Still disease in children

Contents

Still’s Disease, Juvenile Arthritis, and Rheumatoid Arthritis: What’s the Difference?

Systemic juvenile idiopathic arthritis (SJIA) is one of seven types of juvenile (childhood) idiopathic arthritis, or JIA (idiopathic means “of unknown origin”). SJIA may sometimes be referred to as pediatric Still’s disease, which is named after the doctor who first reported it in children in the late 1800s.

SJIA accounts for about 10 percent of JIA cases, says Jay Mehta, MD, a pediatric rheumatologist and associate program director of the pediatrics residency program at The Children’s Hospital of Philadelphia, and associate professor of clinical pediatrics at the University of Pennsylvania’s Perelman School of Medicine. JIA affects between 1 in 1000 and 1 in 2500 children, or 30,000 to 75,000 children, in the United States, according to 2015 census data estimates.

Related: What Does Arthritis Pain Feel Like?

When the disease develops after age 16, it’s called adult-onset Still’s disease (AOSD). “Up to 10 percent of rheumatoid arthritis cases in U.S. adults may be AOSD,” says Brian Golden, MD, clinical associate professor of medicine in the division of rheumatology at NYU Langone Medical Center in New York City.

AOSD usually strikes young adults from ages 16 to 35, but it can develop at any age. AOSD is essentially the same disease as SJIA, but it is less common than SJIA, for several reasons. “In young children, the immune system is quite naïve and rapidly processing new exposures, but as we get older, our immune systems mature and we are able to recognize more exposures based on previous experience,” says Anjali Sura, MD, a pediatric rheumatologist at SUNY Upstate University Hospital in Syracuse, New York, who has treated both children and young adults.

In addition, diseases that affect the innate immune system, including Stills, tend to appear at a younger age than diseases that affect the adaptive immune system, such as rheumatoid arthritis, she explains. “It’s also likely that there are some genetic and environmental factors involved as well, but we don’t know for sure,” she adds.

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What Causes Arthritis in Children and Young People, Such as SJIA and AOSD?

The disease is due to an overactive innate immune system, making it different from most other types of chronic arthritis, which involve the adaptive immune system. (The adaptive immune system makes specific antibodies to specific substances, whereas the innate system launches a more general response). SJIA and AOSD are systemic — meaning they affect the entire body — and are also idiopathic, meaning the cause is unknown. Although SJIA and AOSD are diseases of the immune system, they are not considered autoimmune, as are most types of rheumatoid arthritis, lupus, or Sjögren’s syndrome; instead, they’re considered autoinflammatory diseases.

No one knows exactly why the innate immune system goes awry, though it may be a response to an infection or have a genetic component. “But not everyone with the genetic markers gets the disease, and not everyone with the disease has the genetic markers,” says Dr. Mehta.

Symptoms include:

  • A daily high fever of 102 degrees F or higher that lasts for about four hours and typically spikes in the afternoon, but can occur anytime (For a SJIA diagnosis, the fever must be present for two or more weeks.)
  • A salmon-pink rash that can appear anywhere but often shows up on the limbs and trunk, and comes and goes — often along with a fever
  • Joint pain and swelling in any joint, frequently in the knees, ankles, wrists (in adults), and the cervical spine joints (in children)
  • Generalized muscle pain (myalgia)
  • Lymph node swelling

In many cases the rash and fever occur together, followed by joint pain and inflammation days to months later, says Dr. Sura. But she has also seen cases where the joint symptoms develop first or not at all, particularly if patients are diagnosed early on and begin treatment, thus preventing the progression of the disease.

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In children, the traditional thought is that about one-third of those with SJIA will have a “one and done” episode: They develop initial symptoms, get diagnosed, start on medication that quells symptoms, and can eventually curtail some or all of their meds, says Mehta, adding that the “one and done” scenario is growing thanks to earlier and increased usage of biologic drugs (see below).

In Mehta’s experience, and in some recent literature, over one-half of children started on IL-1 blockers quickly go into remission and are able to discontinue medication. The remainder of those with SJIA will have one of two trajectories: They will experience remission with periods of flare-ups or have constant disease activity with inflammation and arthritis. “Many children will outgrow SJIA, but we don’t have great data on this since they transition to adult rheumatologists and we often don’t know the outcomes,” says Mehta.

In about 10 percent of SJIA cases (and more rarely in adults), a potentially deadly complication called macrophage activation syndrome (MAS) can develop. In MAS, there is overwhelming systemic inflammation that can affect any organ, including the heart and lungs. Signs of MAS include an unrelenting high fever, enlarged lymph nodes, and an enlarged spleen and liver. Early treatment is vital, as the condition causes death in about 8 percent of cases.

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In adults, some older research has suggested that about one-third of those with AOSD will have one episode of fever, rash, or joint pain symptoms (or a combination of two or more of these) that’s short-lived and doesn’t recur, although some experts believe that increased and earlier use of biologic drugs is able to stop the disease progression in its tracks for some young adult sufferers. For the remainder of patients, the disease is likely to be chronic, whether that involves periodic episodes every few weeks, months or years, or continual symptoms. “We really need better and newer data to know exactly how adult patients are doing,” says Sura.

Diagnosing Systemic Juvenile Idiopathic Arthritis (SJIA) and Adult-Onset Still’s Disease (AOSD)

Because there’s no hard-and-fast blood test for SJIA or AOSD, doctors must diagnose the disease based on symptoms, by eliminating other diseases, and by assessing certain biological markers. Blood test results that can indicate SJIA or AOSD include:

  • High ferritin levels (a protein that stores iron)
  • A high white blood cell count (a high count can indicate an immune disorder or an inflammatory condition)
  • High levels of interleukin 1 (a type of protein produced by immune cells that can indicate inflammation)
  • A high erythrocyte sedimentation rate
  • A high C-reactive protein level

(Note that the rheumatoid arthritis factor is usually negative in SJIA and can also be negative for AOSD.)

Musculoskelatal X-rays and ultrasound are also used to assess joint damage for diagnosis and remission.

