of human IgG₁

Chimeric IgG₁ Anti-TNF alpha antibodies – mouse antibodies and constant region of human antibody

Recombinant human IgG₁ monoclonal antibody

Binds to

Soluble TNF alpha

Soluble TNF alpha and membrane-bound TNF alpha

Half-life

4 days

Weeks

2 weeks

Route

Subcutaneous

Intravenous (IV)

Subcutaneous

Dose

0.4 mg/kg/dose/twice weekly or 0.8 mg/kg once weekly

3–6 mg/kg/dose

24 mg/m²

Frequency

Biweekly or weekly

As 0, 2, 6 weeks and then every 8 weeks

Every 2 weeks

Methotrexate use

Optional

Recommended (to prevent anti-infliximab antibodies)

Optional

Risk of tuberculosis

T-cell co-stimulatory blockade: A selective T-cell co-stimulation modulator abatacept has been shown to be very effective in children with polyarticular JIA both in the short term and long term, up to 21 months [33, 34]. The 2011 ACR guidelines suggest it be used in poly-JIA patients refractory to anti-TNF agents [5].

Anti-IL 1 agents: There are several agents: anakinra, rilonacept and canakinumab. These agents have a role only for the child with SJIA and SJIA with macrophage activation syndrome (MAS). Anakinra is used as a daily subcutaneous injection and is rapidly effective for the systemic features with a slower response for the articular complaints [5, 35].

Anti-IL 6: Tocilizumab, an IL 6 blocker, is useful in both SJIA and PJIA. This drug has not been mentioned in the ACR guidelines of 2011 as it had not received FDA approval at the time. It is very effective, is safe and has a rapid onset of action [5, 36, 37].

B-cell blockade: The anti-CD 20 molecule rituximab is very effective in adult rheumatoid arthritis. There is no class I evidence for its use in JIA; however, there are recent reports of the effectiveness of rituximab in both PJIA and SJIA which need to be replicated in other centres [38, 39].

Biosimilars

These are generic biological drugs intended to have the same efficacy as the innovator and are being used in many countries due to their low cost. However, as these are high molecular weight proteins with complex structures and produced in biological systems, they are different from chemical generic compounds. Minor differences in post-translational modifications (e.g. glycosylation, deamidation), microheterogeneity (difference in charge), etc., may lead to difference in pharmacokinetics, pharmacodynamics, efficacy and immunogenicity [40]. Thus, they need trials to determine their efficacy and immunogenicity.

CTP13 is the first US FDA-approved biosimilar in rheumatology. It has been proven to have similar pharmacokinetic profile, TNF neutralization capacity and complement dependent cytotoxicity as the innovator infliximab (Remicade). The Phase 1 trial [PLANETAS] with 250 patients (125 in study and 125 in Remicade reference product arm) showed similar efficacy and toxicity including immunogenicity [41]. The PLANETRA phase 3 study with 606 patients also showed similar results [42]. No trial of biosimilars is available for children with JIA. In India multiple biosimilars are available but rigorous well-planned studies are lacking. Their clear role as regards switching from innovator to biosimilar, use as substitutes as is done for usual drugs is still to be determined.

Standard Guidelines for JIA Management

There are several recently published guidelines that will be briefly reviewed: the ACR guidelines of 2011 [5], the revised ACR guidelines of 2103 [35], the CARRA recommendations of 2015 [43] and the NHS guidelines of 2015 [44].

ACR Guidelines for JIA Management

The ACR has chosen to describe the pathways of care for five groups of children: oligo disease, poly disease, SJIA with systemic features, SJIA with articular disease and finally the child with axial disease [5]. Each category has defined prognostic features and low, moderate and high level of disease activity. The pathways for disease management in each category of disease vary per the prognostic features and burden of disease. The key points that have not been covered in the ACR recommendations are:

The indications for systemic glucocorticoids for the treatment of synovitis were not considered, owing to a lack of published evidence.
The treatment of uveitis, enthesitis and macrophage activation syndrome was not considered.
The role of folic acid and the weaning of methotrexate/biologic response modifiers/abnormal liver function tests have not been discussed [45].

The therapies are heavily weighted to the developed world as there is a strong emphasis on the use of biologics which is not the reality in most parts of the world. The reader is referred to the paper by Beukelman et al [5] for a detailed study. Of note, the cost of BRMs for a 30 kg child in India such as etanercept or infliximab is about 6000 USD per annum, an amount unaffordable by the vast majority of families who self-pay for the medication.

The ACR 2013 Modifications of the 2011 Guidelines

[36] Addressed the newer agents available for management of SJIA since the publication of the 2011 guidelines. It discusses three options for the management:

SJIA with active systemic features and varying arthritis: the therapeutic arms suggested were anakinra or glucocorticoid monotherapy (for mild disease use NSAIDs). Therapy was stepped up to sequential anti-IL 1 agents or tocilizumab if the disease continued. Calcinuerin inhibitors were suggested only after sequential failure of both agents. Methotrexate and intra-articular steroids could be added to any arm.
SJIA without active systemic features but with active synovitis: the upfront use of methotrexate or leflunomide was suggested and stepping up to abatacept, 1 L 6/IL1 blocker as needed.
SJIA with features of MAS: For this subgroup systemic glucocorticoids, anakinra and calcinuerin inhibitors were recommended either sequentially or in combination.

