Clinical and therapeutic complications of juvenile idiopathic arthritis (JIA)

Whether the manifestations of the disease are extraarticular or articular, recognizing these sequelae is of paramount importance. Neglecting them can severely impair a child’s quality of life and, in rare cases, may even be fatal. Complications can also serve as indicators of “silent” articular disease; indeed, many juvenile idiopathic arthritis (JIA) patients initially visit a physician due to complications, which subsequently leads to their JIA diagnosis.

Screening for juvenile idiopathic arthritis complications is an essential component of disease progression monitoring, as these complications have become an integral part of the disease trajectory. Research has demonstrated that early and regular screening is crucial. Such proactive measures enable the timely identification and treatment of complications, which often require specific therapies beyond the standard JIA treatment regimens⁽¹⁾.

Therefore, it is profoundly important to diagnose complications early to implement the appropriate treatments tailored to the specific condition. This approach not only addresses the immediate issues, but also prevents further deterioration of the child’s health⁽²⁾.

Hence the authors explored the clinical and therapeutic complications encountered in the “Sf. Maria” Emergency Clinical Hospital for Children, Iaşi, Romania, between 2020 and 2023, as well as other complications that are worth being mentioned in a cohort of 167 patients recorded as diagnosed with JIA.

Clinical complications

Juvenile idiopathic arthritis exhibits a higher prevalence in girls compared to boys, as shown in Figure 1, a phenomenon likely influenced by a complex interplay of genetic, hormonal and immunological factors that render females more susceptible to autoimmune conditions⁽³⁾. In our study cohort of a total of 167 patients, 65% were females, with higher percentages in 2022 and 2023. Also, during the COVID-19 pandemic, the incidence of newly diagnosed JIA cases notably declined in 2020-2021. This reduction can be attributed to several factors: pandemic-related restrictions, limited access to healthcare services, leading to delays in seeking medical attention and subsequent diagnoses. Additionally, the immunosuppressive therapies essential for managing JIA heightened the risk of severe COVID-19 complications, prompting patients and caregivers to avoid hospital visits to minimize potential exposure to the virus.
 

Anterior uveitis represents one of the most serious complications of juvenile idiopathic arthritis, as it can severely diminish the quality of life in afflicted children. This condition occurs in approximately 10% of JIA patients, and juvenile idiopathic arthritis is recognized as the most prevalent systemic disorder among children with uveitis^(4,5). In the “Sf. Maria” Emergency Clinical Hospital for Children, Iaşi, it accounted for 8% of the complications in 2023, with one case resulting in posterior synechiae and cataract formation due to treatment noncompliance (Figure 2).
 

Growth impairment, in terms of low height for age below the 5^th percentile, accounted for 14% of complications in the “Sf. Maria” Emergency Clinical Hospital, Iaşi, in 2023 (Figure 2), for 5% of complications in 2022, for 23% in 2021, and for 33% of complications in 2020. Worldwide, it accounts for approximately 35% to 40% of children with the condition. This impairment can manifest as a generalized reduction in body stature, or it may be localized to the affected limb. Growth disorders are linked to long-term disability, adversely impacting both the patient’s and their family’s quality of life, and posing a significant economic burden.

Similar to other complications of JIA, growth disorders are influenced by the duration and activity of the disease, with more severe cases observed in patients exhibiting high, long-term inflammatory profiles, particularly in the systemic and polyarticular subtypes of JIA. Additional risk factors, such as early age of onset and prolonged corticosteroid use, can significantly exacerbate growth retardation. Severe growth retardation is characterized by a body height in the lowest third percentile of the population.

In 2022, one case of macrophage activation syndrome (MAS) was recorded, one of the most severe and life-threatening complications associated with juvenile idiopathic arthritis, which unfortunately deceased, despite therapy. MAS is characterized by an overwhelming inflammatory response, driven by excessive activation and proliferation of macrophages and T-lymphocytes. Clinically, it presents with persistent high fever, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy, which can rapidly progress to multiorgan failure if not promptly recognized and treated.

Additionally, inflammatory anemia and depression are prevalent, reflecting the chronic inflammatory state and the psychological burden of living with a chronic disease. Collectively, these complications underscore the necessity for a comprehensive and multidisciplinary management of JIA to address both the physical and psychological aspects of the disease.

