initial presentation of juvenile rheumatoid arthritis

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Juvenile idiopathic arthritis

Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is the most common type of arthritis in children under the age of 16.

Juvenile idiopathic arthritis can cause persistent joint pain, swelling and stiffness. Some children may experience symptoms for only a few months, while others have symptoms for many years.

Some types of juvenile idiopathic arthritis can cause serious complications, such as growth problems, joint damage and eye inflammation. Treatment focuses on controlling pain and inflammation, improving function, and preventing damage.

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The most common signs and symptoms of juvenile idiopathic arthritis are:

Pain. While your child might not complain of joint pain, you may notice that he or she limps — especially first thing in the morning or after a nap.
Swelling. Joint swelling is common but is often first noticed in larger joints such as the knee.
Stiffness. You might notice that your child appears clumsier than usual, particularly in the morning or after naps.
Fever, swollen lymph nodes and rash. In some cases, high fever, swollen lymph nodes or a rash on the trunk may occur — which is usually worse in the evenings.

Juvenile idiopathic arthritis can affect one joint or many. There are several different subtypes of juvenile idiopathic arthritis, but the main ones are systemic, oligoarticular and polyarticular. Which type your child has depends on symptoms, the number of joints affected, and if a fever and rashes are prominent features.

Like other forms of arthritis, juvenile idiopathic arthritis is characterized by times when symptoms flare up and times when symptoms may be minimal.

When to see a doctor

Take your child to the doctor if he or she has joint pain, swelling or stiffness for more than a week — especially if he or she also has a fever.

Juvenile idiopathic arthritis occurs when the body's immune system attacks its own cells and tissues. It's not known why this happens, but both heredity and environment seem to play a role.

Risk factors

Some forms of juvenile idiopathic arthritis are more common in girls.

Complications

Several serious complications can result from juvenile idiopathic arthritis. But keeping a careful watch on your child's condition and seeking appropriate medical attention can greatly reduce the risk of these complications:

Eye problems. Some forms can cause eye inflammation. If this condition is left untreated, it may result in cataracts, glaucoma and even blindness.

Eye inflammation frequently occurs without symptoms, so it's important for children with this condition to be examined regularly by an ophthalmologist.

Growth problems. Juvenile idiopathic arthritis can interfere with your child's growth and bone development. Some medications used for treatment, mainly corticosteroids, also can inhibit growth.
Ferri FF. Juvenile idiopathic arthritis. In: Ferri's Clinical Advisor 2021. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 29, 2020.
Questions and answers about juvenile arthritis. National Institute of Arthritis and Musculoskeletal and Skin Diseases. https://www.niams.nih.gov/health_info/juv_arthritis/. Accessed Oct. 29, 2020.
Juvenile arthritis. American College of Rheumatology. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Juvenile-Arthritis. Accessed Oct. 29, 2020.
Juvenile arthritis. American Academy of Orthopaedic Surgeons. http://orthoinfo.aaos.org/topic.cfm?topic=a00075. Accessed Oct. 29, 2020.
6 ways arthritis can affect your eyes. Arthritis Foundation. http://www.arthritis.org/living-with-arthritis/comorbidities/eye-conditions/eye-arthritis.php. Accessed Oct. 29, 2020.
Ringold S, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the treatment of juvenile idiopathic arthritis: Therapeutic approaches for non-systemic polyarthritis, sacroiliitis and enthesitis. Arthritis Care and Research. 2019; doi:10.1002/acr.23870.
Momah T, et al. Juvenile idiopathic arthritis: Old disease, new tactics. Journal of Family Practice. 2019; https://www.mdedge.com/familymedicine/article/196058/rheumatology/juvenile-idiopathic-arthritis-old-disease-new-tactics. Accessed Oct. 29, 2020.

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initial presentation of juvenile rheumatoid arthritis

Doctor of Medicine (M.D.) in 1984 from University of Tennessee School of Medicine

Oct 7, 2018 2 min read

JRA Symptoms: What are Early Signs and Symptoms?

Juvenile rheumatoid arthritis, like adult RA, shared symptoms with many different types of arthritis. However, patients with JRA usually share some common side effects.

What to look for

It can take years for many kids to receive a proper JRA diagnosis. If you notice your child has any of the common arthritis symptoms, you should speak with their doctor or pediatrician immediately.

Common JRA symptoms include:

High fevers
Loss of appetite
Joint swelling

If your child is experiencing stiff joints in the morning, especially in their hands and knees, you should speak with a medical professional as soon as possible.

What to expect from JRA symptoms

Joint problems.

Juvenile rheumatoid arthritis typically affects hands and feet, and may also lead to morning stiffness, where a child’s joints are uncomfortably stiff for about 45 minutes after waking up.

If you believe your child may be developing JRA, you may notice them limp or have trouble moving around in the morning. You may also notice swelling in one knee, although rheumatoid arthritis usually develops in both knee joints at the same time.

Systemic JRA

Joint pain may not be the only problem for patients with JRA. Many children experience rashes and fevers, usually occurring at the same time. This is called systemic JRA. Over time, this condition can cause nodes to appear around joints, and even near the child’s neck.

Inflammation in the eyes

Some children will start experiencing eye problems if they have or are developing JRA. Continual eye pain and vision problems usually don’t occur immediately, but may happen over time.

Stunted growth

In early years, many children with JRA experience slower-than-normal growth, with some joints developing faster than others. This leads to legs and arms of different lengths, and may even affect a child’s overall height. In most cases, children diagnosed with JRA at a young age grow at a slower rate than others.

JRA may develop in any, or all, of the above methods. In some rare cases, patients will have joint problems throughout their body, and experience organ damage due to high inflammation.

Remissions and Flare-Ups

Many children experience symptoms for months or even years, and then go through remission, side effects may disappear completely, only to return months later.

In between these periods, symptoms will occasionally get much worse for a short period of time — this is called a flare-up. Many children experience a few flare-ups throughout remission while others will go months, or even years, without side effects.

With any type of rheumatoid arthritis, each case is different. Juvenile rheumatoid arthritis is no exception. Thankfully, there are ways to improve these symptoms and fight against JRA. Proper diet and low-impact exercise are great ways to control inflammation, and doctors can prescribe some helpful medications that will fight against dangerous side effects.

If you or your child are experiencing symptoms associated with rheumatoid arthritis, please see a doctor immediately.

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Introduction:

JRA is not simply rheumatoid arthritis (RA) in children. It is also not a single disease. It is a group of arthritis conditions with a wide variety of manifestations occurring in about 1 in 1,000 children. Although less common than the adult form of RA, JRA is as common in this age group as juvenile diabetes and more common than cystic fibrosis.

There are 3 major forms of JRA: pauciarticular (meaning ‘few joints’) onset, polyarticular (meaning ‘many joints’) onset, and systemic onset. These subsets of JRA will be further described below, but each displays a distinctly different pattern. This variability and lack of similarity between most forms of JRA and adult RA have led some to prefer the term “juvenile chronic arthritis.”

While the long-term outlook of JRA varies with different forms of the disease, over 1/3 of children in general will have active disease that persists into their adult lives, while the remainder experience a remission by the time they reach adulthood. Moreover, 30-50% of patients experience significant limitations in daily functioning 10 years after the onset of their disease. For these reasons, prompt recognition of and proper therapy for JRA are crucial and can have a lasting impact on the quality of the child’s life.

