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.

• Splenomegaly

  Lymphadenopathy, splenomegaly, hepatomegaly, and sore throat are also common. Pericarditis, pleuritis, pericardial effusion and pleural effusion may occur but is less likely. They present as underlying complications. 8. [slideshare.net]

  (Y) 5 (83) 5 (71) 7 (39) Hepatomegaly OR splenomegaly (I) 5 (83) 6 (86) 10 (56) Only splenomegaly (N) 2 (33) 3 (43) 1 (6) Splenomegaly AND Hepatomegaly (N) 3 (50) 2 (29) 6 (33) Yamaguchi criteria 5 (83) 7 (100) 11 (61) All patients with “suspected” sJIA [ped-rheum.biomedcentral.com]

  Minor criteria may include sore throat, lymphadenopathy, negative rheumatoid factor, abnormal liver function tests, hepatomegaly or splenomegaly. Five criteria are needed for diagnosis with at least two of them being major. [press.mu-varna.bg]

  Adult-onset Still disease classically is described as a triad of: high fevers arthralgia salmon-colored rash Less common are: sore throat hepatic dysfunction splenomegaly lymphadenopathy Elevated inflammatory markers (e.g. [radiopaedia.org]

  […] fever with spike in the evening) persisting for a minimum of 15 days, with at least one of the following manifestations: skin rash (evanescent, non-fixed erythematous rash that accompanies fever spikes), generalized lymphadenopathy, hepatomegaly and/or splenomegaly [stillsdisease.org]

• Generalized Lymphadenopathy

  Appearance of rash, hepatosplenomegaly, serositis and generalized lymphadenopathy. [symptoma.com]

  lymphadenopathy, hepatomegaly and/or splenomegaly, or serositis (pleuritis or pericarditis). [stillsdisease.org]

  Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. [rheumnow.com]

  It differs from classical rheumatoid arthritis in that it is more often marked by acute febrile onset, and generalized lymphadenopathy and hepatosplenomegaly are more prominent. [icd10data.com]

• Cervical Lymphadenopathy

  After an initial improvement, the high fever and skin rash returned, and cervical lymphadenopathy was detected. Lymph node, bone marrow, and rash cutaneous biopsies were performed. [scielo.br]

  He also had inflamed throat without any exudates or cervical lymphadenopathy. Musculoskeletal exam showed minimal tenderness in bilateral ankles and knees with normal active and passive range of motion. [hindawi.com]

• Fever

  Symptoms tend to be more pronounced during fever spikes and may be completely absent once the fever has resolved, which might be of great help in the diagnostic workup. [symptoma.com]

  Still's Disease Symptoms Fever Fever is part of the body's own disease-fighting arsenal. Rising body temperatures apparently are capable of killing off many disease-producing organisms. For that reason, low fevers should normally go untreated. [medicinenet.com]

  The fever tends to spike several times during the day. It usually peaks at night and then improves in the morning. Children also have joint pain, swelling, or both. This may become more painful when their fever is high. [webmd.com]

  The duration of fever is telltale and may last 1-3 days (familial Mediterranean fever, CAPs, Muckle Wells) or 5-21 days (TRAPS) or daily (AOSD, SoJIA, Schnitzler syndrome). [rheumnow.com]

• Pain

  Of all patients with Still's disease, 100% have high intermittent fever, and 100% have joint inflammation and pain, muscle pain with fevers, and develop persistent chronic arthritis. [medicinenet.com]

  […] cell count Severe anaemia Abdominal pain In many cases, skin rash and fever may occur intermittently for months or even years before joint pain and swelling develop. [dermnetnz.org]

  Migrane Minor Burns Mouth Ulcers Mumps Muscle Pain Muscular Pain Musse (Wart) Musse (Wart) Nasal Polypa DNA Nausea Neck And Shoulder Pain Nervous Neuro Fibroma Night Fall Obesity Osteoporosis Otitis Eedia/Externa Ovarian Fivroid Paralysis Pariya Parkenson [spakshomeopathy.com]