Certain conditions are often ruled out before doctors consider SJIA or AOSD. And because the disease shares features with other more common conditions, there can be a delay in diagnosis and treatment. This is especially concerning for SJIA, since untreated SJIA can impair musculoskeletal growth (just like JIA).

“Pediatricians will often try antibiotics for what they think are back-to-back viral infections, then they will refer the child to an oncologist, who will rule out cancers, sometimes with a bone marrow biopsy,” says Mehta. It’s often not until the child tests negative for cancers that they are referred to a rheumatologist, causing weeks or months of delay in a diagnosis. “Ideally, a pediatrician will refer a child to a pediatric rheumatologist,” says Mehta. But there are only about 400 pediatric rheumatologists in the country, which makes the referral process difficult. Oftentimes, rheumatologists who treat adults end up diagnosing SJIA in children.

For adults, doctors may first consider a chronic infection or cancer of the immune system, such as lymphoma. Other conditions that a primary care doctor will want to rule out are tuberculosis, bacterial endocarditis, and rheumatic fever, says Dr. Golden. Once these are eliminated, the doctor may refer the patient to a rheumatologist, who will then consider rheumatologic diseases such as AOSD.

Related: Speaking Arthritis: A Glossary of Terms Used to Describe Symptoms, Tests, Treatments, and More

Treating AOSD and SJIA

The first course of treatment for AOSD is often anti-inflammatory drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, followed by biologics, drugs that are often injected or infused, and which block the activity of inflammatory cytokines. Because there are more medicines approved for SJIA than AOSD, doctors generally treat AOSD with some of the same drugs as SJIA.

“Putting patients on NSAIDs and steroids first to get the disease under control, and then using other drugs, such as biologics, yields a good response,” says Golden, adding that some patients can get off of medication altogether. Although some research shows that the traditional RA drug methotrexate (Rasuvo, Trexall) is less effective for SJIA and AOSD, some doctors prescribe it as a way to lower the dosage of steroids needed to control inflammation; long-term use of steroids can increase the risk of osteoporosis, cataracts, weight gain, diabetes, cardiovascular risk, and more, says Golden. (Some research has found that methotrexate is less effective for AOSD and SJIA than it is in other RA conditions.)

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The greatest area of research for both AOSD and SJIA is with the biologic drugs, including Kineret (anakinra), Actemra (tocilizumab), and Ilaris (canakinumab), which block IL-1 cytokines and IL-6 cytokines, both of which are thought to play a role in the disease. Doctors may also use the IL-1 blocker Arcalyst (rilonacept) or Kevzara (surilumab), a new IL-6 blocker.

Some new research is being conducted on IL-18 blockers, since IL-18 cytokines may be elevated in those with MAS, and knowing a person’s IL-18 status could predict who is more likely to develop MAS. However, tests are not yet commercially available.

And for those whose disease is resistant to IL-1 and IL-6 blockers, JAK inhibitors (Janus kinase inhibitors) hold promise, according to research published in November 2018 in Current Rheumatology Reports, although large patient trials are still needed to fully understand their efficacy.

With SJIA, patients with mild disease are often started on NSAIDs, and they may do well on this treatment alone. However, for those with moderate or severe disease, biologic drugs are often the first step in order to get symptoms under control. (Steroids are used sparingly in children because of the concern over their effect on growth.)

For children with severe or longstanding SJIA, doctors have recently become aware that lung disease — with symptoms like shortness of breath, rapid breathing, and coughing — may develop, necessitating additional treatment says Mehta. The reason for the development of lung disease and the optimal treatment for it are still being investigated.

Because many of the drugs used to treat SJIA, AOSD, and RA suppress the immune system, patients must be monitored carefully for infections. But all experts agree that risks associated with drug side effects are far, far less worrisome than the risks of not treating the condition aggressively. “Patients are scared of the treatment, but I stress to them that uncontrolled disease is much more risky, especially when you consider the danger of developing MAS,” says Sura. And the outcome is hopeful for those undergoing drug treatment: “Children tend to do really well with treatment, and we can prevent long-term effects of the disease,” says Mehta.

In addition to drug therapy, regular physical activity — especially for children, who are still growing and developing — is key to keeping joints flexible and muscles strong (which is important for supporting joints), and in helping to reduce pain.

Does this patient have juvenile inflammatory arthritis?

Juvenile inflammatory arthritis (aka juvenile idiopathic arthritis, JIA) is, by definition, a diagnosis of exclusion. The term itself encompasses, at a minimum, seven different patterns of arthritis. The overall definition is “an inflammatory arthritis beginning before the patient’s 16th birthday, lasting 6 weeks or more in the absence of any other cause.”

The subtypes are:

  • Oligoarticular arthritis, persistent.

  • Oligoarticular arthritis, extended.

  • Polyarticular arthritis, rheumatoid factor negative.

  • Polyarticular arthritis, rheumatoid factor positive.

  • Systemic Onset.

  • Seronegative arthritis and enthesitis.

  • Psoriatic arthritis.

Each subtype has been strictly defined with its own exclusion criteria, which are necessary and useful for research studies. Practically speaking, there are patients who do not fit neatly into any definition and fall into the last category of “undifferentiated”.

Oligoarticular arthritis

The most common presentation of JIA is an oligoarticular arthritis, particularly in the knee, although the ankle and wrist joints are often affected. By definition, oligoarthritis is arthritis in four or fewer joints. Persistent oligoarthritis remains as four or fewer joints through the lifetime of the disorder. It most commonly presents in girls between the ages of 2 and 5, with a female to male ratio of approximately 4:1.

The arthritis is relatively painless and the most common presenting symptom, other than obvious joint swelling, is an altered gait, i.e. “My child walks funny”. These children most often have a positive ANA and are at highest risk for an associated asymptomatic anterior uveitis. Extended oligoarthritis remains as such during the first 6 months to 1 year, but a small number of additional joints will become inflamed after that time.

