Analysis of Peripheral Blood Lymphocytes in Patients With Juvenile Idiopathic Arthritis With Respect to Disease Subtypes and Therapy

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children.

JIA is an umbrella term defining several forms of chronic arthritis with an onset before the age of 16 years, persisting for more than six weeks and with an unknown cause.

Based on the current International League of Associations in Rheumatology classification criteria (ILAR 2003) , different subtypes of JIA can be distinguished, essentially by a very limited set of clinical features (number of affected joints in the first six months of disease, extra-articular manifestations like fever or features of psoriasis) and serology (presence or absence of rheumatoid factor, RF). The most frequently diagnosed JIA subtypes are oligoarticular JIA (oJIA), polyarticular JIA (pJIA), and systemic JIA (sJIA). Less frequently occurring subtypes are enthesitis-related JIA, psoriatic arthritis, and undefined arthritis.

The pathophysiology mechanisms associated to JIA development are related to an abnormal activation of immune system cells such as B cells, T cells, natural killer (NK) cells, dendritic cells (DCs), monocytes, neutrophils, plasma cells, and to the production and release of pro-inflammatory mediators that ultimately lead to cartilage and bone destruction and systemic manifestations.

JIA has been classically considered a T-cell driven autoimmune disease, except for sJIA subtype, in which innate immune cells have a central role in disease pathogenesis. However, the detection of autoantibodies reacting with different target antigens in JIA patients suggests a central role of B cells in JIA pathophysiology.

Therapeutic intervention of jia begins at diagnosis with non-steroidal anti-inflammatory drugs (NSAIDs) followed by disease-modifying anti-rheumatic drugs (DMARDs, most often methotrexate) and/or corticosteroid intra-articular injection.

NSAIDs obtain both analgesic and anti-inflammatory effects. Local corticosteroid joint injections are effective in synovitis and may be a first-line treatment for oligoarthritis alone or in addition to DMARDs. Systemic administration of high dose corticosteroids provides good short-term effect, especially in sJIA patients.

The American College of Rheumatology (ACR) recommends early use of DMARDs, specifically MTX, leflunomide and/or sulfasalazine.

MTX is considered to be the first choice DMARD for oligo- and pJIA when NSAIDs and intraarticular steroids are insufficient.

MTX is also considered to be effective in children with PsJIA, though the axial manifestations limits prescription of MTX and so TNF inhibitors are typically required in these cases.

Leflunomide may be used as an alternative DMARD for pJIA in cases of MTX intolerance.

Sulfasalazine is recommended for patients with moderate activity of ERA with active peripheral arthritis, but is inefficient in case of sacroiliitis.

The emergence of biologic treatments has changed the prognosis for many JIA patients, whose condition did not improve adequately on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), mainly methotrexate, or experienced side effects because of them. TNF-α inhibitors, such as etanercept, adalimumab , infliximab are widely used in JIA. In fact, etanercept is one of the most frequently prescribed biologics for JIA in many countries, including the United Kingdom. (19) Other biologics include tocilizumab , anakinra and canakinumab , abatacept and rituximab . The efficacy of biologics varies depending on the disease subtype.

Most healthy children have episodes of mild infections during the first years of life. In most cases, these episodes are respiratory or gastrointestinal viral infections. Children with juvenile idiopathic arthritis (JIA) have an allegedly higher risk of infection compared with healthy children because of their underlying condition.

Treatments used in JIA include corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologic agents, all of which can increase the frequency of common mild infections and the risk of severe and opportunistic infections.

Disease-modifying anti-rheumatic drugs (DMARDs) help manage JIA by reducing inflammation and preventing joint damage, slowing the progression of the disease.

These therapies work by suppressing the immune system, which can lead to infection, despite growing evidence regarding the efficacy and safety of these drugs for children with JIA, it is unclear whether these agents increase the risk of infections - or whether the risk is increased to all or to only specific infections.

Moreover, there is a proportional relationship between the severity of the disease and the intensity of the treatment administered, and this association might constitute a confounding factor when assessing susceptibility to infections.

Besides novel findings, there is still little data available regarding the alteration of immune cells which control infection.