Table 3. Summary of recommendations for pharmacological interventions in JIA based on included CPGs.
N.B. This is meant as a summary of the recommendations only. Please refer to the official CPGs before providing treatment to patients.
| ACR 2011 & 2013 [29,30] | GKJR 2012 [27] | RACGP 2009 [28] | ||||
|---|---|---|---|---|---|---|
| Recommend: Yes/No/Unsure (Grade) | Details | Recommend: Yes/No/Unsure (Grade) | Details | Recommend: Yes/No/Unsure (Grade) | Details | |
| NSAIDs | ||||||
| Celecoxib | Yes (Grade B-C, level I) | not been approved in children; use if diclofenac, naproxen, ibuprofen and indomethacin are contraindicated | 2–4 mg/kg b.i.d. | |||
| Diclofenac | Yes (Grade A, level I) | ≥14 years old | 1 mg/kg b.i.d. | |||
| Ibuprofen | Yes (Grade A, level I) | ≥6 months; treat pain, fever | 10 mg/kg 3–4 times daily | |||
| Indomethacin | Yes (Grade A, level II) | ≥2 years old | 0.5–1.0 2–3 times daily | |||
| Meloxicam | No (Level II) | ≥15 years old; recommendation grade not given | 0.15–0.30 mg/kg o.d. | |||
| Naproxen | Yes (Grade A, level I) | ≥1 year old | 5–7.5 mg/kg b.i.d. | |||
| Piroxicam | 0.2–0.4 mg/kg o.d. | |||||
| NSAID monotherapy | 1) Hx ≤4 joints: Yes (Level B); 2) Hx ≥5 joints: Yes (Level C); 3) sJIA active systemic features (no active arthritis): Unsure/No (Level D); 4) sJIA, active arthritis (no active systemic features): Yes (Level B) | 1) with GC injections; for low disease activity (DA), no joint contracture, no features of poor prognosis (FPP); 2) without GC injections uncertain if active arthritis; do not continue >2 months if active arthritis; 3) appropriate before diagnosis and evaluating systemic arthritis, uncertain if active fever–inappropriate when fever and MD global ≥7/10; initial Tx if MD global <5 + any AJC; inappropriate if MD global ≥5 + AJC >0; inappropriate to continue Tx >1 month if DA continued; 4) initiate if low DA without FPP (with/without GC injections); uncertain to continue >1 month for any DA level (Level D); if no previous Tx for 1 month max if AJC >0 (Level D); inappropriate for >2 months if continued disease activity (Level D) | Yes (Grade B) | Initial drug of choice to reduce pain and inflammation; see RACGP 2009 for details on dosing of specific NSAIDs | ||
| Topical NSAIDs | No (Grade D) | No studies available | ||||
| Steroids | ||||||
| Glucocorticoid (intra-articular injection) | 1) Hx ≤4 joints: Yes (Level C); should show improvement for initial 4 months (Level A); 3) sJIA active systemic features (no active arthritis): Yes (Level C); 4) sJIA, active arthritis (no active systemic features): Yes (Level C) | 1) any pt active arthritis, any disease level, prognostic features, or joint contracture; 3) can consider adding it any time during treatment; 4) initial Tx if AJC ≤4; uncertain as monotherapy if AJC >4; unsure about repeat injections as only Tx for ≥1 joint | Yes (Grade B, level I) | Triamcinolone hexacetonide; possible as part of first line Tx; triamcinolone hexacetonide preferred over triamcinolone acetonide due to efficacy | ||
