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Medications to Treat Inflammatory Disease

Non-steroidal anti-inflammatory drugs (NSAIDs) can relieve symptoms but are not disease modifying in Juvenile Idiopathic Arthritis (JIA); there are concerns about long term risk (including renal and cardiovascular disease).

  • Sugar-free preparations help to reduce risk of dental caries. 
  • NSAIDs act by inhibiting enzymes (cyclo-oxygenase-1 (COX-1) and COX-2) involved in prostaglandin synthesis resulting in analgesic, anti-inflammatory, and antipyretic effects. 
  • There are two broad groups of NSAIDs—the older, traditional, non-selective NSAIDs (e.g. ibuprofen, naproxen, aspirin) that inhibit both COX-1 and COX-2 and the newer, selective COX-2 inhibitors that predominantly inhibit COX-2 (e.g. celecoxib). The clinical effects of NSAIDs depend largely on their selectivity for these enzymes. The non-selective group acting widely resulting in varying degrees of analgesic, anti-inflammatory and anti-pyretic and anti-platelet effects, where as the selective group has less gastrointestinal tract side effects. 

Corticosteroids are potent immunosuppressants but their use is limited by troublesome side-effects (weight gain, growth retardation, osteoporosis and cataracts) and the risk of adrenal suppression.  

  • Administration is given by oral, intra-articular, intravenous, intramuscular and topical routes (for eyes).
  • If a child is taking oral corticosteroids, optimizing dietary intake of calcium and vitamin D is important; the role of calcium and vitamin supplements to reduce the risk of osteoporosis is unclear. 
  • Intra-articular corticosteroids are highly effective, safe and is first-line treatment for oligo-articular JIA. Young children require sedation or anaesthetic for the procedure, although in the older child inhaled analgesia (e.g. nitrous oxide) may be used. 
  • Pulsed intravenous methylprednisolone is often used to induce remission at disease onset, during flares of polyarthritis or in those with features of systemic-onset JIA or multisystem disease, and is a useful bridging agent whilst starting MTX therapy. 
  • Topical corticosteroids (eye drops) treat uveitis although systemic immunosuppression (including MTX or biologics) are often used if uveitis does not respond to eye drops alone. Periocular injections can be given to control uveitis. 

Methotrexate (MTX) is the most widely used DMARD in the treatment of JIA and is often used in other inflammatory diseases.

  • The exact mechanism of action remains unclear. MTX needs to be monitored for side effects (cytopenia, abnormal liver function tests) but often nausea is the main problem.
  • Long term use of MTX (>30 years) demonstrates a good safety profile in JIA although there is the potential of long term unknowns including impact on fertility and malignancy risk.
  • MTX is slow to take effect (often 3 months) and often other measures (such as joint injections or Intravenous or oral steroids may be used as bridging agents); MTX is usually started immediately after the diagnosis is confirmed in all types of JIA other than oligoarticular JIA (joint injections are first line), although in the latter, MTX is used in oligoarthritis that is extending or failing to respond to intra-articular corticosteroids or a critical joint is affected (e.g. hip, wrist).
  • MTX is given once a week, by tablet or liquid, but the preferred route is by subcutaneous injection (which can be delivered and administered at home). 
  • Nausea (and mouth ulcers) are often the main reasons for stopping MTX or switching to other drugs including biologics. Strategies to minimise nausea involves omitting NSAIDs on the day of MTX administration, administering the drug on a weekend evening preceded by an anti-emetic and continuous low dose folic acid supplementation.
  • Other adverse effects (e.g  mild elevation of serum liver enzymes and mild bone marrow suppression are uncommon, often transient and related to intercurrent infection).
  • Serious complications, including malignancy and infertility, have not been reported to date. MTX is a teratogen so appropriate advice regarding contraception is needed.