Features of JRA:

Before discussing the different forms of JRA, it is important to remember a few issues important when dealing with arthritis in children. First of all, JRA is often diagnosed late due to the fact that children may communicate symptoms differently or that symptoms may be misinterpreted as “growing pains.” In younger children, the only sign that joint disease is present may be a limp or a reduction in playtime activities without any complaints on the part of the child.

Secondly, JRA, as well as some of the therapies, affect growth. This may be manifest as general growth impairment or as unequal growth of a limb. Depending on the stage of growth, inflammation of a joint may either speed up or shut down the rate of growth, leaving the child with one leg or arm that is longer than the other.

Pauciarticular onset (PaO) is the most common form of JRA and is also the form with the best long-term outcomes. Children with this type of JRA typically experience pain and/or swelling of one or a few joints in the lower limbs, such as the hip, knee, or ankle. Even within this group of patients, there are 2 subsets, one with an average onset around the age of 2 where girls predominate, and one with an average onset around the age of 10 that is seen more commonly in boys. In the latter group of patients, lower back and heel pain are more common, and some of these children evolve into a condition known as ankylosing spondylitis (AS) when they become adults (see related section).

Polyarticular onset (PoO) JRA most closely resembles adult RA. These children experience pain and swelling in small and large joints, typically in a symmetrical pattern. The hands, wrists, elbows, knees, ankles, and feet are the most common joints involved. Like PaO disease, patients with PoO JRA can be divided into two groups, one beginning at an average age of 3 and one beginning at an average age of 12. Girls outnumber boys in both of these subsets of patients. Deforming changes and joint damage are more common in PoO disease than in any other form of JRA.

Systemic onset (SO) disease is characterized by fever, often occurring once per day, elevated white blood cell count, a transient rash, and less commonly inflammation of the lining of the heart or lungs or enlargement of the lymph nodes, liver, or spleen. Joint disease in SO JRA may either resemble the PaO or PoO forms of the disease, but in some children the joint disease may be minimal or absent (somewhat of a misnomer in a disease classified as arthritis). The average age of onset is 5 years, and boys and girls are equally affected. While it is the least common form of JRA, both growth impairment and life-threatening complications occur more commonly in SO JRA than in the other two forms.

To some extent or another, iritis or uveitis (inflammation of the eyes) may occur in all forms of JRA. This complication occurs more commonly in patients with PaO JRA than in other forms, affecting up to 25-30% of these children, versus 5% or less of those with PoO or SO disease. While the eye may become red, painful, or blurry when iritis is present, this process is often silent and slowly progressive. For this reason, screening for eye disease through an ophthalmologist is recommended routinely, anywhere between one to four times per year depending on the child’s age and type of JRA. Your doctors will make individual recommendations to patients and families depending on these factors.

To diagnose any form of JRA, one or more swollen joints must be observed for at least 6 weeks, and other causes of bone or joint disease (tumors, infections, injuries, etc.) must be excluded. To classify a patient as “juvenile,” symptoms should be present before the age of 16. The most important factors in making a diagnosis of JRA are the history of the symptoms and the findings on examination of the joints.

Classifying the form of JRA present depends on the number of swollen joints present during the first 6 months of the disease. If 4 or fewer joints are involved, the child has PaO disease; if there are 5 or more joints involved, the child has PoO disease. SO JRA can be diagnosed if a daily intermittent fever is present along with the arthritis or the skin and internal organ involvement. When arthritis is absent, the diagnosis is more difficult to confirm.

Laboratory testing is less helpful in JRA than in adult RA or lupus. While many abnormalities may be present in certain children and may help classify their disease, it is not unusual for children with active arthritis to have entirely normal laboratory studies. Markers of inflammation, while often elevated, are unreliable at measuring disease activity is most JRA patients. A positive rheumatoid factor, found in most patients with adult RA, is infrequently seen other than in older children with PoO disease. The antinuclear antibody, seen in almost all patients with lupus, may be positive in up to 1/2 of patients with PaO or PoO JRA, at times causing physicians to mislabel a JRA patient as having lupus. The gene HLA-B27, seen in most patients with AS, is positive in about 1/2 of older children with PaO disease.

X-ray studies of involved joints are most useful to assess for joint damage, evaluate the growth status of a limb, and exclude other diagnoses. Because of concerns regarding radiation exposure in children, these studies are ordered less frequently than in adult patients. Magnetic resonance imaging (MRI) may be used if evaluating for a bone or soft tissue tumor but is not routinely needed diagnose JRA.

The goals of therapy for JRA are to reduce symptoms but more importantly prevent or at least minimize the long-term complications of the disease, namely joint damage and loss of function. Just as JRA has many forms, the treatment required to achieve these goals also consists of many different strategies.

Non-steroidal anti-inflammatory drugs (NSAIDs) , such as ibuprofen (Motrin) and naproxen (Naprosyn) are often sufficient to treat milder JRA. In fact, over 1/2 of patients will respond to such therapies, and an additional 1/2 that fail will respond to treatment with a different NSAID. Responses are generally seen within 1 to 3 months, after which time other therapies must be considered. Depending on the age of the child, oral suspensions or syrups may be preferred over pills.

Corticosteroids such as prednisone are effective in JRA but must be used with caution. While these medications rapidly reduce swelling and pain in involved joints and reduce signs of SO JRA, there is a risk of infection, weight gain, weakening of the bones, as is the case with adults taking these medications long-term. An additional consideration in children is that steroids slow down growth when given for prolonged periods of time. For these reasons, corticosteroids are often best used for temporary treatment of disease flares. An additional role of steroids is to administer by joint injection in patients with PaO disease where one or two joints are swollen. The procedure is best performed under general anesthesia in younger children. This approach may reduce contractures of the limb or limit problems with growth of a limb.

Disease modifying anti-rheumatic drugs (DMARDs) should be started in a child with JRA failing to respond to NSAIDs after 2 to 3 months of therapy. Methotrexate (MTX), given as a once weekly dose, is the drug many physicians prefer due to the evidence that this agent improves function and limits joint damage in JRA. Children with PoO or SO JRA are given this medication more frequently than those with PaO JRA. Reduction in blood counts, elevation of liver enzymes, and susceptibility to infection are potential side effect to monitor but generally are less frequent in children than in adults.

Other DMARDs that are often effective in JRA include sulfasalazine (Azulfadine), hydroxychloroquine (Plaquenil), cyclosporine (Neoral), azathioprine (Imuran), and leflunomide (Arava). In general, less evidence is present to support the effectiveness of these therapies in JRA, but for PaO JRA, sulfasalazine appears to be particularly effective in certain patients.

Tumor necrosis factor (TNF) antagonists such as etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) have recently been shown to be quite effective in treating JRA. While only Enbrel is approved by the FDA for treating JRA, the other agents in this class also appear to be equally effective. As in adults, a risk for infection does seem to be increased in patients using these medications. Because of the cost of these therapies and the need for either injection or intravenous infusion, TNF antagonists are generally used in patients resistant to standard therapies, particularly for children with PoO disease.

A recent preliminary observation is that anakinra (Kineret), a medication that blocks the effects of a chemical known as IL-1, seems to be quite effective in treating SO JRA. This medication must be given by daily injection, is expensive, and does somewhat increase the risk of infection. Nonetheless, the promising early results suggest that Kineret may play a prominent role in treating SO JRA resistant to other medications.