  Children also have joint pain, swelling, or both. This may become more painful when their fever is high. Symptoms come and go over days, weeks, or months. Children with a low fever can seem to be fine. [webmd.com]

• Lymphadenopathy

  Appearance of rash, hepatosplenomegaly, serositis and generalized lymphadenopathy. [symptoma.com]

  MAS is a severe, potentially life-threatening disorder, and clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, neurologic dysfunction, and coagulopathy. [stillsdisease.org]

  Lymphadenopathy, splenomegaly, hepatomegaly, and sore throat are also common. Pericarditis, pleuritis, pericardial effusion and pleural effusion may occur but is less likely. They present as underlying complications. 8. [slideshare.net]

  Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. [rheumnow.com]

• Weight Loss

  Weight-loss support: While more research has to be done in this area, turmeric does show some promise when it comes to encouraging weight loss. [deskgram.co]

  Frequently a dramatic drop in serum albumin will parallel a dramatic drop in hematocrit and weight loss. [rheumaknowledgy.com]

  Poor appetite, nausea, and weight loss are common. There is also commonly swelling of the lymph glands, enlargement of the spleen and liver, and sore throat. [checkorphan.org]

  Other symptoms of AOSD include: sore throat swollen and tender joints inflamed or swollen lymph nodes muscle pain abdominal pain pain associated with deep breathing weight loss In some extreme cases, individuals develop an enlarged liver or spleen. [healthline.com]

  Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. [rheumnow.com]

• Fatigue

  In both children and adults the clinical picture includes arthritis, fever, fatigue, rash, leukocytosis, adenopathy, and hepatosplenomegaly. [medscape.com]

  Children, who develop JRA often experience fatigue, stiffness, and some joint pain. There are seven types of Juvenile Rheumatoid Arthritis: Systemic Juvenile Idiopathic Arthritis: This type of arthritis affects the child’s entire body. [dovemed.com]

  Extreme fatigue can accompany waves of high fevers that rise to 104 degrees F (41 degrees C) or even higher and can rapidly return to normal levels or below. [stillsdisease.org]

  Extreme fatigue can accompany waves of high fevers that rise daily to 102 degrees F (39 degrees C) or even higher and rapidly return to normal levels or below. Fever spikes often occur at nearly the same time every day. [checkorphan.org]

  AOSD is classified as an inflammatory illness that often causes fatigue and swelling in joints, tissues, organs, and lymph nodes. [healthline.com]

• Pleural Effusion

  Visceral complications (pericarditis, pleural effusion or serous peritonitis with abdominal pain) may be present. [orpha.net]

  Cervical spine radiographs may demonstrate: atlantoaxial subluxation odontoid erosions ankylosis, especially of the facet joints Hepatosplenomegaly may be seen on abdominal radiographs, and pericardial or pleural effusions may be seen on chest radiographs [radiopaedia.org]

  […] this type of ASD is most destructive to joints Other less common, but more serious symptoms can include myalgia, inflammatory myopathy, liver abnormalities, pleuritis, pericarditis, splenomegaly, pericardial tamponade, myocarditis, pulmonary fibrosis, pleural [hss.edu]

  Some patients develop inflammation around the heart (pericarditis) and lungs (pleuritis), with occasional fluid accumulation around heart (pericardial effusion) and lungs (pleural effusion). [checkorphan.org]

  Followed 5 days later by fever, the patient presented dyspnea, cough and hypoxemia, the imaging studies showed unilateral consolidation and pleural effusion. [springerplus.springeropen.com]

• Nausea

  Memory Menopause (Stop Period Before Age ) Menorrhagia (Excess Bleeding During Period) Menses Problems Menstrual Cramps (Body Pain During Period ) Migrane Minor Burns Mouth Ulcers Mumps Muscle Pain Muscular Pain Musse (Wart) Musse (Wart) Nasal Polypa DNA Nausea [spakshomeopathy.com]