Therapeutic complications

Corticosteroids, commonly prescribed in the management of juvenile idiopathic arthritis, play a pivotal role in mitigating inflammation and controlling disease activity. These potent anti-inflammatory agents work by modulating the immune response, thereby reducing the symptoms and progression of JIA. However, their prolonged use is associated with a spectrum of adverse effects. One significant side effect is the development of obesity, a consequence of altered metabolism and increased appetite induced by corticosteroids. This weight gain not only affects physical health, but also contributes to psychological distress and reduced quality of life in affected individuals.

Moreover, the immunosuppressive nature of corticosteroids can lead to heightened susceptibility to infections. Chronic Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Candida infections, including stomatitis, are particularly concerning in this context. These infections thrive due to the dampened immune surveillance caused by the long-term corticosteroid use. EBV is of particular interest as it has been implicated in the pathogenesis of JIA; it can either act as a potential trigger for the onset of the disease, or persist as a chronic infection due to ongoing immunosuppression. This highlights the delicate balance required in corticosteroid therapy to effectively control the disease while minimizing the risk of opportunistic infections. Thus, the use of corticosteroids in JIA necessitates careful monitoring and a comprehensive approach to mitigate their adverse effects while maximizing the therapeutic benefits.

Methotrexate, a cornerstone in the treatment of juvenile idiopathic arthritis, is renowned for its efficacy in controlling inflammation and preventing disease progression. However, its administration is frequently accompanied by gastrointestinal side effects, notably nausea and dyspepsia. These adverse reactions are particularly troublesome for young patients, potentially leading to poor adherence and suboptimal therapeutic outcomes. Methotrexate-induced nausea and dyspepsia result from its effect on rapidly dividing cells in the gastrointestinal tract, disrupting normal mucosal integrity and function⁽⁶⁾. This can manifest as persistent discomfort, diminished appetite, and overall aversion to the medication. Addressing these side effects is crucial for maintaining treatment adherence and ensuring the long-term management of JIA, often necessitating the use of adjunctive therapies such as antiemetics or dose adjustments to improve patient tolerance and quality of life⁽⁷⁾.

As shown in Figures 3 and 4, most of the therapeutic complications in our patients were due to corticotherapy, leucopenia being the only modification related to methotrexate therapy at this point. Otherwise, immunosuppression, infection and Cushing’s disease (obesity) were present in most of the patients^(8-10).
 

Despite the abundance of studies aimed at investi­ga­ting and elucidating juvenile idiopathic arthritis, nu­me­rous questions remain unanswered. While signi­fi­cant breakthroughs have been made, the pathoge­ne­sis, etiol­ogy and risk factors associated with JIA conti­nue to elude the full understanding. Additionally, an unequivocal cure for this disease remains out of reach. Among the many facets of JIA that are still not fully understood, the complications arising from this condition are particularly notable. These complications can cause irreversible damage and significantly diminish a child’s quality of life^(11-13).

Given the severity and potential consequences of these complications, it is imperative for healthcare providers to be well informed about the spectrum of conditions that may coexist with juvenile idiopathic arthritis. Clinicians must maintain a high index of suspicion and actively monitor for the development of these complications. Moreover, the importance of initiating aggressive treatment early in the disease course cannot be overstated. Achieving and maintaining inactive disease status have been shown to be one of the most effective strategies in preventing the onset of complications⁽¹⁴⁾.

Timely recognition and management of complications are crucial in preserving the quality of life for children with juvenile idiopathic arthritis. However, the first step in addressing these issues is the thorough systematic and regular screening. Patients – particularly those at high risk for developing complications – should undergo routine and periodic evaluations to detect early manifestations. This is especially pertinent for the so-called “silent complications” of JIA, which can have a subtle and insidious onset. Early detection through screening can facilitate prompt intervention and potentially prevent complications from progressing to a more severe stage^(15,16).

In conclusion, further research is urgently needed to enhance our understanding of JIA and its associated complications. The body of knowledge available today is significantly greater than it was a decade ago and, with continued efforts, we hope to achieve even greater insights in the coming years⁽¹⁷⁾. Advancing our understanding of this disease will not only improve the management of juvenile idiopathic arthritis, but also preserve and enhance the quality of life for afflicted children. By addressing the complexities of juvenile idiopathic arthritis comprehensively, we can move closer to a future where the burden of this disease is significantly reduced and its impact on young lives is mitigated. 

Autori pentru corespondenţă: Alice-Nicoleta Azoicăi E-mail: agrudnicki@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.