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Enthesitis-Related Arthritis

Juvenile Idiopathic Arthritis Enthesitis Related Arthritis

Enthesitis-related arthritis (ERA) is an inflammatory disease of the entheses, peripheral joints, as well as the axial skeleton. This HLA B-27 condition is a subtype of juvenile idiopathic arthritis.

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Patients with ERA typically experience episodes of inflammation in the tendons and ligaments, pain and tenderness in the enthesis and possibly swelling. They also have features of arthritis. Hence the clinical picture of is a combination of both subtypes.

The onset of ERA is typically insidious. Children with ERA initially exhibit moderate and intermittent involvement of multiple peripheral joints and entheses [17] with oligoarticular arthritis of the lower limbs. At the time of diagnosis, the knees, hips, ankles and sacroiliacs are affected and the presence of tarsitis is indicative of ERA [1]. As the disease progresses, axial involvement becomes apparent.

The overall health status of these individuals is poor [17]. When the disease is active, up to 10% of patients will develop systemic manifestations such as fever, weight loss, fatigue, muscle weakness, muscle atrophy, and lymphadenopathy [18]. The presence of fever may cause misidentification of ERA for septic arthritis and hence delay the diagnosis.

Diagnostic criteria

The ILAR diagnostic criteria for ERA outlines that arthritis and/or enthesitis should be accompanied with two of the following characteristics, which are 1) sacroiliac tenderness and/or inflammatory pain in the lumbosacral spine, 2) positive HLA-B27 test, 3) the onset of arthritis in a male aged 6 years or older, 4) acute anterior uveitis , and 5) a positive family history of diseases associated with HLA-B27 (enthesitis-related arthritis, ankylosing spondylitis, reactive arthritis, acute anterior uveitis, or inflammatory bowel disease along with sacroiliitis).


Rare sequelae include aortic insufficiency, restrictive lung disease, and eye related conditions such as conjunctivitis.