Occasionally, iritis or a manifestation of SO JRA involving another part of the body may guide therapy more so than the joint disease. In this event, preventing vision loss or damage to different organs must also be factored in as a goal of therapy. Fortunately, the above medications generally treat these features of the disease as well, but a more aggressive approach may be needed in children with some of these complications of JRA.

Physical therapy is another important addition to the treatment of JRA in many children. Maximizing strength and function in diseased joints and splinting or stretching to minimize contractures or deformities are reasonable approaches to treating this disease and allow the child to actively participate in his or her recovery.

Finally, because many children with JRA feel isolated from their peers due to their limitations, activities in the community sponsored by the Arthritis Foundation or other such organizations can play a valuable role by providing support. Information for the child’s teachers and classmates provided by the Foundation can also assist in their understanding of the disease. Arthritis camps, support groups for families, and other programs help the child and the family realize that they are not alone with JRA.

Much can be done for JRA, but it must first be recognized and appropriately treated. As education of the community and medical professionals improves and therapies continue to be developed, hopefully so will the care provided to children suffering from various forms of JRA improve.

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Clinical manifestations and treatment of the pediatric rheumatoid patient

Affiliation.

1 Department of Orthopaedic Surgery, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. [email protected]
PMID: 20470954
DOI: 10.1016/j.cpm.2009.12.006

The management goal of juvenile rheumatoid arthritis (JRA) is to achieve early diagnosis and treatment so that arthritis can be resolved at an early stage, which avoids long-term damage and provides a good outcome of the affected inflammatory joints. This article describes presentation, classification, evaluation, and treatment of JRA as it relates to the foot and ankle. Because the course of JRA is complex and the optimal management is highly variable in each patient, this article can only offer recommendations. Actual treatment should be individualized to meet the conditions of each patient.

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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Antirheumatic Agents / therapeutic use
Arthritis, Juvenile / classification
Arthritis, Juvenile / diagnosis*
Arthritis, Juvenile / therapy*
Clinical Laboratory Techniques
Diagnostic Imaging
Foot Deformities, Acquired / diagnostic imaging
Foot Deformities, Acquired / etiology
Foot Deformities, Acquired / therapy*
Joint Capsule / surgery
Medical History Taking
Orthopedic Procedures
Physical Examination
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Radiography
Synovectomy
Tendons / surgery
Anti-Inflammatory Agents, Non-Steroidal
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Review Article
Published: 06 February 2024

Treatment of non-systemic juvenile idiopathic arthritis

Susan Shenoi ORCID: orcid.org/0000-0002-2495-594X 1 ,
Gerd Horneff 2 , 3 ,
Amita Aggarwal 4 &
Angelo Ravelli ORCID: orcid.org/0000-0001-9658-0385 5 , 6

Nature Reviews Rheumatology volume 20 , pages 170–181 ( 2024 ) Cite this article

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Juvenile idiopathic arthritis

Therapeutics

In the past two decades, the treatment of juvenile idiopathic arthritis (JIA) has evolved markedly, owing to the availability of a growing number of novel, potent and relatively safe therapeutic agents and the shift of management strategies towards early achievement of disease remission. However, JIA encompasses a heterogeneous group of diseases that require distinct treatment approaches. Furthermore, some old drugs, such as methotrexate, sulfasalazine and intraarticular glucocorticoids, still maintain an important therapeutic role. In the past 5 years, information on the efficacy and safety of drug therapies for JIA has been further enriched through the accomplishment of several randomized controlled trials of newer biologic and synthetic targeted DMARDs. In addition, a more rational therapeutic approach has been fostered by the promulgation of therapeutic recommendations and guidelines. A multinational collaborative effort has led to the development of the recommendations for the treat-to-target strategy in JIA. There is currently increasing interest in establishing the optimal time and modality for discontinuation of treatment in children with JIA who achieve sustained clinical remission. The aim of this Review is to summarize the current evidence and discuss the therapeutic approaches to the management of non-systemic phenotypes of JIA, including oligoarthritis, polyarthritis, enthesitis-related arthritis and psoriatic arthritis.

In the past two decades, important progress has been made in the management of juvenile idiopathic arthritis, including the availability of new therapeutic agents and the shift towards early aggressive interventions.

Several randomized controlled trials, therapeutic recommendations and consensus treatment plans have facilitated a more rational approach to therapy.

Contemporary therapeutic goals include early achievement of disease control, sparing use of glucocorticoids and the prevention of disease-related and treatment-related morbidity.

The application of the treat-to-target strategy, an innovative treatment modality that has already been explored successfully in pivotal therapeutic studies, is now garnering increased interest.

The variability in clinical presentation and course of juvenile idiopathic arthritis implies that the therapeutic choices, optimal targets and treatment strategy might be different across disease categories.

The research agenda calls for innovative trials that improve remission rates and pave the way for refined precision studies, personalized medicine and, ultimately, future prevention.

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Treatment of systemic juvenile idiopathic arthritis

Claas H. Hinze, Dirk Foell & Christoph Kessel

Alberto Martini, Daniel J. Lovell, … Nicolino Ruperto

Persistence and adherence to biologic therapies in juvenile idiopathic arthritis

Juan Carlos Nieto-González, Laura Trives-Folguera, … Indalecio Monteagudo Sáez

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Susan Shenoi

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Distinguishing Septic Arthritis from Juvenile Idiopathic Arthritis at Initial Presentation

—distinction of septic arthritis from juvenile idiopathic arthritis remains difficult, but several clinical findings may suggest jia..

By Caroline Gamse, PhD Reviewed by David Fernandez, MD, PhD, Assistant Attending, Adult Rheumatology, Hospital for Special Surgery, New York, NY

Despite the clinical differences between septic arthritis (SA) and juvenile idiopathic arthritis (JIA), no sufficiently sensitive diagnostic predictors exist to differentiate between these 2 conditions upon initial presentation, a new study reports. 1 However, patients with SA and JIA do show somewhat distinct patterns of response following short-term clinical interventions, allowing clinicians to prescribe appropriate care soon after onset.

The findings, published in Archives of Diseases in Childhood , outline an observational study performed by Camille Aupiais, MD, with the Hôpital Robert Debré, in Paris, France and colleagues to compare the features at onset and following short-term intervention of different types of arthritis in juveniles, to determine at what point they can be clinically differentiated. Distinguishing between septic arthritis, juvenile idiopathic arthritis, and arthritis of other causes early on is essential so that patients are treated appropriately and without the induction of additional joint damage.

According to the researchers, while joint disease is rare in children, its most common cause is septic arthritis. Juvenile arthritis may also be caused by transient synovitis, reactive arthritis, various inflammatory diseases (eg, hemarthrosis, Kawasaki disease, villonodular synovitis, chronic recurrent multifocal osteitis), or juvenile idiopathic arthritis (JIA). 1 Due to the rarity of these conditions, and their variable presentations and disease courses, providers often struggle to distinguish among them. 2

“Many diagnostic criteria have been developed to differentiate between transient synovitis and SA, but no such criteria have been determined to distinguish JIA from SA,” the study authors write. This is of note because the treatments for SA and JIA are distinct, including emergent surgical joint drainage and intravenous antibiotics to avoid infectious complications from SA, 3 while JIA requires referral to a rheumatologist who may treat with non-steroidal anti-inflammatories (NSAIDs), intra-articular glucocorticoid injections, disease-modifying anti-rheumatic drugs (DMARDs), and/or biologics. 4

“Joint drainage and immobilisation may delay appropriate treatment of JIA if it is misdiagnosed, resulting in additional disease progression and increased joint erosion and disability,” the authors add, making early differential diagnosis of juvenile arthritis essential to proper care.