| Glucocorticoid (systemic) | 3) sJIA active systemic features (no active arthritis): Yes (Level D); 5) sJIA with features concerning for MAS: Yes (Level C) | 3) initial Tx active fever and MD global ≥7; initiate after ≤2 wks for all pts with active fever (Level C); no published data on doses and routes; initial monotherapy (oral or IV) up to 2 weeks max when MD global <5 + AJC >4 OR MD global ≥5 (Level C); inappropriate to continue GC monotherapy ≥1 month if DA continues (Level D); continued disease Tx after NSAID monotherapy failed when MD global <5 + AJC >0 OR MD global ≥5 (Level C); can consider adding GC treatment any time (Level D); 5) GC monotherapy ≥2 weeks is inappropriate when continued features concerning MAS (Level D) | Yes (Grade A, level III) | For highly AD; for pts with sJIA, complications (uveitis, pericardial effusion), RF-positive JIA; use while waiting for therapeutic effect of DMARD Tx to be complete; not recommended for long-term use; not recommended to continuously give 0.2 mg/kg of a prednisolone equivalent to pts | ||
| Prednisolone/prednisone | Yes (Level III) | for severe sJIA; can be used as oral medium- or high-dose Tx; can also be used as IV pulse Tx; recommendation grade not given | ||||
| DMARDs | ||||||
| Azathioprine | (Level II) | not been approved in children; 1.5–3 mg/kg per day orally in 1–2 doses | ||||
| Leflunomide | 1) Hx ≤4 joints: Unsure; 2) Hx ≥5 joints: Yes (Level B); 3) sJIA active systemic features (no active arthritis): Yes (varies); 4) sJIA, active arthritis (no active systemic features): Yes (Level C); 5) sJIA with features concerning for MAS: No (Level D) | 2) initial Tx when high DA and FPP; use after trial of NSAIDs for high DA and no FPP; 3) for continued disease Tx if MD global <5 + AJC >0 after GC monotherapy (Level C), an IL-inhibitor (Level D), or tocilizumab (Level D); if MD global ≥5 + AJC >0 after trial of IL-1 inhibitor/tocilizumab (Level C); inappropriate if AJC = 0 + any MD global (Level D); 4) initial Tx when AJC >4; continued disease Tx if AJC >0 after intraarticular injection (level C), NSAID monotherapy (Level C), an IL-1 inhibitor (Level D), or tocilizumab (Level D) | Yes (Grade B, level II) | Use only if MTX/etanercept insufficient at treating disease; not been approved in children | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| Methotrexate | 1) Hx ≤4 joints: Yes (Level C); 2) Hx ≥5 joints: Yes (Level B); 3) sJIA active systemic features (no active arthritis): No (Level B); 4) sJIA, active arthritis (no active systemic features): Yes (Level B); 5) sJIA with features concerning for MAS: No (Level D) | 1) Initial Tx if high DA and FPP; start after GC injections if moderate/high DA but no poor prognosis; 2) Initial Tx if moderate/high DA and FPP; initial 1 month after NSAIDs when low DA and FPP; initiate 1–2 months after NSAIDs when moderate DA but no FPP; 3) for initial management active fever without active arthritis; for continued disease Tx if MD global <5 + AJC >0 after GC monotherapy (Level C), an IL-inhibitor (Level D), or tocilizumab (Level D); if MD global ≥5 + AJC >0 after trial of IL-1 inhibitor/tocilizumab (Level C); inappropriate if AJC = 0 + any MD global (Level D); 4) if active arthritis ≤1 month after NSAID monotherapy (with/without GC injections); initial Tx when AJC >4 (Level C); continued disease Tx if AJC >0 after intraarticular injection (level C), NSAID monotherapy (Level C), an IL-1 inhibitor (Level D), or tocilizumab (Level D) | Yes (Grade A, level I) | If NSAIDs and/or GC injections ineffective; use when continuously need systemic GCs OR if high DA; 10–15 mg/m2 oral/SC; ≥ 2 years old; for poly-JIA, psoriatic JIA, uveitis, collagenosis | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| Sulfasalazine | 1) Hx ≤4 joints: Yes (Level B); 2) Hx ≥5 joints: Unsure | 1) after GC injection or NSAIDs with moderate/high DA; for enthesitis-related JIA; uncertain for other JIA onset types; 2) for Tx initiation | Yes (Grade