  • Ratings of pain intensity, physical function, and health status differed significantly between JIA categories. In comparison to other categories of JIA, subjects with enthesitis-related arthritis (ERA) reported worse pain and function.[ncbi.nlm.nih.gov]
  • Pelvis radiographs and dynamic magnetic resonance imaging (MRI) scans for SI joints were obtained simultaneously in all patients who developed inflammatory back pain.[ncbi.nlm.nih.gov]
  • In comparison to controls, patients with ERA reported more pain and had lower pain thresholds at every site, including control sites (P 0.001 for all comparisons).[ncbi.nlm.nih.gov]
  • Personal history of buttock pain or abnormal physical examination of sacroiliac joints predicted MRI sacroiliitis with a positive predictive value of 0.75 (95% confidence interval 0.35-0.95).[ncbi.nlm.nih.gov]
  • The SIJs and AJs should both be imaged in patients with ERA with back pain.[ncbi.nlm.nih.gov]
  • Symptoms include: Pain Swelling Inflammation Heat around the affected area In some cases the affected joint, e.g. toe resembles a sausage due to the extent of the swelling.[medic8.com]
  • The symptoms of ERA include pain with swelling, observed more commonly at fingers, toes and heels that look more like sausages due to inflammation at entheses. Some children may also experience pain or/and swelling at pelvis, chest and elbow.[findarthritistreatment.com]
  • It provides crucial information such as soft tissue swelling, synovitis, edema, and any thickening of the tendons or ligaments.[symptoma.com]
  • This can result in pain and swelling in that joint and it commonly occurs around the knee or the back of the ankle.[patientslikeme.com]
  • Just like DMARDs, they slow down the progress of arthritis and reduce pain, swelling and stiffness.[arthritiscare.org.uk]
  • ERA patients with fever had more active disease at disease onset and poorer outcomes than ERA patients without fever.[ncbi.nlm.nih.gov]
  • Fever was defined as an axillary body temperature 37.5 C and higher and classified into irregular fever, intermittent fever and remittent fever [ 10 ].[journals.plos.org]
  • Familial Mediterranean fever (FMF), caused by mutations in the MEFV gene, is a frequent autoinflammatory disorder in the eastern Mediterranean.[ncbi.nlm.nih.gov]
  • The presence of fever may cause misidentification of ERA for septic arthritis and hence delay the diagnosis.[symptoma.com]
  • The photograph shows a typical rash in systemic onset JIA Systemic onset JIA rash in an Indian child The chart below shows the typical fever chart in systemic onset JIA - the fever often occurs in the evening and the rash may appear at times of fever.[pmmonline.org]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019[patientslikeme.com]
  • When the disease is active, up to 10% of patients will develop systemic manifestations such as fever, weight loss, fatigue, muscle weakness, muscle atrophy, and lymphadenopathy.[symptoma.com]
  • Inflammation can also cause fatigue. You might lose your appetite and have trouble gaining weight as you grow. It’s also possible that you may lose weight. Don’t let pain and fatigue get worse. Stay active to reset your body’s sleep cycle.[healthline.com]
  • Symptoms include: Persistent joint pain or swelling Limited range of motion in joints Redness around joints Fever associated with swollen lymph nodes Swelling of the joints Unexplained skin rashes (usually pink) Limping (particularly in the morning) Fatigue[childrens.com]
  • There are a few factors that may cause problems for school attendance: difficulty walking, minor resistance to fatigue, pain or stiffness.[printo.it]
  • Our results provide a good starting point to study ERA patients with systemic features (e.g., fever, anemia, leukocytosis) as the main manifestations at disease onset.[journals.plos.org]
  • A complete blood count (CBC) may reveal anemia, thrombocytosis, and leukocytosis. Additionally, antinuclear antibody (ANA) tests may be positive. A comprehensive range of studies may also be performed.[symptoma.com]
  • Other possible signs include inflammation of the heart or lungs or their outer linings; anemia; or enlarged lymph nodes, liver or spleen. About 10 percent of children with JIA will have the systemic form.[arthritis.org]
  • This test assesses your child for anemia, an abnormally low blood count. Anemia can be a side effect of inflammation caused by from JIA or caused by intestinal inflammation. Comprehensive metabolic panel.[chop.edu]
  • May be seen in polyarticular JIA but is less common Pericarditis, pleuritis, and severe anemia may develop in patients with systemic-onset JIA.[unboundmedicine.com]
Anterior Uveitis
  • The prevalence of all ILAR criteria at diagnosis, except arthritis and acute anterior uveitis, differed significantly across sites (all p CONCLUSIONS: The majority of children had a pauciarticular onset, and several statistically significant clinical[ncbi.nlm.nih.gov]
  • These children are at risk of developing acute anterior uveitis. A recently devised disease activity index, Juvenile Spondyloarthropathy Disease Activity Index (JSpADA), has been validated in retrospective cohorts.[ncbi.nlm.nih.gov]
  • According to these criteria, the disease is defined by the presence of enthesitis and arthritis, or by the presence of arthritis and at least two of the following: sacroiliac pain and/or spinal inflammation, acute anterior uveitis, presence of the HLA-B27[orpha.net]
  • Common clinical manifestations of ERA include arthritis, enthesitis, and acute anterior uveitis. Axial disease is also common in children with established ERA.[dovepress.com]
  • KEYWORDS: Enthesitis-related arthritis; Juvenile idiopathic arthritis; Outcomes; Pathogenesis; Prognosis; Treatment[ncbi.nlm.nih.gov]
  • Abstract Children with juvenile spondyloarthropathy, classified as enthesitis-related arthritis (ERA) under the International League of Associations for Rheumatology classification of juvenile idiopathic arthritis, usually experience both arthritis and[ncbi.nlm.nih.gov]
  • Using the International League of Associations for Rheumatology (ILAR) system for juvenile idiopathic arthritis, most childhood SpA is classified as enthesitis-related arthritis.[ncbi.nlm.nih.gov]
  • Differential diagnosis The differential diagnosis should include infectious arthritis and other inflammatory diseases, as well as haematooncologic diseases that may lead to arthritis (in particular, connective tissue diseases and acute leukaemia).[orpha.net]
  • OBJECTIVE: To evaluate the efficacy and safety of etanercept in patients with enthesitis-related arthritis (ERA) in juvenile idiopathic arthritis (JIA). METHODS: This was a 2-phase study in JIA patients with active, refractory ERA.[ncbi.nlm.nih.gov]
  • Patients with oligoarthritis or polyarthritis who were admitted during the same period (n 55) and individuals from a national population registry (n 55) were matched for sex and age and used as controls.[ncbi.nlm.nih.gov]
  • OBJECTIVE: The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic[ncbi.nlm.nih.gov]
  • Abstract The approval of etanercept for the treatment of the juvenile idiopathic arthritis (JIA) categories extended oligoarthritis (ExtOA), enthesitis-related arthritis (ERA) and psoriasis arthritis (PsA) was recently added to the approval for the treatment[ncbi.nlm.nih.gov]
  • Many children have oligoarthritis of the lower limbs. Oligoarthritis means that the disease involves 4 or fewer joints. Patients developing chronic disease may have polyarthritis.[printo.it]
  • Extended oligoarthritis The Oligoarthritis pattern typically spreads to involve 5 or more joints and shows a tendency for the large joints.[enthesis.info]
Sacroiliac Pain
  • According to these criteria, the disease is defined by the presence of enthesitis and arthritis, or by the presence of arthritis and at least two of the following: sacroiliac pain and/or spinal inflammation, acute anterior uveitis, presence of the HLA-B27[orpha.net]
Joint Tenderness
  • tenderness or inflammatory lumbosacral pain - HLA B27 positive - arthritis in a male over 6 years of age - acute anterior uveitis - history of ankylosing spondylitis, enthesitis related arthritis, sacroillitis with inflammatory bowel disease, reactive[eurotmj.com]
  • ERA was defined according to the ILAR criteria [ 1 ]: onset of arthritis before the 16th birthday and persisting for at least 6 weeks; arthritis and enthesitis, or arthritis or enthesitis with at least 2 of (a) presence of or a history of sacroiliac joint[ped-rheum.biomedcentral.com]
Muscular Atrophy
  • Three patients (6.1%) had severe muscular atrophy. Four (8.2%) patients had growth failure; pubertal delay was seen in 2 (4.1%). Secondary amyloidosis was seen in 1 (2.0%). None of the patients had ocular damage.[ped-rheum.biomedcentral.com]