Clues from short-term treatment outcomes

In the current study, Aupiais and colleagues performed a retrospective analysis on children hospitalized in a tertiary pediatric orthopedics and rheumatology center who underwent joint aspiration for a first episode of arthritis. Using the French National Hospital Discharge Database, the authors were able to identify children with a diagnosis of arthritis according to the International Classification of Diseases, 10 th Revision. 5 Diagnosis was defined as joint pain and/or functional disability associated with clinical and/or radiological joint effusion. Because inflammatory arthritis cases are exceedingly rare, children from the rare maladies database (CEMARA) who were followed for JIA were also screened to see if they met inclusion requirements.

Children aged 3 months to 16 years who were hospitalized for a first episode of arthritis, with onset of symptoms less than 6 weeks prior to hospitalization, and who underwent surgical joint aspiration at diagnosis were analyzed for clinical and biological differences at presentation as well as following initial medical interventions. The goal was to determine if those who were ultimately diagnosed with JIA as opposed to SA could be differentiated prior to joint aspiration. Importantly, children with undocumented sepsis, secondary arthritis, associated myelitis, underlying fracture or foreign body, prior anti-inflammatory treatment, or certain underlying conditions were excluded so that critical diagnostic criteria could be compared.

Following standard guidelines, all children who presented with joint effusion associated with fever, high C-reactive protein (CRP), or high white blood cell (WBC) counts were suspected of having SA and were submitted for joint aspiration. Investigators reviewed the ultimate diagnosis given to each patient after follow-up, and the study cohort was separated into 3 groups. SA was defined as arthritis associated with bacteria detected in blood or synovial fluid by culture or molecular methods (PCR for Kingella kingae DNA and/or universal 16S ribosomal RNA sequencing to detect evidence of bacteria). JIA was defined as arthritis of unknown etiology that began before the 16th birthday and persisted for at least 6 weeks, based on diagnosis by a pediatric rheumatologist. Any arthritis that did not fill the criteria for SA, JIA, or other well-established diagnoses was classified as “arthritis with no definitive diagnosis.” 1

Several variables were compared between the 3 groups. Children with SA (n=63), JIA (n=17), and arthritis with no definitive diagnosis (n=45) displayed no significant differences in C reactive protein (CRP) levels, overall white blood cell (WBC) counts, or neutrophil counts. The clinical diagnosis in 37 of the 45 patients without a definitive diagnosis was SA with a negative synovial fluid culture or PCR/sequencing, and were treated with antibiotics. At onset, median synovial WBC count was significantly higher in those with SA, being over 50,000 cells/mm 3 in 86.2% of SA, 50.0% of JIA, and 31.6% of ‘arthritis with no definitive diagnosis’ ( P <.001).

Children with SA were significantly younger than those of the other 2 groups ( P <.001), and presented exclusively with monoarthritis. At presentation, platelet counts were higher in those with JIA than in the other 2 groups ( P =.01), and JIA was associated with a higher frequency of family history of inflammatory disease ( P =.03) and a longer duration of local symptoms prior to admission ( P =.04), than the other 2 groups. Finally, fibrinogen was lower in the ‘no definitive diagnosis’ group than in the other 2 groups ( P =.03) upon admission. While these differences may be suggestive of one condition over another, there was enough overlap between conditions to prevent initial diagnosis based on these parameters.

Next, the authors measured how each type of patient responded to various treatments. Time to apyrexia for children with initial fever, and time to obtaining a CRP level <10 mg/L were compared between groups. Time to apyrexia following joint drainage was longer for patients with JIA relative to patients in the other 2 groups ( P < .001), with Kaplan-Meier estimates of the probability of apyrexia at 2 days being 40% for JIA, 82% for SA, and 88% for ‘arthritis with no definitive diagnosis.’ Overall, the median time to reach CRP <10 mg/L was 7 days; at this time point, 18% of JIA, 62% of ‘arthritis with no definitive diagnosis,’ and 82% of SA patients had reached normal CRP levels. Combined, these data show that the median time between drainage and apyrexia or for CRP to return to normal levels were shorter for patients with SA than JIA.

Finally, 58.8% of patients with JIA experienced extra-articular symptoms (erythematous rash or macrophage activation syndrome) during hospitalization, while no patients in the other groups exhibited such symptoms. These observations suggest that the persistence of fever and inflammatory markers, along with extra-articular symptoms, favor diagnosis of JIA.

Conclusions

According to the researchers, despite the distinct etiology of SA vs JIA, it remains difficult to distinguish these conditions at onset, especially in an emergent setting. Therefore, joint aspiration is appropriate for any child who presents with an initial episode of arthritis lasting less than 6 weeks, especially in cases of monoarthritis.

They add that based on short-term clinical outcomes following these interventions, JIA may be implicated if there is slow resolution of fever and inflammation following joint drainage and antibiotic treatment. This is especially true if the patient exhibits extra-articular symptoms, has a long history of symptoms before seeking medical attention, or has a strong family history of inflammatory disease.

“Clearly, the diagnosis of arthritis in children needs to be improved. A prospective study would be useful to avoid missing data and a reporting bias, and to more systematically define the diagnosis,” they suggest.

Published: May 23, 2017

1. Aupiais C, Basmaci R, Ilharreborde B, et al. Arthritis in children: comparison of clinical and biological characteristics of septic arthritis and juvenile idiopathic arthritis. Arch Dis Child . 2017;102:316-322. doi: 10.1136/archdischild-2016-310594.
2. Van Mater H, Balevic SJ, Freed GL, et al. Prescribing for children with rheumatologic disease: perceived treatment approaches between pediatric and adult rheumatologists. Arthritis Care Res . 2017 [epub ahead of print]. doi: 10.1002/acr.23273.
3. Montgomery NI, Epps HR. Pediatric septic arthritis. Orthop Clin North Am . 2017;48(2):209-216. doi: 10.1016/j.ocl.2016.12.008.
4. Stoll ML, Cron RQ. Treatment of juvenile idiopathic arthritis: a revolution in care. Pediatr Rheumatol Online J . 2014;12:13. doi: 10.1186/1546-0096-12-13.
5. World Health Organization. International Statistical Classification of Diseases and Related Health Problems, 10th Revision . Geneva: World Health Organization. 2010.

Juvenile Idiopathic Arthritis

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Published: 02 January 2024

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Murugan Sudhakar 1 &
Sathish Kumar ORCID: orcid.org/0000-0003-2137-7475 1

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Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The International League of Associations for Rheumatology (ILAR) has defined JIA as “arthritis of unknown etiology persisting for ≥6 wk with an onset at <16 y of age, after excluding other causes of joint inflammation”. Synovial inflammation is the result of a complex interplay of aberrant immune systems (both adaptive and innate) in a genetically susceptible individual, with possible external stimuli/triggers. Diagnosis of JIA essentially remains clinical, and laboratory investigations usually help to assess the severity of disease activity. Few investigations like antinuclear antibodies (ANA), human leukocyte antigen (HLA)-B27, and rheumatoid factor (RF) help to categorize or prognosticate a child with JIA. Timely use of effective therapeutic interventions including biological has shown good long-term outcomes of JIA.