Polyarticular arthritis, rheumatoid factor negative

Polyarticular arthritis, rheumatoid factor negative is an arthritis of five or more joints, developing within the first 6 months of disease. It most often has its onset before age 5, although it is not uncommon to start later in childhood. It is also more common in girls than boys with an estimated ratio of 3:1.

Polyarticular arthritis, rheumatoid factor positive

Polyarticular arthritis, rheumatoid factor (RF) positive disease is an arthritis of five or more joints in the presence of a positive RF, which should remain positive in a second assay, at least 3 months after the initial test. Its most common onset is at puberty or in adolescence, but RF positive arthritis is not uncommon in younger children. It most often mimics adult-onset rheumatoid arthritis with small joint, bilaterally symmetrical arthritis. Like adult RA, it is most predominant in females with the female: male ratio estimated at 6:1 in some studies.

Systemic Onset juvenile idiopathic arthritis

Systemic Onset juvenile idiopathic arthritis (SOJIA) (in the past called Still’s disease) can have either a polyarticular or oligoarticular presentation of arthritis, together with fever and rash. The fever is classically described as “quotidian” or a daily fever spike, which will rise to above 101°F or 38.5°C and return to normal within several hours in the absence of antipyretics. There may be one or two fever spikes/day.

Early on in the disease, the fevers may not follow this classic pattern but after 1-2 weeks will develop the quotidian pattern. The rash of Systemic Onset arthritis is a slightly raised, salmon-colored rash. It will come and go (evanescent) and will reappear in different areas of the body (non-fixed) with a predilection for the warmer sites such as the axillae and trunk. It can appear urticarial and in some cases will be pruritic.

The rash most often is seen at the time of the fever, but other physical stimuli such as heat or scratching the skin will bring it out (Koebner phenomenon). Systemic arthritis is seen throughout childhood and adolescence with essentially an equal F:M ratio.

Enthesitis-related arthritis

Enthesitis-related arthritis (ERA) may be an oligoarticular or polyarticular disorder, accompanied by tenderness at the entheses. This definition encompasses a group of disorders including juvenile ankylosing spondylitis, arthritis associated with inflammatory bowel disease and what in past was labeled type II pauciarticular JRA. It is often HLA-B27 positive and has an onset after age 6. It is more common in males with a sex ratio F:M of 1:7 or more.

The involved joints are most commonly hips, knees, ankles and sacroiliac joints, but spinal involvement often occurs later on in the course of the arthritis. Acute anterior uveitis is an associated feature. It is often symptomatic, but may be silent, similar to that seen in oligoarticular JIA.

Psoriatic arthritis

Psoriatic arthritis is an arthritis associated with psoriasis. In the absence of psoriasis, dactylitis and the typical psoriatic nail changes such as pitting and onycholysis are sufficient to make the diagnosis. Similarly in the absence of psoriasis, arthritis with either of the above manifestations along with a first degree relative with psoriasis is diagnostic of psoriatic arthritis.

It is usually an asymmetric oligoarthritis involving small and medium to large joints. It may involve the entheses and at times is difficult to distinguish from ERA. The female to male ratio is approximately 2:1. The mean age of onset has been reported as 6 years.

Differential diagnoses

The differential diagnoses of the arthritis in children are dependent on the duration of the arthritis, pattern of expression and associated signs and symptoms.

An acute onset monoarticular arthritis associated with severe pain is suggestive of a septic joint, associated osteomyelitis or tumor. The pain can be of such severity that the patient has difficulty falling asleep or can be awakened with pain. The patient may or may not have fever. However, Toxic Synovitis, particularly of the hip, can be extremely painful. It is not usually associated with fever.

Lyme arthritis, which must be considered in any patient living in or having visited an endemic area, is usually painless. It is often an intermittent arthritis of several days duration associated with an extremely large effusion.

Pain is a much more common complaint in patients with polyarticular JIA. However, with exquisitely painful arthritis, a tumor diagnosis – leukemia, lymphoma or metastatic solid tumor – must be considered. A bacterial etiology, in the absence of immune dysfunction, is unlikely in polyarticular disease. Chronic recurrent multifocal osteomyelitis, a sterile bone inflammation of unknown etiology, is also to be considered.

A multi-joint arthritis can be triggered by any number of viruses, with rubella and hepatitis B being the most common in unvaccinated persons and parvovirus B19 likely the most frequent in North America. Alpha viruses triggering arthritis and rash are seen in Australia and South Asia. Epstein-Barr virus, cytomegalovirus, adenovirus, and herpes viruses have also been reported to cause arthritides in susceptible individuals.

Gastrointestinal infections with salmonella, shigella, yersinia and campylobacter can trigger a reactive arthritis.

Other rheumatologic disorders such as Systemic Lupus Erythematosus (SLE), Mixed Connective Tissue Disease (MCTD), and Sarcoidosis, among others can mimic JIA.

What tests to perform?

Laboratory evaluation is dependent on the associated signs and symptoms as well as the number of joints involved. Recommended laboratory tests, reason for ordering and interpretation are as follows:

White Blood Cell Count (WBC)

WBC will be elevated in Systemic Onset JIA often to over 20,000. WBC may be modestly elevated in polyarticular disease. It should be normal in oligoarticular JIA, psoriatic arthritis, and ERA. WBC may be normal, elevated or low in leukemic disease; there may be blast forms. WBC is low in SLE.

Hemoglobin/Hct

The hemoglobin may be modestly to severely low (below 7g) in SOJIA, arthritis associated with active inflammatory bowel disease, or other rheumatologic disorders. It may be modestly low in polyarticular arthritis. It may be normal or very low in leukemic disease. It should be normal in oligoarticular arthritis.

Differential count

In SOJIA there is most often a neutrophil predominance that may be indistinguishable from a bacterial infection. In leukemic disease there may be blast forms. The differential is usually normal in both polyarticular and oligoarticular juvenile arthritis.

Platelet count

In both SOJIA and polyarticular JIA the platelet count is elevated, reflecting an inflammatory process. In SOJIA, it may be as high as 1 million. In leukemias, the platelet count is most often low to normal. In oligoarticular JIA, the platelet count should be in the normal range.

