Juvenile idiopathic arthritis is a rare disease that isn’t all that rare. Certain therapies can even trigger other rare diseases in affected children and adolescents.
Die 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 tissues. It 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 every year. The prevalence is 20-30 cases per 100,000 children and adolescents.
The 7 categories
The terminology of chronic arthritis in children has evolved from juvenile chronic arthritis (JCA) and juvenile rheumatoid arthritis (JRA) to JIA since 1995. According to the International League of Associations for Rheumatology (ILAR) consensus conference in 2001, there are seven categories of JIA:
- Oligoarthritis
- Rheumafaktor (RF)-positive Polyarthritis
- HF-negative Polyarthritis
- systemic arthritis
- Psoriasis-Arthritis
- Enthesitis-related arthritis
- undifferentiated arthritis.
These subtypes have different phenotypes, genetic predispositions, pathophysiology, laboratory findings, disease course, and prognosis. Although chronic arthritis is obligatory for all subtypes, the extra-articular and the systemic manifestations characterized each specific subtype. Recently, a new preliminary data-driven classification proposed for JIA and formally validated by the Pediatric Rheumatology International Trial Organization (PRINTO).
What is going on behind the scenes?
The cause and trigger of chronic arthritis in JIA remain unclear. Abnormal immune responses elicited by the interactions between environmental factors in a genetically susceptible individual are speculative. Some environmental factors such as antibiotic exposure and cesarean deliveries are potential risks; However, breastfeeding and household siblings are potential safeguards.
Swollen and painful joints are hallmarks of many autoimmune rheumatic diseases. In several of these diseases, establishedthat Neutrophile exhibit an altered phenotype and behavior in the synovial fluid of inflamed joints, 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), where activated T cells accumulate in inflamed joints. The suppression of T cells by neutrophils has been demonstrated by mechanisms describedin those reactive oxygen species (ROS), arginase-1, direct cell-cell contact and anti-inflammatory cytokines are involved.
In contrast, the role of microorganisms such as Parvovirus B19, Epstein-Barr-Virusintestinal bacteria, Chlamydophila pneumoniae and streptococci yet not clearly clarified.
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Characteristics |
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disease name |
Juvenile Idiopathic Arthritis |
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frequency |
4–5 /100.000 |
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disturbed function |
Autoimmune disease with genetic dysposition (CD-25 gene), viral infections, trauma |
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therapy |
NSAIDs Corticosteroids DMARDs (Biologicals) |
Treatment is symptomatic
JIA is treated analogously to rheumatoid arthritis in adults. The basic therapy consists of disease-modifying anti-inflammatory drugs (DMARD), sometimes Corticosteroids and, if necessary, 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 harm 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 evolved over time with modern aggressive treatment – including methotrexate and biologics – decreased.
Physiotherapy emphasizes freedom of movement with minimal stress on the joints – swimming is often a good option. Patients should engage 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.
Die Use of IACIs for JIA is a safe and effective method of treating 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.
Die guidelines of the American College Rheumatology (ACR) from 2019 recommend the early use of conventional DMARDs – especially methotrexate – for the initial therapy in patients with polyarticular JIA in view of the proven advantages over NSAIDs. In patients with moderate or high disease activity, b-DMARDs (Biologicals) if second-line therapy recommended.
Biologicas change therapy
The introduction of biologicals 20 years ago significantly changed the pharmacotherapy of juvenile idiopathic arthritis. Biologicals are among the most successful innovations, not only in rheumatology. In addition to their potent efficacy and rapid onset of recovery, biologicals offer an option for preventing long-term damage and a realistic prospect of remission.
Many pediatric rheumatic diseases can safely treated with biologicas will. Because severe allergic reactions to these drugs are rare – but possible. The Biological Infliximab can be drug-induced, for example, in patients with juvenile idiopathic arthritis Pityriasis lichenoides trigger, so a casuistry of Boswell et al.
Pityriasis lichenoides chronica (PLC), is also a rare disease that can range 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 miracle drug?
Anakinra is also used successfully as a biological. It is a biosynthetic analogue 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 pro-inflammatory 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 following an inadequate response to corticosteroids, it should be prescribed as first-line therapy. In addition, a higher than recommended dose of anakinra – which was often required to achieve an adequate therapeutic response – without significant side effects well tolerated. In hyper-inflammatory patients, anakinra can be life-saving and even allow corticosteroids to be avoided.
Overall, the results of a study by Giancane et al. the long-term safety profile of anakinra in patients with sJIA and show 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).
That’s what the guideline says
The actual 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 application of glucocorticoids should be used in cases of high disease activity for non-systemic and systemic forms of JIA. Long-term use should not take place due to undesirable 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.
- Either Etanercept as well as Adalimumab were mostly investigated 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 following failure of a DMARD.
- Tocilizumab should be used in methotrexate-refractory polyarticular JIA either in combination therapy with methotrexate or as monotherapy. This can be done either as an alternative to a TNF blocker or following an inadequate response to a TNF blocker.
- Anakinra, Canakinumab, glucocorticoids, or tocilizumab should be given priority in active sJIA. Long-term therapy with glucocorticoids should be avoided.
Image source: Ksenia Chernaya pexels