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PMC10325069

Initial presentation of early rheumatoid arthritis

Lauri Weman

1 University of Eastern Finland and Jyväskylä Central Hospital, Jyväskylä, Finland

2 Finnish Institute for Health and Welfare (THL), Data and Analytics, Helsinki, Finland

Laura Kuusalo

3 Department of Internal Medicine, University of Turku and Turku University Hospital, Turku, Finland

Johanna Huhtakangas

4 Division of Rheumatology, Kuopio University Hospital, Kuopio, Finland

Johanna Kärki

5 Department of Children and Adolescents, Kanta-Häme Central Hospital, Hämeenlinna, Finland

Paula Vähäsalo

6 Department of Children and Adolescents, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital and Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland

Maria Backström

7 Department of Paediatrics, Wellbeing Services County of Ostrobothnia, Vaasa, Finland

8 Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland

Tuulikki Sokka-Isler

Associated data.

The Quality Register data must be used strictly for the purposes of the Quality register, by the specialists nominated for this task, under the Finnish Institute for Health and Welfare, which is supervised by the Ministry of Social Affairs and Wealth. The Finnish Institute for Health and Welfare is the owner of the data. Queries concerning the quality register data can be directed to the institute FinData, which is mandated to grant approval to use anonymized quality register data for research purposes. E-mail: if.atadnif@atad .

To study the joint distribution and clinical picture of rheumatoid arthritis (RA) at the initial presentation in seropositive (anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) positive) and negative patients and the effect of duration of symptoms on the clinical picture.

Data of patients who received reimbursement for DMARDs for newly diagnosed RA in 1/2019 to 9/2021 were extracted from the national databases. Joint counts, presence of symmetrical swelling, other disease activity measures, and patient reported outcomes (PROs) were compared in seropositive and negative patients. Regression analyses were applied to compare clinical variables in patients with duration of symptoms of <3, 3–6, and >6 months, adjusted for age, sex, and seropositivity.

Data of 1816 ACPA and RF-tested patients were included. Symmetrical swelling was present in 75% of patients. Seronegative versus positive patients had higher value for all disease activity measures and PROs including median swollen joint count (SJC46 10 versus 5) and DAS28 (4.7 versus 3.7), (p<0.001). Patients diagnosed in <3 months had higher median pain VAS (62 versus 52 and 50, p<0.001) and HAQ (1.1 versus 0.9 and 0.75, p = 0.002) compared to those with a duration of symptoms of 3–6 and >6 months. Patients diagnosed >6 months were ACPA-positive more frequently (77% versus 70% in other groups, p = 0.045).

Incident RA presents mainly as symmetric arthritis. Seronegative patients have higher disease burden at the initial presentation. Patients experiencing more severe pain and decreased functional ability are diagnosed earlier, regardless of ACPA- status.

Before the introduction of modern diagnostic tools, incident rheumatoid arthritis (RA) was recognized as symmetric polyarthritis. Symmetry was one criterion in the previous 1987 classification criteria for RA [ 1 ], which were developed to differentiate RA from other types of inflammatory arthritides. Symmetry of joint erosions has been observed in patients with early RA diagnosed in the early 1990’s [ 2 ] and in patients with established RA in 1963–1996 [ 2 , 3 ]. However, no studies have been conducted recently on the symmetry of joint involvement at the presentation of RA [ 4 ]. Although not part of the current classification criteria [ 5 ], symmetry of arthritis is still being taught in textbooks and medical schools, as one of the hallmarks of incident RA. However, considering RA only in cases with symmetric polyarthritis might postpone the suspicion of early RA in primary health care.

In the 2010 ACR/EULAR classification criteria for RA, more emphasis has been placed on serology [ 5 ] without requirement for symmetry. With the 2010 criteria, early RA is now presented mainly in two forms with 6 criteria fulfilled, either seropositive RA, which can be oligoarthritis without elevated inflammatory markers, or seronegative RA, which is usually polyarthritis with elevated inflammatory markers. In fact, it is getting obvious that autoantibodies are the hallmark of RA and seronegative RA is a distinct entity [ 6 ] with different risk factors [ 7 , 8 ] and outcomes compared to seropositive RA [ 9 ]. Our recent study indicated that seronegative RA turns out to be a spectrum of different conditions when observed for 10 years [ 10 , 11 ]. Nonetheless, seronegative active arthritis requires early identification and tightly controlled treatment with Disease Modifying Antirheumatic Drugs (DMARDs) as it also causes significant treatable disease burden to patients [ 12 ].

First in the 1970’s [ 13 ] and more widely since the 1990’s, it has been recognized that RA should be identified and its treatment initiated as soon as possible to facilitate good outcomes [ 13 , 14 ]. With multiple studies showing that early recognition is crucial, it has since been emphasized as an important approach for the management of RA [ 15 ]. It has also been shown that treatment initiation within the first 12 weeks after the first symptoms might be the best window of opportunity in terms of treatment outcomes [ 16 , 17 ]. Some studies suggest that the duration of symptoms has decreased during the current millennium [ 18 ]. However, there are still notable delays in terms of treatment initiation. For example, only 31% of patients with incident RA were examined by a rheumatologist within 12 weeks of the first symptoms in the Netherlands in 1993–2006 [ 19 ]. In the UK, patients with early RA visit their general practitioner 4 times on average before being referred to a specialist according to a report from 2008–2009 [ 20 ].

Therefore, our objective was to study the initial presentation of RA in a nationwide setting, with a focus on the serological status and symmetry of joint swelling, as well as the effect of duration of symptoms.

Patients with incident RA are diagnosed and treated in rheumatology outpatient clinics in Finland. According to the national guidelines, DMARDs are started at the time of the diagnosis together with a medication reimbursement application, prepared by the rheumatologist. The reimbursement is granted by the Social Insurance Institution of Finland (KELA) for DMARDs. In addition to granting reimbursements for patients with chronic illnesses, such as RA, KELA also maintains a database of the individuals, containing the ICD code of the diagnosis, date of the reimbursement and basic demographic data of the individuals.

For the current study, patients who received their first reimbursement for DMARDs prescribed for the treatment of RA between 1/2019-9/2021 were identified in the KELA database. Clinical and demographic data were extracted from The Finnish Rheumatology Quality Register, using the individual identification code. To capture the data at the time of the diagnosis, clinical data were extracted from the most recent visit within 0 to 90 days prior to the date of the medication reimbursement; visits occurred between 23 rd November 2018 and 30 th August 2021. All patients were over 16 years old and could not be diagnosed as any other specific arthritis. The ACR/EULAR 2010 classification criteria were used to aid in diagnosing the patients [ 5 ].

Following variables were collected at the time of the diagnosis of RA and were available for analyses.

Demographic variables

Age in years
Sex; male subjects/female subjects
Smoking status: current smoking; having ever smoked
Employment status for patients under 65 years old; currently working, unemployed, disabled and not in work force such as home makers and students

Disease characteristics

Duration of symptoms
Fulfillment of ACR/EULAR 2010-criteria [ 5 ].

Clinical variables

Swollen joint count (SJC) and Tender joint count (TJC) on 46 joint counts
Distribution of swollen and tender joints on 46 joint counts
Presence of symmetrical swelling in the MCPs, PIPs, wrists, MTPs, knees, ankles, and the elbows
C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and DAS28 scores
Investigator’s global assessment of disease activity (Dr.global)
Patient reported outcomes (PROs) such as pain, fatigue, and Patient Global Assessment (PGA)
Self-reported functional capacity according to the Stanford Health Assessment Questionnaire (HAQ).