  […] temperature spikes, skin rash, and painful, stiff joints.[4,5,9] An acute flare of SJIA (or an active phase) often looks like this: Fever Lasting longer than 2 weeks Recurs daily in the early morning or afternoon, and sometimes in the evening too Sickness (nausea [periodicfevers.com]

  Poor appetite, nausea, and weight loss are common. There is also commonly swelling of the lymph glands, enlargement of the spleen and liver, and sore throat. [checkorphan.org]

  Poor appetite, nausea, and weight loss may occur. Lymphadenopathy, splenomegaly, hepatomegaly, and sore throat are also common. Pericarditis, pleuritis, pericardial effusion and pleural effusion may occur but is less likely. [slideshare.net]

• Loss of Appetite

  (A.H.U.3/23-25) 70.  Emaciation loss of appetite with fever point toward a chronic diarrhea with infective etiology or  In long course due to malabsorptions, fat malabsortption to be particular will cause deficiency of fat soluble vitamins in body. [slideshare.net]

• Hepatomegaly

  Lymphadenopathy, splenomegaly, hepatomegaly, and sore throat are also common. Pericarditis, pleuritis, pericardial effusion and pleural effusion may occur but is less likely. They present as underlying complications. 8. [slideshare.net]

  Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. [rheumnow.com]

  Minor criteria may include sore throat, lymphadenopathy, negative rheumatoid factor, abnormal liver function tests, hepatomegaly or splenomegaly. Five criteria are needed for diagnosis with at least two of them being major. [press.mu-varna.bg]

  […] typically daily high fever with spike in the evening) persisting for a minimum of 15 days, with at least one of the following manifestations: skin rash (evanescent, non-fixed erythematous rash that accompanies fever spikes), generalized lymphadenopathy, hepatomegaly [stillsdisease.org]

  Hepatomegaly or splenomegaly. Abnormal liver function tests.Negative tests for RF and ANA. [ncbi.nlm.nih.gov]

• Hepatosplenomegaly

  Appearance of rash, hepatosplenomegaly, serositis and generalized lymphadenopathy. [symptoma.com]

  In the absence of cutaneous eruptions, the presence of an adenopathy, hepatosplenomegaly or serous effusion also confirm the diagnosis. There is no specific biological sign. [orpha.net]

  Migratory salmon colored light pink rash involving the trunk and/or extremities and hepatosplenomegaly are also frequently observed in patients with systemic onset. [radiopaedia.org]

  In both children and adults the clinical picture includes arthritis, fever, fatigue, rash, leukocytosis, adenopathy, and hepatosplenomegaly. [medscape.com]

• Arthritis

  Idiopathic Arthritis (Still Disease) - Pipeline by Novartis AG, H1 2016 Systemic-Onset Juvenile Idiopathic Arthritis (Still Disease) - Pipeline by Oncobiologics, Inc., H1 2016 Systemic-Onset Juvenile Idiopathic Arthritis (Still Disease) - Pipeline by [gii.co.jp]

  Arthritis: This type of arthritis does not seem to be associated with any of the other types of arthritis categories, or it may fit into multiple categories. [dovemed.com]

  Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/gene-expression-analysis-of-adult-onset-stills-disease-and-systemic-juvenile-idiopathic-arthritis-suggest-a-single-disease-continuum/. [acrabstracts.org]

  […] belong under juvenile idiopathic arthritis?. [ped-rheum.biomedcentral.com]

• Arthralgia

  The disease is characterized by the following features : hectic fever > 39° C, arthralgia or arthritis, rash, neutrophilia and systemic inflammation. The prognosis of the disease is functional and vital. [ncbi.nlm.nih.gov]

  Among the 13 patients with “suspected” sJIA, 6 patients had neither arthralgia nor arthritis and 7 patients had arthralgia without ever having had arthritis. [ped-rheum.biomedcentral.com]

  Clinically, the most classic manifestations of AOSD are fever, rash, sore throat, and arthralgia with fever and arthralgia being the most common among them [13]. [hindawi.com]

  Arthralgia, involving one, but more frequently two or more joints, is the most frequent finding after fever, usually involving the knee, wrist and ankle. [symptoma.com]

