Patients with juvenile onset Stills disease develop both systemic and visceral symptoms. Fever spikes that appear on an almost daily basis is seen in practically all patients [1]. Arthralgia, involving one, but more frequently two or more joints, is the most frequent finding after fever, usually involving the knee, wrist and ankle [7]. Synovial cysts are also a frequent finding in these patients, while additional complaints include a macular rash, serositis (either pericarditis or pleuritis), generalized lymphadenopathy and hepatosplenomegaly [3] [5]. Symptoms tend to be more pronounced during fever spikes and may be completely absent once the fever has resolved [3], which might be of great help in the diagnostic workup.

The diagnosis rests on clinical grounds and proposed criteria include [1]:

• Presence of quotidian fever for at least two weeks followed by the onset of arthralgia.
• Appearance of rash, hepatosplenomegaly, serositis and generalized lymphadenopathy.
• Absence of psoriasis and other autoimmune diseases with positive HLA-B27 mutations, such as ankylosing spondylitis, Reiter's syndrome or sacroilitis with inflammatory bowel disease (IBD) in either the patient or his/her first-degree relatives.
• Normal values of rheumatoid factor (RF).

From these facts, it can be concluded that a thorough physical examination and carefully obtained patient history are vital parts of the diagnostic workup. Laboratory studies may reveal leukocytosis and elevation of acute-phase reactants - CRP, ESR and fibrinogen [3].

Until the introduction of novel immunomodulating agents, NSAIDs and corticosteroids were the mainstay of managing symptoms such as fever, rash and joint pain [9]. Because of their long-term use and severe adverse effects over time, however, methotrexate and recently approved IL-1 and IL-6 antagonists have dramatically improved the course and outcome of patients suffering from juvenile onset Stills disease. Although glucocorticoids are still considered as a valuable option, anakira (IL-1 antagonist) and tocilizumab (IL-6 antagonist) have shown much better results and are becoming the foundation of patient management [10]. Tocilizumab may be even combined with methotrexate, but clinical trials still need to prove its safety and efficacy in infants and young children [11].

The prognosis of patients is variable. Approximately 50% of individuals will enter complete remission with appropriate therapy, but the remaining 50% will develop life-long, progressive symptoms that may be severely debilitating [9]. Amyloidosis and macrophage activation syndrome (MAS) are two important and potentially life-threatening complications. Amyloidosis is seen in approximately 5-15% of patients, depending on the geographical regions, and may lead to end-stage kidney disease, with 10-year survival rates established to be around 75% [1]. MAC is an even more serious complication, characterized by overt activation of macrophages and development of severe liver disease, neurological deficits and aggravation of existing symptoms [3]. The appearance of both conditions almost solely depend on the effectiveness of treatment, illustrating the importance of an early diagnosis and appropriate management.

Contrary to all other forms of juvenile idiopathic arthritis, in which mutations of HLA genes are responsible for the development of symptoms, the presumed etiological model includes abnormalities of genes and gene products that induce upregulation of various pro-inflammatory cytokines, mainly IL-1, IL-6, TNF-α and MIF [3]. A myriad of additional cytokines, such as IL-4, IL-10, IL-18, as well as myeloid-related protein 8 and 14 (MRP) have been associated with juvenile onset Stills disease [1], but further studies are required to solidify their roles. The exact reason why these molecules activated and why does dysregulation of genes responsible for their activation occurs, however, remains a mystery.

SoJIA constitutes approximately 10-30% of all JIA cases and its prevalence rates are estimated around 3.5 per 100 000 individuals [1]. Incidence rates vary between 0.4-0.9 per 100,000 individuals across different studies [1] [7]. Despite the fact that young age is a prerequisite for classification of patients into this category of JIA (< 16 years), several studies have shown that the majority of individuals present within their first 5 years of life [1]. Unlike in other forms of JIA, where significant predilection toward females is observed, gender distribution is equal when it comes to juvenile onset Stills disease [3].

The pathogenesis of juvenile onset Stills disease starts with dysregulation and polymorphism of genes that are responsible for regulation of cytokine production. IL-1, IL-6 and TNF-α are the principal pro-inflammatory molecules that have their established roles in the development of this disease. IL-1 is one of the most potent mobilizers of the cells of the immune system, while concentrations of IL-6 and the course of symptoms are shown to be in strong correlation by several studies [4]. When activated, these cytokines cause numerous harmful effects in the human body, including osteopenia as a result of enhanced osteoclastic activity by IL-6, thrombocytosis, leukocytosis and stimulation of acute-phase reactants such as C-reactive protein, fibrinogen and erythrocyte sedimentation rate (ESR) [1] [5]. The role of nuclear factor kappa b (NF-κB) and RANK ligand in the systemic forms of JIA is yet to be determined, but their roles in induction of osteoporosis have been well documented [8]. As a result of cumulative cytokine production and their activation, systemic and visceral symptoms appear.