The Initial Medication

The medications of interest were methotrexate (MTX), other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as hydroxychloroquine (HCQ) and sulfasalazine (SSZ), biological DMARDs (bDMARDs) and janus kinase (JAK) inhibitors, as well as systemic glucocorticoids (GC).

Duration of symptoms is the time between the first symptoms and the diagnosis of RA, recorded in months. At the initial visit, the patient was asked when he/she recognized the first symptoms of RA.

ACPA- positivity was defined by the laboratory reference values, which was ≥ 7 kU/l.

RF-positivity was defined by the laboratory reference values, being ≥ 15 IU/ml.

Fulfilment of the ACR/EULAR 2010 criteria was calculated by the examining physician, who counts the items in the ACR/EULAR 2010-criteria. If the total score adds up to 6 or more points, the ACR/EULAR 2010-criteria are met, when other reasons that can explain the condition are excluded [ 5 ].

Joint counts

The presence of swollen and tender joints was calculated using a 46 joint count including proximal interphalangeal (PIP), and metacarpophalangeal (MCP) joints, interphalangeal (IP) joints of the thumbs, wrists, metatarsophalangeal (MTP) joints, distal interphalangeal (DIP) joints of big toes, temporomandibular joints as well as ankle-, knee-, hip-, elbow- and shoulder joints.

Symmetrical swelling was analyzed from the MCPs, PIPs, wrists, MTPs, knees, ankles and the elbows, according to the 1987 criteria [ 1 ]. A patient was considered to have symmetrical swelling if he/she had bilateral swelling in the same anatomical site. Symmetrical joint tenderness wasn’t analyzed as it wasn’t in the 1987 criteria [ 1 ].

CRP and ESR were determined according to the laboratory reference values for women and men in different age groups. A reference value of below 10 mg/l was normal for CRP. An elevated ESR included values of ≥ 20 mm/h for women younger than 50 years, ≥ 30 mm/h for women over 50 years and ≥42 mm/h for women over 85 years and ≥ 15 mm/h for men younger than 50 years, ≥20 mm/h for men over 50 years and ≥30 mm/h for men over 85 years.

DAS28 was used to describe disease activity [ 21 ].

Dr . global included the physicians’ assessment of rheumatic activity on the 0–100 mm Visual Analog Scale (VAS), where 0 equals no disease activity and 100 maximal disease activity.

PROs included the self-assessment of pain, fatigue, and PGA on the 0–100 mm VAS, where 0 equals no symptoms and 100 maximal discomfort.

HAQ was used to describe the functional capacity of patients. It is scored from 0 to 3, a score of <0.5 is a sign of good functional status. In this study, we used HAQ without ‘‘aids and devices” due to its better accuracy in clinical studies [ 22 , 23 ].

The Initial Medications were analyzed in following groups:

MTX monotherapy
MTX in combination with (an)other csDMARD(s)
csDMARD monotherapy or a combination
bDMARD with or without MTX
JAK-inhibitor with or without MTX
GC, regardless of DMARDs

Clinical and demographic variables were determined for all patients and for seropositive and negative patients. Comparisons were conducted between seropositive and negative patients as well as between only ACPA-positive and only RF-positive patients with clinical variables. The use of medication was determined only for seropositive and seronegative patients and their use was compared between these groups.

Methods to study the effect of duration of symptoms on disease activity

Three groups were formed according to the duration of symptoms before receiving the diagnosis: patients with a duration of symptoms of <3 months (group 1), patients with a duration of symptoms of 3–6 months (group 2) and patients with a duration of symptoms of over 6 months (group 3). SJC46, TJC46, serological status, CRP, ESR, DAS28, PROs, HAQ, and Dr.global were compared between these groups.

Statistical methods

Descriptive statistics were used with mean values with standard deviation (SD) and median values with interquartile ranges (IQR) depending on the way a value is distributed. Chi-square test was used to compare categorical variables. P = 0.05 was set as a threshold for statistical significance. Regression models were used to compare clinical and demographic variables, ANOVA for continuous variables and logistic regression for dichotomous correlatives and for comparisons of median values transformed as median splits. Adjustments for age and sex were used in the comparisons of patients by ACPA-status. Variables were adjusted for seropositivity, age and sex in the comparisons of groups by duration of symptoms.

Analyses were conducted using the R Statistical language (version 4.2.1; R Core Team, 2022) on Ubuntu 20.04.5 LTS.

Ethical issues

This study was conducted as a register-based study using data from the Finnish Rheumatology Quality Register, which is kept by the Finnish Institute for Health and Welfare (THL), which granted the approval for the study. In a register-based study, patient consent was not required.

A total of 2017 patients with incident RA were identified in the database. ACPA and/or RF were available for 1816 (90%) patients, which were included in the analyses. Of these, 1444 (80%) were seropositive and 372 (20%) were seronegative. A total of 5 (0.3%) seropositive patients weren’t tested for ACPA, as they were already RF-positive. Vice-versa, 83 (6%) patients weren’t tested for RF, as they already had a positive ACPA-result. The mean (SD) age was 59 (16) years for all patients. For seropositive and negative patients, the corresponding numbers were 59 (15) and 60 (16) (p<0.001). A total of 1034 (57%) patients overall, 850 (59%) seropositive patients and 184 (49%) seronegative patients were under 65 years old at the initial visit (p = 0.002) ( Table 1 ).

A total of 19% of all patients were current smokers and 55% had ever smoked. The corresponding proportions were 21% and 57% for seropositive patients and 12% and 46% for seronegative patients (p<0.001 for both comparisons, adjusted for age and sex). In terms of employment status, a total of 69% of all patients were employed, 20% disabled, 8% unemployed and 4% weren’t currently in work force. No major differences were found between seropositive and negative patients ( Table 1 ).

The median (IQR) duration of symptoms before being diagnosed was 4 (2, 10) for all patients. For seropositive patients it was 5 (2, 10) and 4 (2, 8) for seronegative patients (p = 0.030, adjusted for age and sex).

The proportions of patients fulfilling the ACR/EULAR 2010-criteria at the initial presentation were 88% for all patients, 91% for seropositive and 74% for seronegative patients (p<0.001, adjusted for age and sex) ( Table 1 ).

Swollen- and tender joint counts

The median (IQR) SJC46 was 6 (3, 10) for all patients. For seropositive patients it was 5 (2, 9) and 10 (6, 15) for seronegative patients (p<0.001). The values for TJC46 were 6 (3, 11) for all patients and 5 (2, 10) and 10 (5, 18) for seropositive and negative patients, respectively (p<0.001, adjusted for age and sex) ( Table 2 ).

For all patients, 23% had two or less swollen joints at the initial presentation, 25% had 3–5 and 52% had ≥6 swollen joints on the 46 swollen joint count. The corresponding proportions were 26%, 28% and 46% for seropositive patients and 9%, 16% and 75% for seronegative patients (p<0.001, adjusted for age and sex) ( Table 2 ).

A total of 23% of all patients had two or less tender joints in the 46 tender joint count, 25% had 3–5 and 52% ≥6 tender joints. For seropositive patients the proportions were 26%, 28% and 46% and 14%, 16% and 70% for seronegative patients (p<0.001, adjusted for age and sex) ( Table 2 ).