ESR and/or CRP

These are markedly elevated in SOJIA and usually somewhat elevated in polyarticular JIA and ERA. They are essentially normal in oligoarticular arthritis; if elevated a consideration of another inflammatory process such as IBD should be entertained.

Hepatic function panel

Transaminases are usually normal to very modestly elevated in SOJIA. A marked elevation is suggestive of a potentially life-threatening complication of Macrophage Activation Syndrome (MAS).

In an acute polyarthritis in the absence of features suggestive of SOJIA, elevated transaminases are suggestive of a viral associated arthritis or SLE. These are normal in polyarticular and oligoarticular JIA. It is also needed as a baseline level to monitor toxicity of therapeutic agents.

Albumin, globulin, A/G ratio often shows a reversal in IBD as well as acute rheumatic fever. Some patients with SLE or MCTD have a markedly reversed A/G ratio even in the absence of renal disease.

Ferritin

Elevated ferritin is found in SOJIA; excessive elevations are suggestive of macrophage activation syndrome (MAS).

Lactate dehydrogenase (LDH)

LDH is a marker of cell death. It is elevated in leukemia and other tumors and high levels, particularly in the presence of severe pain, would suggest an evaluation for tumor should be pursued. Elevations would also be suggestive of a hemolytic process more common to SLE than the juvenile arthritides.

D-dimer

This marker of active fibrin degradation is elevated in Systemic Onset JIA.

Rheumatoid factor (RF)

Rheumatoid factor should be ordered in patients with polyarticular arthritis and for research classification. As patients with SLE and chronic bacterial infections can be RF positive, it is not diagnostic for RF positive polyarticular JIA. It is not positive in the oligoarticular disorders, psoriatic arthritis or ERA. It may be useful to follow as some patients RF turns negative when their disease is controlled. Two positive tests, 12 weeks or more apart, are necessary to classify patients with having RF positive arthritis.

Anti-cyclic citrullinated peptide antibody (anti-CCP)

This test is more specific than RF for classic rheumatoid arthritis. It is useful as an aid to diagnosis in polyarticular arthritis, but like RF should be ordered in polyarticular disease and for research classification.

ANA

ANA is positive in a large fraction of the healthy population; it is therefore not a helpful screen for rheumatologic disease. ANA is only useful as a diagnostic test in those rare situations where it is necessary to help distinguish JIA from SLE. In patients with JIA, ANA should be tested in order to classify the frequency of ophthalmologic examinations to evaluate for uveitis. Patients who are ANA positive are at the highest risk for this complication.

HLA-B27

This should be ordered for research classification purposes as it is not useful as a diagnostic test. Approximately 8-10% of the Caucasian population will be positive.

Atypical ANCA/anti-S. cerevisiae antibody panel

Patients with enthesitis-related arthritis and whose symptoms (low hemoglobin, weight loss, abdominal pain) are suggestive of IBD might benefit from a serologic screen for these diseases. Even if these are negative, a high index of suspicion suggests consideration of a gastroenterology evaluation.

Joint fluid aspiration

A joint fluid aspiration with bacterial culture and Gram stain is strongly recommended in patients with acute arthritis, fever and pain, particularly with refusal to bear weight. Joint fluid WBC count and differential is also recommended. However, WBC of over 25,000 with a predominance of neutrophils can be seen in JIA and Lyme arthritis as well as in a septic joint

Imaging

Patients with arthritis should have standard x-rays of the affected joints performed to evaluate for signs of early erosive disease, tumor or infection at initial diagnosis.

Patients who have pain at rest or whose pain is out of proportion to what is commonly seen in arthritis should have the affected area imaged by MRI. In general, evaluation for structural derangement (e.g. torn meniscus) does not require intravenous gadolinium contrast media. However, evaluation of active synovitis is best seen by comparison of pre- and post-contrast images.

The use of diagnostic ultrasound in pediatric arthritis is a developing field. Follow-up x-rays can be considered every 1-2 years, depending on response to therapy.

Biopsy

Biopsies in JIA per se are rarely required. Patients with fever and arthritis who do not demonstrate the classic SOJIA rash, quotidian fever or laboratory abnormalities of this disorder should be considered for a bone marrow aspiration +/- biopsy as leukemia can have an arthritic presentation in a minority of cases. Similarly, patients whose imaging studies are suggestive of another disorder should be considered for a biopsy of the suspicious lesion.

There are no large scale, long term outcome data for the various types of JIA. The relatively recent availability of biologic agents may have a significant effect on improving the long term outcome. However retrospective chart reviews have been performed to evaluate periods of clinical remission off medication (remaining in remission for >1 year off medication).

How should patients with juvenile inflammatory arthritis be managed?

Management strategies differ depending on the type of JIA. As uveitis has been reported in all types of JIA, a slit lamp examination at diagnosis and follow up at appropriate intervals is critical.

Patients with an oligoarticular pattern of arthritis should be managed with anti-inflammatory doses of NSAIDs while the evaluation for JIA mimics is proceeding. After other diagnoses are eliminated from consideration, intra-articular long-acting corticosteroid injection (IACI) is recommended. In many studies using hexacetonide as the remittive agent has provided the longest duration of response.

As to the number of joints that can be injected, it is left to the discretion of the treating physician after consideration of the age of the patient, need for general anesthesia and any co-morbid conditions.

The response rate and duration has been reported as 60-80% at 6 months. In the face of complete resolution of the arthritis, concomitant therapy is not necessary. Unless the response is of short duration, i.e. less than 3-4 months, a relapse can be treated with a second injection. Those patients who do not respond to IACI should be treated with the same regimen as patients with polyarticular disease.

Polyarticular arthritis (RF-positive and -negative)

As with oligoarticular arthritis, NSAIDs are the agent of choice while other diagnoses are under consideration. Once the diagnosis is assured, the early use of disease-modifying anti-rheumatic drugs (DMARDs) is recommended.