Children presenting with an arthritis clinical picture warrant a complete assessment through a personal and family history, a thorough physical exam, and the appropriate studies. The diagnosis may not be apparent during the physical exam, and therefore, various studies are utilized for clarification.

Laboratory test

While laboratory studies are not definitive or specific, there may be abnormal findings. For example, inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) may be elevated. A complete blood count (CBC) may reveal anemia, thrombocytosis, and leukocytosis. Additionally, antinuclear antibody (ANA) tests may be positive. A comprehensive range of studies may also be performed.


Ultrasonography can identify enthesitis that was not previously observed on physical examination of the child [19] [20]. Findings with this imaging tool include calcifications, tendon thickening, enthesophytes, hypoechogenicity, and increased power Doppler signal [21]. This technique can differentiate enthesitis from other noninflammatory diagnoses.

The use of ultrasonography is advantageous for children with regards to its noninvasiveness, lack of radiation, easy accessibility, and low cost.

MRI is becoming a routine test in the assessment of sacroiliitis. This study is a sensitive indicator of disease activity , which is demonstrated by subchondral or periarticular bone marrow edema (BME). It provides crucial information such as soft tissue swelling, synovitis, edema, and any thickening of the tendons or ligaments [22].

There is debate regarding the use of whole body MRI (WB-MRI) tests to be used in conjunction with a physical exam and radiographs for the evaluation of the disease activity in these children [22]. While MRI is expensive, it may provide cost-effective benefits in the long-term due to its ability to identify and manage early stages of sacroiliitis.

While radiographs are considered the gold standard for diagnosing juvenile spondyloarthropathy , this modality lacks the sensitivity for the diagnosis of early sacroiliitis. X-rays of single affected joints can be effective in ruling out differential diagnoses. They reveal findings such as soft tissue swelling, osteopenia, osteoporosis, narrowing of the joint spaces, periostitis, growth abnormalities, intra-articular bony ankylosis, etc.

  • A complete blood count (CBC) may reveal anemia, thrombocytosis, and leukocytosis. Additionally, antinuclear antibody (ANA) tests may be positive. A comprehensive range of studies may also be performed.[symptoma.com]
  • Susceptibility to AS varies between different HLA-B27 subtypes; data on the relationship of susceptibility to JIA-ERA with HLA-B27 types are scant.[ncbi.nlm.nih.gov]
  • Forty patients (75.5%) were positive for HLA-B27. MEFV analysis was performed for patients who were HLA-B27 negative.[ncbi.nlm.nih.gov]
  • Differences in the prevalence of clinical criteria across study sites and by human leukocyte antigen (HLA)-B27 status were assessed using the Wilcoxon rank-sum or chi-square test, as appropriate.[ncbi.nlm.nih.gov]
  • Additionally, HLA-B27 positivity is found in almost half of patients while some will also have a family history of HLA-B27 associated diseases.[symptoma.com]
  • There is also the association with the presence the human major histocompatibility antigen HLA-B27, but the role of this antigen in disease determination remains hypothetical.[orpha.net]


According to the American College of Rheumatology (ACR), The therapeutic approach is dependent on factors such as the activity of the disease, current regimen, whether features of poor prognosis are present, and the treatment groups. The latter consists of 1) the number of affected joints: four or less versus five or more, 2) active sacroiliac arthritis, 3) systemic arthritis without active arthritis, and 4) systemic arthritis with active arthritis. The chapter will discuss the various classes of pharmacotherapy agents and the general escalation of treatment.


