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Chronic arthritis: children with diseased joints

Juvenile idiopathic arthritis is a rare disease that is not that rare. Certain therapies can even cause other rare diseases in children and adolescents.

Juvenile idiopathic arthritis (JIA) is a group of rare diseases characterized by inflammation of joints or connective tissue. JIA can also affect other organs or connective tissue. This is a heterogeneous group of idiopathic inflammatory arthritis that affects children under the age of 16 and lasts six weeks or longer.

The incidence of juvenile idiopathic arthritis is 4 to 5 cases per 100,000 children. Approximately 750 to 1,500 new cases are observed each year. The incidence is 20-30 cases per 100,000 children and adolescents.

The 7 categories

The terminology of chronic arthritis in children has evolved since 1995 from juvenile chronic arthritis (JCA) and juvenile rheumatoid arthritis (JRA) to JIA. According to the International League of Societies for Rheumatology (ILAR) consensus conference in 2001, there are seven categories of JIA:

  • Oligoarthritis
  • Ruma factor (RF)-positive polyarthritis
  • HF-negative Polyarthritis
  • systemic arthritis
  • Psoriasis-Arthritis
  • Enthesitis-related arthritis
  • undifferentiated arthritis.

These subtypes have different phenotypes, genetic predisposition, pathophysiology, laboratory findings, disease course and prognosis. Although chronic arthritis is mandatory for all subtypes, the extra-articular and systemic manifestations characterized each specific subtype. Recently, a new preliminary data-driven classification for JIA was proposed and formally validated by the Pediatric Rheumatology International Trial Organization (PRINTO).

What goes on behind the scenes?

The cause and trigger of chronic arthritis in JIA remains unclear. Abnormal immune responses elicited by the interactions between environmental factors in a genetically susceptible individual are speculative. Some environmental factors such as exposure to antibiotics and cesarean births are potential risks; However, breastfeeding and household siblings are potential safeguards.

Swollen and painful joints are features of many autoimmune rheumatic diseases. In several of these diseases, neutrophils in the synovial fluid of inflamed joints have been found to exhibit an altered phenotype and behavior, leading to local inflammation. Neutrophils are not only pro-inflammatory mediators, but also immune regulators. One of its immunoregulatory effects is its ability to suppress T-cell proliferation and cytokine production.

T cells play a central role in the pathogenesis of juvenile idiopathic arthritis (JIA), with activated T cells accumulating in inflamed joints. Neutrophil suppression of T cells has been described by mechanisms involving reactive oxygen species (ROS), arginase-1, direct cell-cell contact, and anti-inflammatory cytokines.

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On the other hand, the role of microorganisms such as parvovirus B19, Epstein-Barr virus, intestinal bacteria, Chlamydophila pneumoniae and streptococci have not yet been clearly elucidated.

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Characteristics

disease name

Juvenile idiopathic arthritis

frequency

4–5/100,000

disturbed function

Autoimmune disease with genetic disposition (CD-25 gene), viral infections, trauma

therapy

NSAIDs

Corticosteroids

DMARDs (Biologics)

Treatment is symptomatic

JIA is treated analogously to rheumatoid arthritis in adults. Basic therapy consists of disease-modifying anti-inflammatory drugs (DMARDs), sometimes corticosteroids, and sometimes nonsteroidal anti-inflammatory drugs to relieve symptoms.

Treatment of JIA requires anti-inflammatory and immunomodulatory drugs, as well as physical therapy. Surgery, nutritional support and psychosocial support may also be needed. The choice of pharmacological treatment depends on the disease subtypes, the severity and damage of the disease, the associated disease and family acceptance. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of initial symptomatic treatment for all subtypes. NSAID use in JIA has declined over time with modern aggressive treatment—including methotrexate and biologics.

Physiotherapy emphasizes freedom of movement with minimal stress on the joints – swimming is often a good option. Patients should participate in moderate fitness, flexibility and strengthening exercises.

steroids first

Intra-articular corticosteroid injections (IACIs) are mainly applicable to chronic rheumatoid arthritis and osteoarthritis of the knee. They can be used as initial therapy, alone, or as emergency therapy when nonsteroidal anti-inflammatory drugs are ineffective.