  Major Criteria Fever of >39°C for >1 week Leukocytosis >10,000/microL with >80% polymononuclear leukocytes (predominating granulocytes) Salmon colored rash (usually over the trunk or extremities, non-pruritic) Arthralgia and/or Arthritis >2 week Minor [slideshare.net]

• Myalgia

  Classical Presentation: Fever, salmon-colored rash, lymphadenopathy, myalgias, FERRITIN... ev negative ---------------- Juvenile idiopathic Arthritis, which has 3 forms 1) Pauciarticular few joints 2) Poliarticular many joints 3) Systemic = Still's Disease [usmleforum.com]

  Intermittent: the disease appears in unpredictable episodes or flares with remissions lasting weeks to years in between Chronic: persistent and active, this type of ASD is most destructive to joints Other less common, but more serious symptoms can include myalgia [hss.edu]

  Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. [rheumnow.com]

  His fever was accompanied by nonpruritic macular skin rash on his trunk, arthralgia of bilateral ankles and knees, myalgia, and night sweats. [hindawi.com]

  She had symmetric arthritis of hands, facial and thoracic skin rash, high morning fever, nausea, myalgia, and sore throat. [scielo.br]

• Ankylosis

  Other prominent manifestations (seen in > 50% of patients) include myalgias, carpal ankylosis, weight loss (> 10% body weight), lymphadenopathy, hepatomegaly, splenomegaly, pleuritis and pericarditis. [rheumaknowledgy.com]

  In the whole group of 18 patients bilateral involvement of the following joints was also seen: carpus (seven patients), knee (four), tarsus (four), ankle (three); three patients had ankylosis of the cervical spine. [ard.bmj.com]

  Cervical spine radiographs may demonstrate: atlantoaxial subluxation odontoid erosions ankylosis, especially of the facet joints Hepatosplenomegaly may be seen on abdominal radiographs, and pericardial or pleural effusions may be seen on chest radiographs [radiopaedia.org]

  Narrowing of the wrist carpometacarpal and intercarpal joint spaces which may progress to bone ankylosis is a classic radiographic finding of adult-onset Still's disease (AOSD) [17][18]. [ncbi.nlm.nih.gov]

• Joint Swelling

  It causes joint swelling, pain, stiffness, and loss of motion. It can affect any joint, but is more common in the knees, hands, and feet. In some cases it can affect internal organs as well. [icdlist.com]

  Arthritis, with joint swelling, often occurs after rash and fevers have been present for some time. [checkorphan.org]

  Corticosteroids, such as prednisone may be used to control high fever spikes, severe joint swelling and pain, and complications with internal organs. [jointhealth.org]

  Signs Similar to adult form of Rheumatoid Arthritis Joint Swelling with warmth (not red and hot) Differences from Adult Rheumatoid Arthritis Higher fever Rheumatoid Nodules are rare Pericarditis and valvulitis are more common Lymphadenopathy and Hepatosplenomegaly [fpnotebook.com]

• Skin Rash

  A faint salmon-colored skin rash characteristically comes and goes and does not itch. [medicinenet.com]

  Skin rash develops in about of 95% of patients. [dermnetnz.org]

  She had symmetric arthritis of hands, facial and thoracic skin rash, high morning fever, nausea, myalgia, and sore throat. [scielo.br]

  These features include high intermittent fever, joint inflammation and pain, muscle pain, faint salmon-colored skin rash, swelling of the lymph glands or enlargement of the spleen and liver, and inflammation of the lungs ( pleuritis ) or around the heart [rxlist.com]

• Eruptions

  In the absence of cutaneous eruptions, the presence of an adenopathy, hepatosplenomegaly or serous effusion also confirm the diagnosis. There is no specific biological sign. [orpha.net]

  Another frequently reported atypical lesion was urticaria and urticaria-like eruptions (11/81;14%). [journals.lww.com]

  An eruption consisting of persistent papules and plaques has been reported frequently and is now estimated to be present in up to 65% of AOSD patients (Lee et al. 2005).This latter eruption is pruritic and often has a linear configuration, thought to [springerplus.springeropen.com]

  DRESS syndrome has an extremely distinctive skin eruption associated with systemic signs after prolonged use of certain drugs (Figure 3). [clinicaladvisor.com]

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].