B, level II) | Use if MTX/etanercept insufficient | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| Nonbiologic DMARD combinations | 1) Hx ≤4 joints: Unsure; 2) Hx ≥5 joints: Unsure; 3) sJIA active systemic features (no active arthritis): Unsure; 4) sJIA, active arthritis (no active systemic features): Unsure | 1) MTX + sulfasalazine and/or hydroxychloroquine; 2) MTX + sulfasalazine and/or hydroxychloroquine; 3) MTX + leflunomide and/or a calcineurin inhibitor) for any AJC or MD global; 4) initiation of a combination (MTX + leflunomide and/or a calcineurin inhibitor) at any AJC | ||||
| Biologics | ||||||
| Abatacept | 1) Hx ≤4 joints: Unsure; 2) Hx ≥5 joints: Yes (Level B); 3) sJIA active systemic features (no active arthritis): Yes (Level D); 4) sJIA, active arthritis (no active systemic features): Yes (Level B); 5) sJIA with features concerning for MAS: No (Level D) | 1) unsure before starting TNFα inhibitor; 2) after 4 months TNFα inhibitor when moderate/high DA and FPP; start after receiving >1 TNFα inhibitor sequentially when moderate/severe DA with FPP; 3) if MD global ≥5 + AJC >4 after trying an IL-1 inhibitor and tocilizumab sequentially; inappropriate when AJC = 0, except if pt tried IL-1 inhibitor and tocilizumab sequentially (unsure); inappropriate if MD global <5 + AJC >0 OR MD global ≥5 + AJC <4 (Level D); appropriate only if had IL-1 inhibitor and tocilizumab sequentially (Level D); unsure if pt tried DMARD + IL-1 inhibitor/tocilizumab; 4) start if received MTX and TNFα inhibitor & has high DA OR moderate DA with poor prognosis; continued disease Tx if AJC >0 after MTX/leflunomide (Level B), anakinra (Level D), or tocilizumab (Level D); 5) not for initiation | Yes (Grade C, level III) | ≥ 6 years old; for pts with poly-JIA (non-systemic) when unresponsive MTX and TNFα inhibitors | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| Anakinra | 2) Hx ≥5 joints: Unsure; 3) sJIA active systemic features (no active arthritis): Yes (Level C); 4) sJIA, active arthritis (no active systemic features): Yes (Level C); 5) sJIA with features concerning for MAS: Yes (Level C) | 3) start if active fever and FPP regardless of intervention currently taken; for all patients who still have/develop active fever with GCs; initial Tx if MD global <5 + AJC >4 OR if MD global ≥5; for continued disease Tx after GC monotherapy (Level A) OR NSAID monotherapy (Level C); 4) start in pts who were given MTX and have moderate/high DA; if Tx with MTX + TNFα inhibitor OR MTX + abatacept in pts with moderate/high DA; inappropriate to initiate anakinra later in disease course–better earlier on; continued disease Tx if AJC >4 after GC injection OR NSAID monotherapy failed (Level B) OR if AJC >0 after Tx of MTX/leflunomide | Yes (Grade A, level II) | Not been approved in children; ≥ 2 years old; for refractory sJIA | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| Canakinumab | 3) sJIA active systemic features (no active arthritis): Yes (Level C); 4) sJIA, active arthritis (no active systemic features): Yes (Level C); 5) sJIA with features concerning for MAS: Unsure (Level D) | 3) continued disease Tx after GC monotherapy (Level A), MTX/leflunomide (Level A), anakinra (Level B), or tocilizumab (Level C); use if MD global ≥5 + any AJC even if had previous NSAID monotherapy (Level C); 4) continued disease Tx–start if AJC >4 after trial of DMARD + anakinra/ tocilizumab (Level B), a DMARD + TNFα inhibitor (Level B), or abatacept (Level C); 5) becomes inappropriate when MD global <5 and no prior intervention, GC monotherapy, or calcineurin monotherapy (Level D) | Not assessed | GPs to refer patient to pediatric rheumatology specialist | ||