Pattern and symmetry of joint involvement at the initial presentation

At the initial presentation, wrists were the most commonly affected joints, with 43.5% of patients having a swollen left wrist and 43.6% a swollen right wrist. Any joint from the right MCP’s was swollen in 9.5 to 34.9% of patients and in 9.7 to 28.7% of patients from the left MCP’s. The corresponding proportions were 9.5 to 31.5% for the right PIP’s and 8.2 to 25.4% for the left PIP’s and 10.3 to 28.0% for the right and 11.0 to 27.6% for the left MTPs. Knees were the most commonly swollen large joints (20.8% for right and 17.2% for the left). The corresponding proportions were 9.6% and 7.9% for shoulders, 13.5% and 12.8% for ankles, 6.8% and 5.9% for elbows and 1.9% and 2.2% for the hips ( S1 Table ).

At the initial presentation of RA, a total of 75% of all patients had symmetrical swelling in any of the anatomical sites. In different anatomical sites, 35% had symmetrical swelling in MCPs, 33% in the PIPs, 34% in wrists, 35% in the MTPs, 12% in the knees, 8% in the ankles and 4% in the elbows. A total of 71% of seropositive patients had any symmetrical swelling, and the corresponding proportion was 91% for seronegative patients (<0.001, adjusted for age and sex). In terms different anatomical sites, seronegative patients had more symmetrical swelling in all sites, with the biggest differences in the wrists compared to seropositive patients (28% in seropositive and 56% in seronegative patients) (p<0.001, adjusted for age and sex) and the MCPs (29% and 56%) (p<0.001, adjusted for age and sex). A total of 34% of seropositive patients had symmetrical swelling in the MTPs and 39% of seronegative patients (p = 0.097) ( Table 2 , Fig 1 ).

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Disease activity measures

The median (IQR) CRP was 8 (3, 25) for all patients with incident RA, 7 (3, 21) for seropositive and 15 (5, 46) for seronegative patients (p<0.001). The median (IQR) ESR was 22 (10, 39) for all patients 20 (10, 37) for seropositive and 26 (12, 46) for seronegative patients (p = 0.006, adjusted for age and sex).

A total of 53% of all patients had normal CRP and 60% normal ESR. For seropositive and negative patients, the proportions were 57% and 35% for CRP (p<0.001) and 63% and 51% for ESR, respectively (p<0.001, adjusted for age and sex) ( Table 2 ).

At the initial presentation, the median (IQR) DAS28-scores were 3.9 (3.1, 4.7) for all patients, 3.7 (3.0, 4.4) for seropositive patients and 4.7 (4.0, 5.7) for seronegative patients (p<0.001, adjusted for age and sex) ( Table 2 ).

For Dr.global, the median (IQR) value was 40 (26, 56) for all patients, 39 (25, 50) for seropositive patients and 50 (38, 69) for seronegative patients (p<0.001, adjusted for age and sex) ( Table 2 ).

Patient reported outcomes

For pain, the median (IQR) VAS-score was 54 (30, 75) for all patients, 51 (30, 74) for seropositive patients and 61 (39, 77) for seronegative patients (p<0.001, adjusted for age and sex). For fatigue, the corresponding numbers were 45 (18, 70), 40 (14, 69) and 52 (31, 73) (p<0.001, adjusted for age and sex) and for PGA they were 50 (25, 67), 48 (23, 64) and 53 (32, 70) (p<0.001, adjusted for age and sex) ( Table 2 ).

The overall median (IQR) HAQ was 0.9 (0.5, 1.4) for all patients, 0.88 (0.38, 1.4) for seropositive patients and 1.1 (0.75, 1.5) for seronegative patients at the initial presentation (p<0.001, adjusted for age and sex) ( Table 2 ).

Initial medication

A total of 17% of seropositive patients and 23% of seronegative patients started with MTX monotherapy, 72% and 67% started MTX + csDMARD, 10% and 11% started csDMARD(s) only, while bDMARDs and JAK-inhibitors were started only for a few patients. GCs were started for 82% of seropositive and 94% of seronegative patients ( Table 2 ).

Effect of duration of symptoms on the clinical picture

Between patient groups by duration of symptoms, there were notable differences in terms of ACPA-positivity, DAS28, ESR, pain and HAQ. For other variables, such as SJC46, TJC46, CRP, Dr.global, fatigue and PGA, the differences between groups were minor and mostly statistically not significant ( S2 Table ).

ACPA-positivity was the most prevalent with a proportion of 77% in group 3, compared to 70% and 70% % in other groups (p = 0.045, adjusted for age and sex). There were similar results also for seropositivity (78%, 77% and 82% in groups 1,2 and 3, p = 0.115)- and RF-positivity (68%, 67% and 71% in groups 1, 2 and 3, p = 0.324) ( S2 Table ).

Disease activity

The median (IQR) DAS28 was 4.1 (3.3, 5.1) in group 1, 4.0 (3.2, 4.8) in group 2 and 3.8 (3.1, 4.5) in group 3 (p = 0.016, adjusted for age and sex). The median (IQR) ESR was 27 (12, 44) in group 1, 20 (10, 36) in group 2 and 18 (9, 34) in group 3 (p<0.001, adjusted for age and sex) and the proportions of patients with a normal level of ESR were 55%, 61% and 66% in the same groups, respectively (p = 0.046, adjusted for age and sex) ( S2 Table ).

For median (IQR) pain, the values in groups 1, 2 and 3 were 62 (35, 78), 52 (30, 72) and 50 (26, 70) (p<0.001, adjusted for age and sex). For median (IQR) HAQ, the values in the corresponding groups were 1.10 (0.50, 1.60), 0.9 (0.50, 1.40) and 0.75 (0.38, 1.20) (p = 0.002, adjusted for age and sex) ( S2 Table ).

Clinical variables between ACPA-positive but RF-negative and RF-positive but ACPA-negative patients

A total of 163 (11% of seropositive patients) were only ACPA-positive and 118 (8% of seropositive patients) were only RF-positive. The mean (SD) age was 53 (17) for solely ACPA- and 62 (14) for solely RF-positive patients (p<0.001) and the duration of symptoms for the same groups were 6 (3, 13) and 4 (2, 7) (p = 0.222). The median (IQR) DAS28 was 3.6 (2.8, 4.2) for only ACPA-positive patients and 4.2 (3.5, 5.0) for only RF-positive patients (p<0.001). The same numbers for median (IQR) HAQ were 0.62 (0.3, 1.1) and 1.1 (0.5, 1.5) (p = 0.033). Besides DAS28 and HAQ, there were no statistically significant differences, though all of the clinical variables were higher for only RF-positive patients ( Table 3 ).

Our main observation was that early RA is still mainly presented as symmetric arthritis, as three out of four patients had symmetrical swelling in any of the anatomical sites of the 1987 criteria at the initial presentation [ 1 ]. Overall, the wrists were the most commonly swollen joints by a significant margin ( S1 Table ). Symmetrical swelling was detected more often overall and at all sites in ACPA negative patients. This was an expected finding since more swollen joints are required to fulfill the criteria for seronegative RA [ 5 ]. Seronegative patients had also higher SJC46 at the initial presentation (median 5 versus 10). Interestingly, the presence of symmetrical swelling was only slightly higher for seronegative patients in the MTPs (34% versus 39%, p = 0.097) ( Table 2 ) despite higher SJC46.