• Pericardial Effusion

  Some patients develop inflammation around the heart (pericarditis) and lungs (pleuritis), with occasional fluid accumulation around heart (pericardial effusion) and lungs (pleural effusion). [checkorphan.org]

  […] or Pericardial Effusion may be present Recurrent evanescent rash Faint salmon colored rash over trunk, palms and soles IV. [fpnotebook.com]

  Some patients develop inflammation around the heart (pericarditis) and lungs (pleuritis), with occasional fluid accumulation around the heart (pericardial effusion) and lungs (pleural effusion). [medicinenet.com]

• Thrombocytosis

  On the basis of this diagnosis, the patient began receiving prednisone, 20 mg twice daily; joint inflammation, fatigue, fever, anemia, leukocytosis, and thrombocytosis rapidly improved. [medscape.com]

  CRP), leukocytosis, thrombocytosis and elevated ferritin are common 3. The cause of adult-onset Still disease is unknown but genetic, environmental and infectious factors may play a role 3,4. [radiopaedia.org]

  Blood cell count for improvement in leukocytosis and thrombocytosis. [clinicaladvisor.com]

  A complete blood count is mandatory to exclude lymphoproliferative diseases; it will typically show an inflammatory anaemia, a leukocytosis with neutrophil predominance and a thrombocytosis. [smw.ch]

• Neutrophilia

  The disease is characterized by the following features : hectic fever > 39° C, arthralgia or arthritis, rash, neutrophilia and systemic inflammation. The prognosis of the disease is functional and vital. [ncbi.nlm.nih.gov]

  Lab findings: anemia of chronic disease (can also appear in non-systemic types[4]), neutrophilia, thrombocytosis, elevated acute phase reactants (ESR, CRP, ferritin). [en.wikipedia.org]

  Leucocytosis is the result of a striking neutrophilia that is probably secondary to bone marrow granulocyte hyperplasia (Pouchot et al. 1991 and Min et al. 2003). [springerplus.springeropen.com]

  The patient’s laboratory tests showed major systemic inflammation with anaemia, neutrophilia, thrombocytosis and hyperferritinaemia. Liver enzymes were normal; total IgG levels were increased, and autoantibodies were all negative. [smw.ch]

  […] the spectrum of differential diagnoses is wide, including infection, neoplasia, and other autoimmune disorders, which should be ruled out before the diagnosis of AOSD can be made. [3] Laboratory markers, particularly the presence of leukocytosis with neutrophilia [journals.lww.com]

• Synovial Cyst

  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. [symptoma.com]

  […] radiographic absorptiometry (DRA) Arthrocentesis and synovial biopsy Pericardiocentesis See Workup for more detail. [emedicine.medscape.com]

• Pleural Effusion

  Visceral complications (pericarditis, pleural effusion or serous peritonitis with abdominal pain) may be present. [orpha.net]

  Cervical spine radiographs may demonstrate: atlantoaxial subluxation odontoid erosions ankylosis, especially of the facet joints Hepatosplenomegaly may be seen on abdominal radiographs, and pericardial or pleural effusions may be seen on chest radiographs [radiopaedia.org]

  […] this type of ASD is most destructive to joints Other less common, but more serious symptoms can include myalgia, inflammatory myopathy, liver abnormalities, pleuritis, pericarditis, splenomegaly, pericardial tamponade, myocarditis, pulmonary fibrosis, pleural [hss.edu]

  Some patients develop inflammation around the heart (pericarditis) and lungs (pleuritis), with occasional fluid accumulation around heart (pericardial effusion) and lungs (pleural effusion). [checkorphan.org]

  Followed 5 days later by fever, the patient presented dyspnea, cough and hypoxemia, the imaging studies showed unilateral consolidation and pleural effusion. [springerplus.springeropen.com]

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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