| Calcineurin inhibitor | 3) sJIA active systemic features (no active arthritis): Yes (Level C) | 3) continued disease Tx only if MD global ≥5 + AJC = 0 after trial of IL-1 inhibitor + tocilizumab sequentially; inappropriate if MD global <5 + AJC = 0 (Level D), but unsure if pt tried IL-1 inhibitor + tocilizumab sequentially OR another DMARD + IL-1 inhibitor/tocilizumab | Not assessed | GPs to refer patient to pediatric rheumatology specialist | ||
| Etanercept | Yes (Grade A, level I) | ≥ 4 years old; for polyarticular JIA | Not assessed | GPs to refer patient to pediatric rheumatology specialist | ||
| Rilanocept | 3) sJIA active systemic features (no active arthritis): Unsure; 4) sJIA, active arthritis (no active systemic features): Unsure; 5) sJIA with features concerning for MAS: Unsure | 3) inappropriate as initial Tx (Level D); unsure if continued DA after trying other Tx options; 4) any AJC | Not been approved in children with JIA 12 years old?? | Not assessed | GPs to refer patient to pediatric rheumatology specialist | |
| Rituximab | 2) Hx ≥5 joints: Yes (Level C); 3) sJIA active systemic features (no active arthritis): Varies; 4) sJIA, active arthritis (no active systemic features): No (Level D); 5) sJIA with features concerning for MAS: inappropriate (Level D) | 2) start after TNFα inhibitor and abatacept in a row when high DA OR moderate DA and FPP; may be better for RF-positive vs. negative pts (informal recommendation); 3) inappropriate when AJC = 0 + any MD global; inappropriate when MD global <5 + AJC <4 (Level D), but unsure if pt tried both IL-1 inhibitor and tocilizumab sequentially; inappropriate if MD global <5 + AJC >4 OR MD global ≥5 + AJC >0, but unsure if pt tried IL-1 inhibitor and tocilizumab sequentially OR a DMARD + IL-1 inhibitor/tocilizumab; 4) AJC ≤4, but unsure if pt tried IL-1 inhibitor and tocilizumab sequentially OR a DMARD + IL-1 inhibitor/tocilizumab; inappropriate if AJC >4, but unsure if pt tried both IL-1 inhibitor + tocilizumab sequentially OR a DMARD + IL-1 inhibitor, tocilizumab, a TNFα inhibitor, or abatacept | Not assessed | GPs to refer patient to pediatric rheumatology specialist | ||
| Tocilizumab | 3) sJIA active systemic features (no active arthritis): Yes (varies); 4) sJIA, active arthritis (no active systemic features): Yes (Level B); 5) sJIA with features concerning for MAS: Unsure | 3) continued DA after GC monotherapy (Level A), MTX/leflunomide (Level B), or anakinra (Level B) for any MD global or AJC; if MD global ≥5 + any AJC regardless if prior NSAID monotherapy (Level C); 4) continued disease Tx when AJC >0 after anakinra OR MTX/leflunomide | Yes (Grade A, level II) | ≥ 2 years old; for refractory sJIA | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| TNF alpha inhibitors | 1) Hx ≤4 joints: Yes (Level C); 2) Hx ≥5 joints: Yes (Level B); 3) sJIA active systemic features (no active arthritis): not assessed in ACR 2011 –Yes in ACR 2013 (Level C); 4) sJIA, active arthritis (no active systemic features): Yes (Level B); 6) active sacroiliac arthritis: Yes (Level C) | 1) after GC injections and 3 months of max tolerated dose MTX when high DA and FPP; after GC injections + 6 months MTX when high DA and no FPP; enthesitis-related JIA pts with GC injections and sulfasalazine trial (without MTX before) and moderate/high DA; 