Methotrexate is generally accepted as the initial DMARD to be used at doses of 15 mg/m² or 0.6 mg/kg once weekly, preferably subcutaneously. Some investigators have demonstrated that doses higher than these do not give any additional improvement, but others have recommended doses as high as 1 mg/kg, up to 40 mg if there is an inadequate response to initial therapy.

Methotrexate alone has been demonstrated to elicit remission while on medication in up to 60% of patients after a mean of 17 months of therapy. Currently, it has been recommended that if significantly active disease remains between 3-6 months after starting methotrexate therapy, a biologic agent, most commonly a TNF-alpha inhibitor should be started. There is no consensus as to whether methotrexate should be continued with the initiation of the biologic agent. Those patients who do not respond to an initial TNF-alpha inhibitor after 3-6 months should be treated with either a second TNF-alpha inhibitor or abatacept.

Corticosteroid injections to particularly painful joints or those resistant to therapy are recommended. Systemic corticosteroids should be reserved to treat those patients whose activities of daily living are severely compromised, with the goal of tapering rapidly as response to long term management is achieved. Although leflunomide has been demonstrated to be effective in JIA, it has not been approved for use in this disease.

Systemic Onset arthritis

Management is distinct depending on the features of the disease. If systemic features predominate (fever, rash), NSAIDs and corticosteroids are initial therapy. If these features are mild, a trial of 2 weeks of NSAIDs alone may be attempted before corticosteroids are given. Upon response, the steroids should be withdrawn via a slow (2-3 months) taper. As some patients have a monocyclic course of SOJIA, some patients may find this course of therapy to be adequate.

If arthritis is a primary feature, NSAIDs and methotrexate can be initiated, similar to therapy for polyarticular JIA. The place for biologic therapy in SOJIA is not yet clear. Tocilizumab, an IL-6 receptor inhibitor (8-12 mg/kg i.v. q 2 weeks), is approved for use in SOJIA and was highly effective in published studies. However, its use is somewhat limited by the need for I.V. infusions.

Anakinra, an IL-1 receptor antagonist, has also been demonstrated to be effective in SOJIA but is not approved for this disease. It is given as a daily injection and has the convenience of self-administration.

Canakinumab, a monoclonal antibody which inhibits IL-1 has recently been approved for use in SOJIA. It is a monthly injection. The TNF-alpha inhibitors are approved for polyarticular juvenile arthritis and can be used in patients with SOJIA. However, they appear to be less effective in this disease than in other types of polyarticular disease.

What happens to patients with juvenile inflammatory arthritis?

The outlook for patients with JIA is markedly improved from 40 years ago due to the use of methotrexate and biologic agents. However, it has become clear that these disease(s) do not vanish upon achieving majority. In a review of over 400 patients, 89% achieved a state of inactive disease, but only 26% were able to maintain that state off medication for 1 year. Of those, only 6 % remained in remission after 5 years.

Untreated or unresponsive disease can result in short stature, limb length discrepancy, joint erosions, joint contractures, muscle atrophy of an affected limb, all of which can adversely affect the quality of life.

Methotrexate can provoke nausea and vomiting, which leads to discontinuation of therapy. Methotrexate can cause birth defects in exposed fetuses and can cause early abortions. Hence, adolescents must be cautioned about appropriate contraception.

TNF-alpha inhibitors render patients more susceptible to intracellular pathogens and certain fungi. Testing for tuberculosis before starting anti-TNF therapy is recommended.

The causal role of TNF-alpha inhibitor in causing hematologic malignancies remains unclear in JIA as it does in adult disease. An increased incidence of these cancers has been reported. However, it is not known whether children with JIA experience these cancers with an increased frequency as compared to the general population.

How to utilize team care?

Ophthalmologic consultation is mandatory to diagnose and treat occult uveitis. Hematology consultation may be helpful to diagnose Systemic Onset JIA if arthritis is minimal and a bone marrow aspiration is necessary.

Orthopedic consultation to perform a joint aspiration for culture may be important in painful monoarticular arthritis when a septic joint is under consideration. Pain consultation will help in the management of significant arthritis-associated pain.

Nursing is critical to help teaching for joint injections and instruct patients on medications and side effects.

Pharmacy has an important role in detection of any drug interactions.

Dieticians are helpful in providing advice regarding healthful diets and assuring adequate calories for growth and development.

Physical and Occupational therapists are essential to maintain joint motion and recommend any aids to maintain activities of daily living.

Child Life Therapy is of great assistance in helping the child cope with the frequent needle sticks needed to administer medications and blood draws to monitor disease activity and drug toxicity.

Are there clinical practice guidelines to inform decision making?

An updated set of guidelines for JIA therapy has recently been published. Guidelines recommending frequency of ophthalmologic follow up are available. Guidelines are limited in that recommendations include off-label use of available medications and do not consider the most recently approved therapy.

What is the evidence?

Beukelman, T, Patkar, NM, Saag, KG, Tolleson-Rinehart, S, Cron, RQ, DeWitt, EM. “2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features”. Arthritis Care Res (Hoboken ). vol. 63. 2011. pp. 465-82. (An algorithm for therapy of all types of JIA, with stratification for higher risk subgroups using consensus criteria. An excellent reference but the recommendations include off-label use of some drugs and have not considered tocilizumab.)

Gottlieb, BS, Keenan, GF, Lu, T, Ilowite, NT. “Discontinuation of methotrexate treatment in juvenile rheumatoid arthritis”. Pediatrics. vol. 100. 1997. pp. 994-7. (A retrospective review demonstrating differences in time to achieve remission varies with type of JRA and that 50% of children will relapse in less than 1 year off methotrexate as a solo agent.)

Heiligenhaus, A, Niewerth, M, Ganser, G, Heinz, C, Minden, K. “Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines”. Rheumatology (Oxford). vol. 46. 2007. pp. 1015-9. (An analysis of the recommendations for the frequency of ophthalmologic examinations based on JIA type, age of onset and duration of disease.)