Children with low disease activity and a clinical picture absent of poor prognostic characteristics can be treated with NSAIDs. In children with a duration of more than 2 months of active disease, monotherapy with NSAID is not appropriate [23].

Patients should be monitored for liver and kidney toxicities with routine CBC, creatinine, liver function tests (LFTs), and urinalysis.


Methotrexate (MTX) is a frequently used DMARD in the treatment of JIA. It is initiated in patients who fail a trial of NSAIDs and/or intra-articular glucocorticoid injections. It is also recommended as the first-line treatment for those with high activity of disease and features suggestive of poor prognosis. While it is effective for arthritis, this is yet to be concluded for patients with enthesitis and sacroiliitis.

This drug, a folic acid analog, is a dihydrofolate reductase antagonist and a modulator of inflammatory cells. MTX may be the initial therapy for young patients with oligoarticular and polyarticular involvement [24]. The drug is administered at an oral or subcutaneous dose of 10–15 mg/m2 weekly [25] [26]. Clinical improvement is observed after 6 to 8 weeks of treatment. There are adverse effects such as nausea, emesis, abdominal pain, cytopenia, liver toxicity, and oral ulcerations.

Another commonly used DMARD is sulfasalazine (SSZ), which is instituted in ERA patients exhibiting moderate or high disease activity with unsuccessful response to NSAIDs or intra-articular glucocorticoid injections [23]. One study reported that SSZ effectively treated oligoarthritis in children with HLA-B27 [27] as another demonstrated improvement in physician and patient assessment [28].

As an analog of 5-aminosalicylihc acid, it plays a role in anti-inflammation and anti-microbial. The drug is given daily at a dose of 30–50 mg/kg with titration over the span of several weeks. Clinical benefit may take 6 to 8 weeks. The side effects of this drug are gastrointestinal disruption, liver toxicity, cytopenia, Stevens-Johnson syndrome, and hypogammaglobulinemia.

According to the ACR, the patients treated with DMARDs should have a baseline and periodic tests such as CBC, creatinine, LFTs performed [23]. Specifically, these studies are monitored one month after beginning treatment, and then every 3 to 4 months in patients with normal results and stable doses.

Biologic agents

Abatacept and antitumor necrosis factor (TNF) drugs such as etanercept and adalimumab are used in JIA without systemic involvement. These have are effective and safe in children with ERA who are refractory to at least one DMARD although it is difficult to maintain remission with this class [29]. The etanercept is subcutaneously injected at a weekly dose of 0.8 mg/kg while adalimumab is weight dependent. The side effect profile includes the risk of developing an infection, hypersensitivity, cytopenias, psoriasis, and malignancy. Prior to starting treatment, patients must be tested for latent

Prior to starting treatment, patients must be tested for latent tuberculosis followed by yearly testing.


Surgical intervention may be warranted in children with severe deformity. Osteotomy, arthrodesis, and total hip and knee replacements are possible procedures.


Children with ERA should be managed through multidisciplinary care that includes a pediatric rheumatologist, orthopedic surgeon, physical and occupational therapists, social worker, and ophthalmologist.


Generally, ERA patients tend to have more pain, lower quality of life, and worse function as compared to the other subtypes of JIA [12]. Additionally, it is harder to sustain remission a year after beginning therapy in ERA individuals [13]. Patients with more than 5 years of active disease are likely to develop a disability as fewer than 20% of patients will have remission 5 years after diagnosis [14].

Factors that are correlated to the progression of the disease include HLA-B27 positivity, tarsitis, the presence of hip arthritis within the first 6 months, and presentation at an age above 8 years [15] [16].


The etiology of ERA has not been elucidated. However, there is likely a genetic link as studies have identified genes that predisposing individuals to ERA [2]. One study depicted an association with the endoplasmic reticulum aminopeptidase 1 (ERAP1) and possible interleukin (IL)-23 receptor (R) genes [3].