CARRA Recommendations 2014 [43]

Childhood Arthritis and Rheumatology Research Alliance (CARRA), a group of North American Pediatric Rheumatologists, developed standardized consensus-driven treatment plans for JIA in 2014. These consensus treatment plans are for all children with JIA with more than five joints involved except for the child with SJIA and include any of the three pathways of care:

Step-up plan: Conventional DMARD followed by BRM similar to the ACR recommendations [5]
Upfront methotrexate and BRM arm similar to the TREAT aggressive treatment arm (methotrexate + prednisolone + TNFi) or the ACUTE study (methotrexate + TNFi) arm [11, 12]
Upfront BRM

The poor prognostic markers identified by the CARRA were one or more of the following: positive Rheumatoid factor (Rf), positive anti-cyclic citrullinated peptide (CCP), arthritis of the hip or cervical spine or radiographic damage. Of note, steroids ranging from intravenous pulse to oral steroids at varying doses are allowed, with the aim that the patient should be off steroid at 3 months from the initiation of therapy.

Biologic Therapies for the Treatment of Juvenile Idiopathic Arthritis (NHS England, E03/PS/a). https://www.engage.england.nhs.uk/consultation/specialised-services-policies/user_uploads/biolgcs-juvenl-idiop-arthrs-pol.pdf [44]

This is a practical and easy-to-use guide available at the web address detailed above. It addresses the use of IV methylprednisolone in the child with aggressive disease and separates out the treatment conveniently into two groups only: OJIA and others. The oligo patient is treated with IAS; if the joints extend to five or more or more than two injections are needed in 12 months or the disease is erosive, the patient is started on methotrexate. For all other subtypes, either IAS or IV steroid is used to induce remission, and methotrexate is used upfront at a dose of 15 mg/m²/week by the subcutaneous route. If the child flares, therapy is stepped up to anti-TNF agents, at least two are tried sequentially at an interval of 3 months. Failing this the alternative BRMs such as tocilizumab, abatacept or rituximab are used. The two exceptions quoted are SJIA with MAS resistant to steroids where anakinra is used and patients with sacroiliitis where anti-TNFi is used upfront.

The above discussion of well-established institutions putting forth somewhat different recommendations for various types of JIA further amplifies the lack of consensus in management.

The Therapeutic Pathways

Synthesizing the data above, the general rules of treatment for each subtype are as follows:

I.

Oligoarticular juvenile idiopathic arthritis (OJIA): Is managed with an NSAID for mild disease, stepping up to intra-articular steroid (IAS) if the child does not respond/has a deformity/has a joint involvement which is a poor prognostic indicator, e.g. the wrist or the ankle. There is a menu choice for the use of NSAIDs; a comparative study that assessed the efficacy of meloxicam and naproxen showed both drugs to be equally effective [46]. Phase IV registry data from the USA showed that naproxen, meloxicam and nabumetone are the most frequently used nonselective NSAIDs and celecoxib is the most commonly used selective NSAID. The safety profile was similar for both nonselective NSAIDs and celecoxib [47]. It has been shown that the early and continued use of intra-articular steroid in young children with OJIA involving the lower extremity may be associated with less leg length discrepancy, probably by decreasing the duration of synovitis. The preferred steroid is triamcinolone hexacetonide (TA), and the duration of remission is longer in the joints of the upper extremity, with concomitant treatment with methotrexate and when the injection was performed under general anaesthesia joint. When repeated IAS injections are needed because of a short efficacy or the patient does not go into clinical remission in 4 months, the therapy is stepped up to methotrexate [5, 48, 49]. The ACR does recommend the upfront use of methotrexate in this subcategory when the disease activity is high and the patient has features of poor prognosis [5].
II.

PJIA: The management options discussed in this section are used for all subcategories of children with JIA with more than four joints involved except for the child with SJIA. The child is started in the very mild case on an NSAID, stepped up quickly to methotrexate and bridging steroids. The latter is the combination used in all but the very mild patient. IAS may be used for the joint with persistent synovitis. An alternative to methotrexate is leflunomide which is effective but is usually reserved only for the child intolerant to methotrexate [5]. If the child has not attained remission in 3–6 months of treatment, it is important to step up to a biologic which in the first instance would be a TNF inhibitor; with failure of one or two TNF blockers, the choice would be abatacept [5, 15, 34]. The TREAT trial suggests that early therapy with a combination of etanercept and methotrexate maybe better as compared to methotrexate alone in children with polyarticular JIA [50]. Adalimumab has been recently approved by the US FDA for use in polyarticular JIA patients older than 4 years of age [51]. A recently concluded clinical trial using golimumab in children with polyarticular JIA failed to meet the primary end point and has not received a licence from the US FDA (ClinicalTrials.gov Identifier:NCT01230827). More recently, a double-blind withdrawal study (CHERISH) has shown that tocilizumab is highly effective in PJIA patients with 45 % of children achieving an ACR 90 at the end of 16 weeks [52]. Newer drugs for treatment of PJIA include rituximab, certolizumab, ustekinumab and tofacitinib. Most of these are under trail [53]. The ACR recommendations do not discuss the use of systemic steroids or combination non-biological DMARDS which is not uncommon in patients who do not respond to methotrexate alone in a resource-constrained setting because of lack of affordability of the biologic response modifiers [54].
III.