Lovell, DJ, Ruperto, N, Goodman, S, Reiff, A, Jung, L, Jarosova, K. “Adalimumab with or without methotrexate in juvenile rheumatoid arthritis”. N Engl J Med. vol. 359. 2008. pp. 810-20. (An open label run-in study which demonstrates the efficacy of adding adalimumab to the therapy of patients who have active disease on methotrexate.)

Lovell, DJ, Giannini, EH, Reiff, A, Cawkwell, GD, Silverman, ED, Nocton, JJ. “Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group”. N Engl J Med. vol. 342. 2000. pp. 763-9. (A landmark study which piloted the open label lead-in design. It was the first double-blind placebo controlled study of a biologic agent in children and demonstrated the efficacy of this TNF-alpha inhibitor in polyarticular course JIA.)

Lovell, DJ, Reiff, A, Ilowite, NT, Wallace, CA, Chon, Y, Lin, SL. “Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis”. Arthritis Rheum. vol. 58. 2008. pp. 1496-504. (The study demonstrates the durability of response and safety of etanercept as a follow up to the original 58 children who remained on open-label extension. Twenty six were in the 8th year of study. The most common SAE was disease flare.)

Niehues, T, Horneff, G, Michels, H, Hock, MS, Schuchmann, L. “Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria”. Rheumatol Int. vol. 25. 2005. pp. 169-78. (A working group report which upon literature review reaches the consensus that methotrexate is efficacious in JIA.)

Pascual, V, Allantaz, F, Arce, E, Punaro, M, Banchereau, J. “Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade”. J Exp Med. vol. 201. 2005. pp. 1479-86. (This study demonstrates the role of IL-1 in Systemic Onset JIA and explores the molecular biology of this disease as well as the response to an IL-1 receptor antagonist.)

Ringold, S, Seidel, KD, Koepsell, TD, Wallace, CA. “Inactive disease in polyarticular juvenile idiopathic arthritis: current patterns and associations”. Rheumatology (Oxford). vol. 48. 2009. pp. 972-7. (This retrospective study demonstrates that of 104 children with polyarticular JIA followed over 30 months, 78% achieved inactive disease by the end of the first year. However, the duration of inactive disease was on average only 8 months.)

Ringold, S, Weiss, PF, Beukelman, T, Dewitt, EM, Ilowite, NT, Kimura, Y. “2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications”. Arthritis Rheum. vol. 65. 2013Oct. pp. 2499-512. (An update of the initial algorithm of therapy with the inclusion of more biologic agents and suggestions for their early use in disease.)

Ruperto, N, Murray, KJ, Gerloni, V, Wulffraat, N, de Oliveira, SK, Falcini, F. “A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate”. Arthritis Rheum. vol. 50. 2004. pp. 2191-201. (An open label trial that demonstrates 15 mg/m2 parenteral methotrexate, to a maximum of 20 mg/week is adequate therapy. Higher doses have no additional benefit.)

Ruperto, N, Lovell, DJ, Quartier, P, Paz, E, Rubio-Perez, N, Silva, CA. “Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial”. Lancet. vol. 372. 2008. pp. 383-91. (Using the same open-label run in period as was used in the initial etanercept trial, abatacept was shown to be effective therapy as measured by time-to-flare on treatment, with some children achieving inactive disease status.)

Ruperto, N, Lovell, DJ, Quartier, P, Paz, E, Rubio-Perez, N, Silva, CA. “Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis”. Arthritis Rheum. vol. 62. 2010. pp. 1792-802. (They show that abatacept treatment resulted in maintained or improved response after 21 months of therapy, with 39% achieving an ACR100 status. Of those children who did not achieve an ACR30 at the end of the initial open label run in, clinically meaningful responses were achieved after long term open label therapy in 73%.)

Ruperto, N, Lovell, DJ, Cuttica, R, Woo, P, Meiorin, S, Wouters, C. “Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension”. Ann Rheum Dis. vol. 69. 2010. pp. 718-22. (Of the original efficacy trial, 39 patients completed a 4 year open label extension. Ten percent achieved an inactive disease status by year 4 but there was a high drop out rate.)

Wallace, CA, Giannini, EH, Huang, B, Itert, L, Ruperto, N,. “American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis”. Arthritis Care Res (Hoboken ). vol. 63. 2011. pp. 929-36. (Validation of the criteria to define remission, both on and off medications in JIA.)

Yokota, S, Imagawa, T, Mori, M, Miyamae, T, Aihara, Y, Takei, S. “Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial”. Lancet. vol. 371. 2008. pp. 998-1006. (The first controlled study showing an IL-6 receptor antagonist is efficacious in Systemic Onset JIA, with 90% of patients achieving a 70% improvement by 48 weeks.)

Rheumatoid arthritis or RA is a form of inflammatory polyarthritis that can lead to joint destruction, deformity, and loss of function. Swelling of the small joints, especially in the hands and feet, is the hallmark of the disease, but most joints in the body can become affected. In addition to the joints, other manifestations of the disease can be seen including subcutaneous nodules, eye inflammation, lowering of the white blood count, and lung disease. Frequent symptoms include fatigue and joint stiffness, especially in the morning and after prolonged periods of rest.

Without appropriate treatment, chronic pain, disability, and excess mortality are unfortunate outcomes of this disease. RA causes joint damage in 80% to 85% of patients, with the brunt of the damage occurring during the first 2 years of the disease. Left untreated, the risk of mortality is increased. Untreated people with RA are twice as likely to die compared with unaffected people the same age.

Common causes of mortality in RA include cardiovascular disease, which accounts for approximately one third to one half of RA-related deaths, and infection, which is associated with approximately one quarter of such deaths. RA is also known to be associated with higher risks for lymphoma, anemia, osteoporosis, and depression.

Rheumatoid Arthritis Disease Information

  • Signs and Symptoms of Rheumatoid Arthritis
  • Pathophysiology of Rheumatoid Arthritis
  • Treatment of Rheumatoid Arthritis

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Is Still’s Disease an Autoinflammatory Syndrome?