Approximately 7% to 37% of all cases of JIA are attributed to ERA [4] [2]. The incidence and prevalence of this condition are increasing [5], as Indian and Chinese studies have implicated ERA as the most prevalent subtype [4]. The epidemiological data is not well elucidated since ERA is a relatively newly recognized class.

With regards to patient demographics, the age of onset is late childhood through adolescence [6]. There is a predilection for males, which make up 60% of patients [2]. Additionally, HLA-B27 positivity is found in almost half of patients while some will also have a family history of HLA-B27 associated diseases [2].

Sex distribution
Age distribution


About 76% to 85% of individuals exhibit a strong association with HLA-B27 [7] [8], which indicates that there is a genetic link. There are 24 distinct subtypes of HLA-B27 with some predisposing to earlier onset [9]. The most common subtype is B2705 [10].

Patients of both genders with HLA-B27 have inflammatory back pain. Specifically, males with HLA-B27 have an older onset, more affected joints in the first three years, as well as involvement of small joints and enthesitis of the lower limbs [11].


This disease cannot be prevented


Enthesitis-related arthritis (ERA) is a chronic, inflammatory pediatric disease that affects the entheses, the peripheral joints, and the axial skeleton [1]. It falls under the scope of juvenile idiopathic arthritis (JIA), which refers to a clinically heterogeneous group of seven diseases. ERA is an HLA-B27-associated disease and shares similarities with juvenile spondyloarthropathy. The etiology of ERA is unknown although studies suggest there may be a genetic component.

The clinical picture features intermittent pain and swelling of multiple joints and entheses and gradually progresses to sacroiliitis in many patients. The International League Against Rheumatism (ILAR) has outlined criteria for the diagnosis of ERA.

The diagnosis is achieved through a comprehensive workup consisting of a detailed personal and family history especially with regards to HLA-B27-related diseases, a physical exam, and key studies. The latter include imaging techniques such as ultrasonography and magnetic resonance imaging (MRI) as well as nonspecific laboratory tests that may guide the diagnosis.

The treatment and management of children with ERA depend on numerous factors such as disease activity, the number of affected joints, features of poor prognosis and others as well. The care is best provided by a pediatric rheumatologist in conjunction with other specialties. The medications used are employed in an escalating manner as needed starting with nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular glucocorticoid injections, disease-modifying antirheumatic drugs DMARDs), and/or other biologic agents.There are specific recommendations that guide the treatment planning. Depending on the clinical picture and response to medications, the regimen may consist of the concurrent use of multiple drugs.

The overall prognosis of ERA is poorer than that of the other subtypes of JIA as children with this disease are at risk of developing a disability and exhibit a likelihood of remission failure.

Patient Information

What is Enthesitis-related arthritis (ERA)?

ERA This is the pediatric form of spondyloarthropathy (which is found in adults). ERA refers to joint pain, arthritis, and inflammation of the enthesitis. The term enthesitis describes the tendons or ligaments that attach to the bones. Hence, this disease is characterized by pain and stiffness in the knee caps, heels, ankles, and backbone.

What are the causes?

The exact cause is not known. There may be a genetic factor that plays a role. Also, as an autoimmune disease, the body's own immune system attacks the joints and the entheses.

What are the signs and symptoms?

During periods of active disease, the patient may have the following:

How is ERA diagnosed?

When a child presents with a clinical picture suggestive of arthritis, the doctor will ask important questions about the history of the patient and family, perform a complete physical exam, and order the appropriate tests such as:

  • Complete blood count
  • Erythrocyte sedimentation rate
  • C-reactive protein
  • Liver enzymes
  • HLA-B27 marker
  • Other important markers of inflammation

Note that this disease is not associated with specific lab results. Patients may have no abnormalities.

Also, the doctor will obtain imaging tests of the affect joints. These tests may include:

  • Ultrasonography
  • MRI
  • X-rays

How is it treated?

The management of these patients should be provided by a team of specialists such as pediatric rheumatologists, physical and occupational therapists, orthopedic surgeons, social workers, and others as needed. The following medications may be used to treat patients:

  • NSAIDs: this is the main treatment
  • Injection with glucocorticoid steroids into the affected joints is another therapy that can be used
  • Disease-modifying antirheumatic drugs such as methotrexate and sulfasalazine are used in patients with high activity of disease
  • Tumour necrosis factor (TNF)-alpha

Surgery may be needed in those with severe joint deformities. Also, physical and occupational therapy is very important in these patients.

Can it be prevented?

There is no way to prevent ERA.



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Last updated: 2018-06-21 19:57