Enthesitis-related arthritis (ERA): There are several clinical components of this disease: peripheral arthritis, enthesitis, arthritis of the hip joint, axial involvement and extra-articular features, most commonly acute anterior uveitis. The treatment depends on the components of disease present in the child. For sacroiliitis the preferred choice is a regular NSAID; if the child does not show a rapid improvement in 10–12 weeks, TNF blockade should be started. With peripheral disease sulphasalazine, methotrexate or IAS may be used. Anti-TNF agents (etanercept and adalimumab) are better suited for patients with axial disease, arthritis and enthesitis [55]. TNF blockers are effective but their withdrawal may not be possible. Recurrent anterior uveitis may benefit with DMARDS as well. For enthesitis, especially of the foot, use of proper shoes can give symptom relief. Local steroids may give good short-term benefit. Recalcitrant enthesitis often needs sustained NSAID or TNF blockade [5, 56]. Most patients with a JIA subtype other than the systemic onset respond well to TNF alpha inhibitors and methotrexate [57].
IV.

Systemic onset juvenile arthritis (SJIA): This is a subcategory of JIA where the systemic features are often troublesome in the early years after the disease onset, and the arthritis may manifest a few weeks or months in the course of the disease. The standard treatment for the systemic features has been NSAIDs/steroids for the systemic features with methotrexate for the arthritis. The ACR recommendations and also a new consensus guideline by the CARRA network have focused heavily on the use of anakinra [5] and tocilizumab [58] for the treatment of the child with SJIA. In a study published in 2015, it was observed that patients who were treated with IL1 antagonists early in the disease course attained inactive disease in a shorter time as compared to the children who were given anti-TNF alpha agents as a first-line biologic [59]. Most children with SJIA respond well to IL-1 and IL-6 inhibitors [57]. Two more anti-IL1 agents have been tried, canakinumab and rilonacept. Canakinumab is a fully human, anti-interleukin-1β monoclonal antibody that in two trials has been proven to be rapidly effective [1]. While canakinumab was approved by the US FDA in 2013, rilonacept is reserved for cases refractory to the other IL 1 antagonists and in cases with active arthritis [35, 60]. A recent review has concluded that canakinumab and tocilizumab are more effective than rilonacept for the management of SJIA [61].
V.

Uveitis associated with JIA: Chronic silent anterior uveitis is most common in young children with JIA when the ANA is positive; these patients are therefore electively screened every 3 months by the ophthalmologist. Topical steroids and mydriatics are used along with methotrexate to achieve an adequate control of the eye inflammation. In children who do not respond, the therapy is stepped up to BRMs. An attempt should be made to keep the steroid drop installation in the eyes to less than two drops per day as the risk of cataract is minimized with this strategy [62–64]. For refractory uveitis associated with JIA, trials have shown that adalimumab has better results as compared to infliximab followed by etanercept. The role of etanercept is controversial and it is currently avoided in children with uveitis [65]. In addition to reducing the eye inflammation, adalimumab helps in the reduction of associated comorbidities due to immunosuppression caused by steroids [66]. TNF inhibitors are often used in more severe disease as their use was seen in patients who were ANA positive and had cataract formation [67].

These treatment pathways have been summarized in the flow charts (Chart 1–4).

Duration of Therapy

Most centres would use the therapy for about 12 months until the patient has remained in remission and then gradually withdraw treatment [17]. This will change, as it has been recently documented in a randomized controlled trial that in patients with JIA in remission, a 12-month vs. 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations, a biomarker of subclinical inflammation, were associated with risk of relapse after discontinuing methotrexate. Maximum flares after withdrawal occurred within the first 6 months, with only a few occurring later than 12 months after stopping therapy [68, 69]. Additionally, when a patient is on combination therapy with methotrexate and a TNFi, and the medications are withdrawn, withdrawal of the TNFi before methotrexate is associated with a much higher risk of flare (89 % vs. 12 %, p < 0.0005) than if the withdrawal is vice versa [28]. This however is very difficult in a country with resource constraints where TNFi is often used for a short while and methotrexate is given for the long term.

Long-Term Care and Issues Faced

The child with JIA needs a competent multidisciplinary team to guide the short- and long-term management. In addition to strict disease control (both articular and non-articular), it is important that generic issues be addressed regularly: growth, puberty, bone health, vocation and finally transition to the adult team when appropriate. Only one invasive cancer was identified in a large sample of individuals with JIA (1834 patients), observed for an average of 12.2 years each. These data suggest that, at least in the initial years following diagnosis of JIA, the risk of invasive cancers overall is not markedly increased [70].

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