Abstract

Systemic juvenile idiopathic arthritis (sJIA), formerly called Still’s disease, is officially classified as a subset of juvenile idiopathic arthritis (JIA). Beside arthritis, it is characterized by prominent systemic features and a marked inflammatory response. Even if it is still included in the group of juvenile arthritides, sJIA is set apart from all the other forms of JIA. This disorder has markedly distinct clinical and laboratory features suggesting a different pathogenesis. sJIA does not show any association with HLA genes or with autoantibodies and is characterised by an uncontrolled activation of phagocytes with hypersecretion of IL-1 and IL-6. Based on clinical and laboratory features, as well as on new acquisitions on the pathogenesis, it seems evident that sJIA is an autoinflammatory disease related to abnormality in innate immune system. The new insights on the pathogenesis of sJIA have therefore dramatically changed the approach to treatment, with the development of targeted treatments (anti-IL-1 and anti-IL-6 agents) more effective and safer than earlier medications.

1. Introduction

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. It is a heterogeneous disease of unknown aetiology encompassing different forms of arthritis, which begins before the age of 16 years and persists for more than 6 weeks. JIA classification is based on the number of joints involved during the first 6 months of disease and on the extra-articular involvement.

Most JIA subsets are characterized by female predominance, prominent arthritis, various degrees of biological inflammation, a strong susceptibility associated with some HLA class II antigens, and an overt or suspected autoimmunity, for example, antinuclear antibodies (ANA) rheumatoid factor (RF) and anticyclic-citrullinated peptide (anti-CCP) antibodies. Dramatic response to anti-TNFα treatments is an important feature, which supports the role of the adaptative immunity in generating chronic inflammation.

2. Still’s Disease as a Subset of Juvenile Idiopathic Arthritis

sJIA was officially classified as a subset of JIA, and the presence of at least one active synovitis was mandatory to support the diagnosis, even if some patients do not present arthritis at disease onset . Moreover, sJIA can have a highly variable outcome, and a monocyclic course with minimal or absent articular complications was reported in about 50% of 56 cases . Other differences with the other subtypes of JIA include an equal sex ratio, marked systemic features with spiking fever, a salmon-colored evanescent rash that comes and goes with fever, serositis, and the absence of autoantibodies.

The recognition of a group of rare diseases, the autoinflammatory diseases (AIDs) appearing to be primarily inflammatory in nature because of their periodicity, strong associations with exogenous triggering events, and lack of associations with class II MHC haplotypes, brought some evidence to look at sJIA as a distinct entity from other subtypes of JIA. Recent advances in understanding the role of IL-1 in the pathogenesis of sJIA brought strong arguments to consider the disease as autoinflammatory rather than autoimmune.

3. sJIA as Autoinflammatory Disease (AID)

AIDs are a large group of diseases affecting primarily the innate immune system. Despite their different molecular mechanisms, they are all characterized by an inappropriate activation of the phagocytes, the key cells of innate immune system. They have in common an overproduction of IL-1β, a prototype of proinflammatory cytokine having pleiotropic properties (Figure 1). Typical clinical manifestations of AIDs are recurrent, seemingly unprovoked, inflammatory attacks of fever with skin involvement, serositis, and arthritis. Laboratory examinations during fever attacks show a prominent acute inflammatory response characterised by a marked leukocytosis (neutrophilia), increased CRP, and serum amyloid protein (SAA). Unlike patients with autoimmune diseases, patients with AID lack high-titers autoantibodies and antigen-specific T cells.


Figure 1
Main effects of IL-1. (1) The action on the hypothalamic-pituitary axis influences the production of the following hormones: adrenocorticotropic hormone (ACTH), growth hormone (GH), vasopressin or antidiuretic hormone (ADH), and somatostatin. IL-1 is responsible for the constitutional symptoms in IL-1-dependent diseases (fever, fatigue, anorexia, and growth delay). (2) Liver synthesis and secretion of acute phase proteins (both by direct IL-1 action and via IL-6 induction). (3) Osteoclasts activation and matrix metalloproteinases (MMPs) synthesis by chondrocytes, resulting in bone resorption and cartilage degradation, respectively. (4) Innate immune system cells activation and proliferation, enhanced gene transcription of proinflammatory molecules (inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX2), and phospholipase A2), proinflammatory cytokines, adhesion molecules, and colony-stimulating factors (CSF).

Historically, AIDs comprised rare disorders of Mendelian inheritance like cryopyrin associated periodic syndrome (CAPS) (autosomal dominant) and familial Mediterranean fever (autosomal recessive). With time, other diseases, less rare and of multifactorial inheritance, like pFAPA syndrome (periodic fever, aphtous, pharyngitis, and adenitis), have joined the group. AIDs uniquely respond to specific IL-1β blockade unlike autoimmune diseases that respond dramatically to anti-TNFα treatments. Over the past decade, a growing number of systemic inflammatory disorders have been placed into the group of AIDs given their response to anti-IL-1 drugs, including sJIA and adult Still’s disease (AoSD) .

4. Clinical Characteristics of sJIA

sJIA represents 10–15% of all JIA, with a broad peak of onset between 0 and 5 years of age, with 2 years being the most common , and an equal sex ratio. It is called Still’s disease (AoSD) when it occurs in patients over the age of 16. AoSD is less common than sJIA but the disease features are the same, even severe arthritis occurs exceptionally. Therefore, sJIA and AoSD likely represent a continuum of the same disease entity .

SJIA is defined by the presence of arthritis in one or more joints associated with spiking fever (a 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, nonfixed erythematous rash that accompanies fever spikes), generalized lymphadenopathy, hepatomegaly and/or splenomegaly, or serositis (pleuritis or pericarditis).

None of the clinical signs is specific to sJIA, especially at presentation, and differential diagnosis can be difficult (bacterial and viral infections, malignancy, and other rheumatic diseases). Moreover, arthritis may be absent at onset and can develop during disease course, usually progressing to a polyarticular and symmetrical involvement.