Preventive measures currently do not exist and the focus remains on long-term follow-up and prevention of complications that may arise from juvenile onset Stills disease. Timely treatment and appropriate management through regular check-ups is mandatory in ensuring a good quality of life.

Juvenile onset Stills disease, also commonly described in literature as systemic-onset juvenile idiopathic arthritis (SoJIA), was initially established at the end of the 19th century when fever, arthritis, splenomegaly and lymphadenopathy were observed in young children by Sir George Frederick Still [1]. Today, together with six other variants, it is one of the forms of juvenile idiopathic arthritis (JIA) and comprises approximately 10-30% of all JIA cases [2]. The appearance of symptoms before 16 years of age distinguishes it from adult-onset Stills disease and the majority of patients present before 5 years of age [1]. Prevalence rates range from 0.4-0.6 per 100,000 individuals across different studies. Gender predilection toward females, which is seen in all JIA subtypes, is not evident in juvenile onset Stills disease and equal distribution among sexes is observed [1]. Although virtually all subtypes of JIA are thought to include mutations of the human leukocytic antigen (HLA), juvenile onset Stills disease stems from altered expression or mutation of genes that code for various pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha (TNF-α) and macrophage migration inhibitory factor (MIF) [3]. In fact, IL-6 has shown to be the most important cytokine in the pathogenesis, as its levels directly correlate with the onset and resolution of disease manifestations [4]. As a result of their increased activity, the appearance of spiking fever, hepatosplenomegaly, rash and lymphadenopathy are considered as hallmarks [5]. Pericarditis or pleuritis are frequently observed in these patients as well [3]. Clinical criteria that include polyarticular pain, daily spiking fever for more than two weeks and several exclusion criteria (history of psoriasis, presence of HLA-B27 mutations and other autoimmune diseases and normal serum values of rheumatoid factor) are used to confirm the diagnosis of juvenile onset Stills disease [1]. The use of corticosteroids, methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs) have been listed as potential treatment modalities, but the introduction of IL-1 and IL-6 antagonists into medical practice has drastically improved patient outcomes [6]. Anakira and tocilizumab, respectively, are recently approved immunomodulating drugs that show superior results to other regimens and provide significantly lower rates of adverse effects. The prognosis of juvenile onset Stills disease is variable, ranging from complete remission to development of complications such as amyloidosis and macrophage activation syndrome (MAS), both being severe and even life-threatening [1]. For these reasons, close monitoring and long-term follow-up of patients with this condition is necessary in order to enable an adequate quality of life, but an early diagnosis is equally important.

Juvenile onset Stills disease was initially discovered more than 100 years ago and today it is more commonly known as systemic-onset juvenile idiopathic arthritis, a condition characterized by severe inflammatory changes in the body as a result of genetic mutations and alterations. Namely, mutations and upregulation of genes that regulate production of molecules such as interleukin 1 and 6, which cause significant inflammation and appearance of symptoms such as fever, joint pain, rash and several other. The exact cause of these mutations is not known and symptoms most frequently start before 5 years of age. Juvenile onset Stills disease develops in less than 1 per 100,000 individuals and genders are equally affected. In addition to fever and joint pain, which are the two most important manifestations, enlargement of liver and spleen (hepatosplenomegaly) is a frequent findings, as is lymph node enlargement, rash, pericarditis and pleuritis. Fever appears almost every day and has shown to aggravate symptoms that may become severely debilitating. Moreover, 50% of patients develop a chronic, progressive course of disease that may lead to complications such as amyloidosis and macrophage activation syndrome, with both being potentially fatal. Amyloidosis can result in kidney failure, while macrophage activation syndrome is characterized by severe onset of liver damage, neurological deficits and further aggravation of existing symptoms. A properly obtained patient history and a thorough physical examination can provide all the information necessary to make a presumptive diagnosis. Laboratory findings may reveal increased white blood cell count and markers of inflammation such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and fibrinogen, but there is no direct test to confirm the disease. Treatment principles are focused on alleviating symptoms through administration of drugs that suppress inflammation, such as corticosteroids and non-steroidal anti-inflammatory drugs, but recent introduction of a newer class of drugs that directly inhibit production of cytokines and other pro-inflammatory molecules has revolutionized the management of patients suffering from this condition. Anakira and tocilizumab are interleukin 1 and 6 antagonists, respectively, and their efficacy is superior to all other drugs, but more importantly, adverse effects are minimal compared to other drugs that are used. Overall prognosis is good with long-term follow-up and therapy, but an early diagnosis is necessary to prevent complications and ensure a good quality of life.

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