2) after 3 months of max tolerated dose MTX/leflunomide when moderate/high DA; after 6 months MTX/leflunomide when low DA; switch TNFα inhibitor after 4 months if moderate/high DA (Level C); switch to a TNFα inhibitor if receiving abatacept for 3 months and high DA with FPP, OR 6 months of abatacept and moderate/high DA (any FPP) (Level D); 3) ACR 2011: not effective for Tx active systemic features; continued disease Tx–start if AJC >4 + any MD global after trial of IL-1 inhibitor/tocilizumab; if AJC >0 + any MD global after trial IL-1 inhibitor + tocilizumab sequentially; inappropriate if MD global <5 + AJC = 0 (Level D), but unsure if tried IL-1 inhibitor + tocilizumab sequentially OR DMARD + IL-1 inhibitor/tocilizumab; inappropriate if MD global ≥5 + AJC = 0 (Level D), but unsure if pt tried IL-1 inhibitor/tocilizumab; 4) concomitant Tx of MTX 3 months when moderate/high DA; may need to switch anakinra to TNFα inhibitor when moderate/high DA–risk is latent systemic DA may be revealed (Level D); continued active Tx–start if AJC >0 after MTX/leflunomide (Level C), anakinra (Level D), or tocilizumab (Level D); 6) after NSAIDs trial when high DA and FPP; after 3 months MTX when moderate/high DA OR moderate DA and FPP, OR after 6 months MTX when moderate DA without FPP; if 3 months sulfasalazine when moderate/high DA, OR 6 months sulfasalazine when low DA without FPP; inappropriate for any MD global (Level D), but unsure when calcineurin inhibitor + anakinra | Yes (Grade A, level I) | if not enough response to NSAIDs and GC injections OR if no response to MTX; for poly-JIA | Not assessed | GPs to refer patient to pediatric rheumatology specialist |
| Other | ||||||
| Hydroxychloroquine monotherapy** | 1) Hx ≤4 joints: No (Level C); 2) Hx ≥5 joints: inappropriate (Level A) | 1) inappropriate for active arthritis; with/without concurrent NSAID Tx; 2) inappropriate to start for active arthritis; with/without concurrent NSAID Tx | Not assessed | Clinical trials revealed limited efficacy | ||
| Autologus stem cell transplantation (SCT) | Level III | Only as a last resort because of serious adverse events | ||||
| Simple analgesics | Yes (Grade C) | Use paracetamol; varies by body mass; seek medical advice for use >48 hours; use as short-term Tx | ||||
| Weak opioids | Yes (Grade D) | Codeine is weak opioid of choice; prescribe with paracetamol for moderate pain of articulations; varies by body mass; seek medical advice for use >48 hours | ||||
| Intravenous immune-globulin (IVIG) | 3) sJIA active systemic features (no active arthritis): inappropriate (Level D); 5) sJIA with features concerning for MAS: inappropriate (Level D) | 3) any AJC or MD global; 5) unsure if pt tried a calcineurin inhibitor + anakinra | ||||
| Comple- mentary and alternative medicines (CAM) | Unsure (Grade D) | Ask pt/parents about use of CAM and possibly inform that no RCTs or systematic reviews available in children; low risk intervention, but interactions with medications a concern | ||||
DMARDs = disease-modifying antirheumatic drugs; NSAIDs = non-steroidal anti-inflammatory drugs; MTX = methotrexate; GC = glucocorticoid
Hx = history; DA = disease activity; FPP = features of poor prognosis (see ACR 2011 & 2013 for detailed description); AJC = active joint count; MD global = physician global assessment (10-point numeric rating scale); SC = subcutaneous; b.i.d. = twice daily; o.d. = once daily; pt = patient
oligo-JIA = oligoarticular JIA; poly-JIA = polyarticular JIA; sJIA = systemic JIA