Other DMARDs, including sulphasalazine, azathioprine, ciclosporin, leflunamide and thalidomide can be useful. The use of gold, penicillamine and hydroxychloroquine has dramatically reduced as they have been shown to be much less effective than MTX. Hydroxychloroquine may be useful in JSLE -especially to help skin disease). Sulphasalazine can be useful in oligoarticular JIA or enthesitis related arthritis. In the child with severe disease, who is resistant to or intolerant of MTX, biologic therapies are often used (see below) although for many parts of the world, access to these is very limited due to their high cost.

Biologic and novel therapies have been a major advance in the management of many inflammatory conditions in both adults and children.

  • They are called ‘cytokine modulators’ or ‘biologics’ and block selectively the effects of pro-inflammatory cytokines.
  • The Table below summarizes biologics used in JIA to date. Not all are licensed for use in children and there are guidelines for their use (see Resources). 
  • More agents are becoming available and there is a move towards 'treat to target' strategies to induce and maintain remission.
  • Many biologic therapies have dramatic impact on disease control and evidence shows sustained improvement with reduced joint damage in children with JIA who had failed MTX due to ongoing disease or intolerance (often nausea and vomiting).
  • Clinical trials are important to establish efficacy and safety but there are concerns about infection risk, impact on fertility and malignancy risk. Monitoring of real life use of biologics is important and there are Registries and cohort studies in progress. 
  • The emergence of biosimilars is likely to result in lower costs and therefore improve access to effective treatments for more children although there are concerns about safety and efficacy.
  • For those few children with severe refractory disease failing to respond to biologics, a further option is T-cell depletion coupled with autologous haematopoietic stem-cell rescue albeit this is limited to specialist centres and needs careful selection of patients.

Monitoring and advice

  • Baseline investigations before starting immunosuppression include excluding infection.
  • Regular blood tests - monitor efficacy and safety of immunosuppressive agents.
  • Vigilance regarding infection is important, especially as the classical symptoms and signs may not be apparent, and urgent referral is warranted if infection is suspected.
  • Patients and families need to know to avoid live vaccines and pregnancy when on MTX or biologics and other immunosuppressives, especially if also on systemic corticosteroids.
  • Families need to know when to seek prompt medical care if the child is unwell and especially if they develop chickenpox or herpes zoster (shingles), as these can be serious and potentially life threatening.

The photograph shows zoster infection in a child who is immunosuppressed 

  • Varicella vaccination should be considered in all patients with incident JIA who are non-immune and before immunosuppression is started.
  • In the young adult or adolescent taking MTX, education about contraception and avoidance of excessive alcohol consumption is essential.

Cytokine modulators currently in rheumatic disease

Generic name

Mechanism of action

Route of administration

Important issues for the child taking cytokine modulators and apply  to all cytokine modulators

Etanercept

TNF-α soluble receptor that binds to circulating TNF and competes with membrane receptor

Subcutaneous injection twice a week

Avoid live viral vaccines
Promote annual flu vaccine
Promote pneumococcal immunization (current advice 5-yearly)

Vigilance regarding infections (e.g. varicella and herpes zoster, Tuberculosis, opportunistic infections such as listeriosis)

Advice regarding travel abroad with medicines and travel insurance

Infliximab

Human–murine chimeric antibody that neutralizes TNF-α

Intravenous infusion. Various regimens, initially every 2 weeks and then every 4–8 weeks

Adalimumab

Fully human monoclonal antibody neutralizes TNF-α

Subcutaneous injection fortnightly

Anakinra

Rilanocept

Canakinumab

IL-1 receptor antagonists

Subcutaneous injection (daily – anakinra, fortnightly rilonacept, Monthly canakinumab

Rituximab

 Anti B cell therapy 

 Intravenous injection given six to 12 monthly

Tocilizumab

IL-6 receptor antagonist

Intravenous infusion fortnightly or monthly

Abatacept

CTLA4-antagonist to block T cell and B cell interaction and initiation of the pro-inflammatory pathway

Given by monthly infusion

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