The disease course can be highly variable. It can be monocyclic, polycyclic with relapses followed by intervals of remission, or unremitting, leading about half of the patients to a chronic destructive arthritis representing the major long-term problem.

SJIA shows a strong association with macrophage activation syndrome (MAS), a form of reactive hemophagocytic lymphohistiocytosis (HLH), characterised by an uncontrolled activation of well-differentiated macrophages releasing a high amount of proinflammatory cytokines, particularly IL-18, which belongs to the IL-1 family. MAS is a severe, potentially life-threatening disorder, and clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, neurologic dysfunction, and coagulopathy. Some studies suggest that up to 50% of sJIA patients might have occult MAS . Heterozygous mutations in genes involved in HLH have been described in some subsets of SoJIA patients and might play a role in the development of MAS . Specific criteria for sJIA-associated MAS have been recently proposed . Interestingly, MAS has been recently included as an individual group of autoinflammatory diseases in an updated classification proposed by Masters et al. .

5. Laboratory

Laboratory tests show a marked inflammatory response with leukocytosis (neutrophilia), thrombocytosis, high C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). In most cases a microcytic anaemia related to prominent inflammation is detected.

Markedly distinct clinical and laboratory features of sJIA suggest a different pathogenesis from the other forms of JIA. Oligopolyarticular form of JIA (the most frequent form) is an antigen-driven lymphocyte-mediated autoimmune disease with abnormality in the adaptive immune system . On the other side, sJIA does not show any association with HLA genes nor with autoantibodies and is characterised by an uncontrolled activation of phagocytes. These features are all consistent with what is observed in autoinflammatory diseases .

6. Pathogenesis of sJIA

Phagocytes including monocytes, macrophages, and neutrophils are the principal activated cells during the early course of sJIA. It has been shown that these cells secrete very high levels of pro-inflammatory cytokines (IL-1, IL-6, IL-18) as well as proinflammatory proteins (S100A8, S100A9, and S100A12) .

7. The Role of IL-1 in sJIA

The discovery of an important role of IL-1 in the etiopathogenesis of sJIA came from studies that analyzed gene transcription patterns in peripheral blood mononuclear cells (PBMCs) from healthy individuals, incubated with serum from patients with active disease. Serum from sJIA patients can induce the transcription of IL-1β and various IL-1-related genes in healthy PBMCs . Activated monocytes from sJIA patients secreted higher amounts of IL-1 (16-fold greater) compared to monocytes from healthy controls. The role of IL-1 was confirmed by studies showing the efficacy of anakinra, a recombinant anti-IL-1 receptor antagonist . Similar results were also reported for the related disorder AoSD .

Several open-label studies reported the clinical efficacy of anakinra in sJIA patients, with response rates around 50% . More recently, a randomised double-blind placebo-controlled study in sJIA reported similar clinical response rates and normalization of the expression of genes involved in IL-1β regulation . Despite a good short-term clinical control, most patients experienced loss of efficacy with ongoing anakinra treatment. The latter might be due to patients selection, being more likely observed in patients with long-standing refractory disease or in those with polyarticular involvement. Accordingly, in a case series of 22 pediatric sJIA patients, a low joint count and high blood PMN were positive predictors of clinical response to anakinra .

Nigrovic et al. recently reported a retrospective study with anakinra as first-line treatment in sJIA, with 59% of patients undergoing remission . Early introduction of anakinra hindered arthritis relapse in 90% of patients. Further studies on the efficacy and safety of anakinra as first-line treatment are needed.

The response to anakinra can therefore identify two subsets of sJIA patients, one with dramatic response similar to that observed in (CAPS) and the other resistant or with an intermediate response .

Preliminary results on canakinumab and rilonacept treatment showed a high efficacy in sJIA patients .

8. The Role of IL-6

The levels of IL-6 are markedly elevated in the serum and synovial fluid of sJIA compared to other subtypes of JIA. Circulating levels are increased during the peak of fever and correlate with clinical activity, systemic features as thrombocytosis and microcytic anemia, growth retardation, osteopenia, and the extent and severity of joint involvement . It has been suggested that polymorphisms involving the promoter elements and genes encoding IL-6 may contribute to the overproduction of IL-6 in sJIA .

The major pathogenic role of IL-6 has been confirmed by the marked efficacy of tocilizumab, a monoclonal antibody targeting the IL-6 receptor, in reducing systemic features like fever and rash and improving inflammatory arthritis .

9. The Role of IL-18

IL-18 is a member of the IL-1 cytokine superfamily, produced mainly by monocytes macrophages in response to viral or bacterial stimuli, which may contribute to the inflammatory process. sJIA, AoSD, and MAS are all characterised by extremely high IL-18 serum levels . Some reports have recently shown its elevation during sJIA flares and during the active phase of MAS . A defective phosphorylation of IL-18 receptor has been reported in sJIA patients .

Based on clinical and laboratory features as well as on the new acquisitions on the pathogenesis, it seems evident that sJIA is an autoinflammatory disease related to abnormality in innate immune system. The marked activation of innate immune system responsible for the multisystem inflammation and the lack of any consistent association with HLA antigens or autoantibodies allow to consider sJIA as an autoinflammatory disease. This hypothesis is further confirmed by the response to anti-IL-1 and IL-6 agents.

Nevertheless, even if there is evidence for IL-1β deregulation on sJIA, further fundamental experiments are needed to explain whether this is due to intrinsic abnormalities in caspase-1 activation or it is rather linked to extrinsic mechanisms involving, for example, the TLRs and NF-KB activation pathway. From a clinical point of view, not every patient may respond completely to IL-1 inhibition, and the presence of polyarthritis is associated to worse results. The development of arthritis could be associated to a cytokine shift towards IL-6 and TNFα. The response of sJIA to tocilizumab (anti-IL-6 agent) is not contradictory because the IL-1β induces downstream secretion of IL-6, which shares many biological properties with IL-1.

The new acquisitions on the pathogenesis of sJIA have therefore dramatically changed its management, with the development of targeted therapy more effective and safer than earlier medications.

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