The use of IACIs for JIA is a safe and effective way to treat synovitis. It can be performed under local anesthesia with or without sedation, or under general anesthesia and is an important treatment option for children with JIA. This treatment, called the ‘bridging effect’, is an alternative to the use of systemic corticosteroids.

The 2019 guidelines of the American College of Rheumatology (ACR) recommend the early use of conventional DMARDs – especially methotrexate – for the initial therapy in patients with polyarticular JIA given the proven advantages over NSAIDs. b-DMARDs (biologics) are recommended as second-line therapy in patients with moderate or high disease activity.

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Biological modification therapy

The introduction of biologics 20 years ago has significantly changed the pharmacotherapy of juvenile idiopathic arthritis. Biologics are among the most successful innovations, not only in rheumatology. In addition to their powerful efficacy and rapid onset of recovery, biologics offer an option to prevent long-term damage and a realistic prospect of remission.

Many pediatric rheumatic diseases can be safely treated with Biologicas. Because serious allergic reactions to these drugs are rare – but possible. For example, biologic infliximab can cause drug-induced pityriasis lichenoides in patients with juvenile idiopathic arthritis, according to a case report by Boswell et al.

Pityriasis lichenoides chronica (PLC), is also a rare disease that can vary from an acute, inflammatory rash to a mild, chronic form. PLEVA, the acute severe subtype, can result in erythematous patches that progress to hemorrhagic or crusted papules.

TNF blockade is known to upregulate type 1 interferons via plasmacytoid dendritic cells. This imbalance of TNF-α and type 1 interferons is thought to be the cause of the paradoxical psoriasis that sometimes occurs with TNF-α inhibitors.

Anakinra – a panacea?

Anakinra is also successfully used as a biological agent. It is a biosynthetic analog of the IL-1 receptor antagonist. It enhances its natural down-regulating effects by blocking the binding of the two isoforms of IL-1 to their receptor. The resulting reduction in proinflammatory signaling is effective in a variety of diseases in which dysregulation of innate immune mechanisms leads to overproduction of IL-1, including juvenile arthritis.

A study by Fingerhutova’ et al. shows that even higher doses are well tolerated. The authors suggest that instead of using anakinra only after an inadequate response to corticosteroids, it should be prescribed as first-line therapy. In addition, higher than recommended doses of anakinra—which were often required to achieve an adequate therapeutic response—were well tolerated without significant side effects. In hyperinflammatory patients, anakinra can be life-saving and even allow corticosteroids to be avoided.

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Overall, the results of a study by Giancane et al. the long-term safety profile of anakinra in patients with sJIA and shows that the overall incidence of adverse events decreases over time. The study also highlights that there is no evidence that long-term treatment with anakinra increases the risk of macrophage activation syndrome (MAS).

This is what the guideline says

The current German guideline evaluates the therapy options as follows:

  • NSAIDs should be used as initial or adjunctive therapy in all subtypes of JIA to improve symptoms of active arthritis.
  • Intra-articular injection of crystalloid glucocorticoid (triamcinolone-hexacetonide) should be used to treat active arthritis in JIA.
  • Systemic administration of glucocorticoids should be used in case of high disease activity for non-systemic and systemic forms of JIA. Long-term use should not occur due to unwanted effects and the availability of other forms of therapy.
  • Methotrexate should be used if NSAIDs are not effective enough, if there is a high or repeated need for steroids, or if there is polyarticular JIA
  • Sulfasalazine can be used in peripheral arthritis of enthesitis-related arthritis.
  • If remission cannot be achieved with conventional systemic DMARDs or if the steroid requirement cannot be permanently reduced below an acceptable dose, biological DMARDs are used.
  • TNF inhibition by adalimumab and etanercept is effective in polyarticular JIA.
  • Both etanercept and adalimumab have mostly been studied in randomized controlled withdrawal design studies in patients with polyarticular JIA. They are now both approved for different JIA subtypes from the age of 2 years.
  • Abatacept can be used in patients with polyarticular JIA after DMARD failure.
  • Tocilizumab should be used in methotrexate-refractory polyarticular JIA either in combination therapy with methotrexate or as monotherapy. This can be done as an alternative to a TNF blocker or after an inadequate response to a TNF blocker.
  • Anakinra, canakinumab, glucocorticoids or tocilizumab should be preferred in active sJIA. Long-term therapy with glucocorticoids should be avoided.

Image source: Ksenia Chernaya pexels

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