Clinical measures and medication

In terms of clinical data, seronegative RA presented significantly higher activity by almost all variables used in the study ( Table 2 ). Similar differences were found between solely ACPA-positive and solely RF-positive patients, though most of the findings weren’t statistically significant ( Table 3 ). In ESR, the difference was only minor between seropositive and seronegative patients (20 versus 24, p = 0.172) ( Table 2 ). Seropositive patients were more likely to fulfill the ACR/EULAR 2010 criteria (82% versus 78) at the time of diagnosis. Patients with seropositive RA were also current smokers more often, (21% versus 12% current smokers) ( Table 1 ), as smoking is a known risk-factor for ACPA-positive RA [ 24 ]. In terms of medication, GCs and MTX as monotherapy was used more frequently in patients that were diagnosed with seronegative RA. The more prevalent use of GCs indicates that some of the diagnoses might have been actually polymyalgia rheumaticas, as our previous studies have suggested [ 10 , 11 ].

Comparison to other studies

The results between seropositive and negative RA were somewhat contradictory compared to earlier research, a change likely caused by aiming at earlier diagnosis in accordance with the 2010 classification criteria. A French study of 354 patients diagnosed between 2002 and 2005 showed that seropositive patients had higher average DAS28 (5.3 versus 5.0) and HAQ (1.0 versus 0.9) than seronegative patients, but similar joint counts and VAS-values of pain [ 12 ]. In our study, the variables were significantly higher for seronegative RA (mean DAS28 of 4.8 versus 3.7 and 1.2 versus 0.93 for HAQ). However, the populations are not directly comparable, as the study had slightly different threshold values for ACPA and RF.

A Danish study of 198 newly diagnosed seropositive and 36 seronegative patients diagnosed in 2010 to 2013 showed lower median SJC44 (8 versus 17), Dr.global (39 versus 49) and DAS28 (3.4 versus 3.9), but similar PROs at the initial presentation in ACPA positive versus negative patients [ 25 ]. On the contrary, our population showed significantly lower PROs at the initial presentation in seropositive versus seronegative patients (51 versus 61 for pain, 40 versus 52 for fatigue and 48 versus 54 for PGA) ( Table 2 ), in addition to other clinical variables.

In terms of duration of symptoms, a previous study of patients diagnosed in 2007–2012 in Canada showed a duration of symptoms of 6.5 months for patients with seropositive RA and 5.4 months for patients with seronegative RA [ 26 ]. This is in line with our results, where the median duration of symptoms was five months for seropositive and four months for seronegative RA ( Table 1 ).

The effect of duration of symptoms on the initial presentation

The overall median SJC46 was the same in all groups by duration of symptoms (median 6 joints) ( S2 Table ) and median DAS28 was higher in the group of patients with a delay of < 3 months compared to patients with a delay of >6 months (4.1 versus 3.8, p = 0.016, adjusted for age and sex). Interestingly, patients with a delay of <3 and 3–6 months were also older than in the group with a delay of >6 months (mean age of 61 and 58 in groups with a delay of <3 and 3–6 months and 56 in the group with a delay of >6 months, p<0.001) ( S2 Table ). It has been shown that older patients utilize health care services more frequently, which might explain the finding [ 27 ]. The overall median CRP and ESR were higher in patients who were diagnosed earlier (11 in the group with a delay of <3 months, versus 8 and 7 in groups with a delay of 3–6 months and >6 months for CRP) and (27 versus 20 and 18 for ESR in the same groups, correspondingly). High laboratory values might have influenced towards early referrals, which in turn lowers the duration of symptoms. In addition, the median VAS-pain and HAQ were also significantly higher in patients who were diagnosed earlier (62 in the group with a delay of <3 months versus 52 and 50 in groups with 3–6 and >6 months, for pain) and (1.10 versus 0.90 and 0.75 for the same groups for HAQ), but ACPA was positive less frequently (77% in the group with a delay of >6 months versus 70% and 70% in other groups, p = 0.045) ( S2 Table ), which indicates that patients experiencing more severe symptoms and limitations in physical activity might seek health care services earlier. ACPA-positivity isn’t necessarily associated with the severity of symptoms. A previous Polish study has shown that the second most important factor for the duration of symptoms of RA is patients’ conviction that the condition will resolve on its own [ 28 ].

Strengths and limitations

The main strength of this study was its large patient population from almost all health care regions, in Finland and that patient data was documented recently allowing an accurate presentation of the current clinical picture.

Although all health care regions are included in the quality register, at the time that was defined as the focus period, not all regions actively recorded clinical data. Therefore, probably not all patients with incident RA could be included. Furthermore, although not recommended, patients may still be diagnosed along with receiving treatment initiation in private practice, which are not involved in the quality register, yet.

One of the weaknesses in register studies is missing data, although the completeness was as high as ≥95% for joint counts and ≥78% for PROs.

Conclusions

Our results indicate that the initial presentation of early RA is still mostly symmetric seropositive arthritis. Furthermore, we found that seronegative RA has significantly higher inflammatory activity and disease burden at the initial presentation by several clinical variables, compared to seropositive cases. However, 25% of patients in the current study didn’t have symmetrical swelling at the initial presentation, which is why all patients with clinical joint inflammation of unknown reason ought to be tested for ACPA and RF and referred to a rheumatology unit if ACPA and/or RF ispositive. Our observations are encouraging in terms that patients experiencing more severe pain and decrease in functional ability might seek health care services earlier. We also found that ACPA—positivity is not necessarily associated with the severity of symptoms.

Supporting information

Funding statement.

We would like to thank The Finnish Psoriasis Association, The Finnish Society for Rheumatology, and Amgen. The author also acknowledges the Research Committee of the Kuopio University Hospital Catchment Area for the State Research Funding (project 5041730, Kuopio, Finland). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability

PLoS One. 2023; 18(7): e0287707.

Decision Letter 0

25 Jan 2023

PONE-D-22-32344Initial presentation of early rheumatoid arthritisPLOS ONE

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Reviewer #1: The authors describe the initial presentation of early rheumatoid arthritis patients in Finland, using national databases. The result may be of interesting to readers, however, I have a couple of concerns. Specific comments are listed below:

1. The authors compare clinical items between ACPA-positive RA patients and negative patients, this is a bit confusing because so called seropositive RA includes RF+/ACPA- patients. This study may include such patients in ACPA negative RA patients, which shows a bit different nuance compared to 'seronegative' RA. More explanation of this may be needed to clarify the characteristics of patient group. I also be interested the clinical feature of ACPA-/RF+ RA patients (can be difficult to investigate, though).

2. We routinely use EULAR/ACR criteria for RA diagnosis in daily clinical practice, and due to the setting of scoring system, it is understandable ACPA negative (seronegative??) RA patients show more swollen joints (symmetrical) or high CRP levels. Therefore, it is natural to predict the results in this study. In other words, what is the most interesting findings in this study, compared to previous findings? Please address more clearly.

3. This study dose not describe initial therapy after diagnosis of RA. Are there any differences (if can)?

Reviewer #2: The authors studied the initial clinical presentation of alarge number of RA patients using national databases from Finland, with a particular interest in the impact of the presence of ACPA on the clinical presentation. A fair concern related to the objective of this study is that patients that do not present with symmetric polyarthritis could be having their diagnosis delayed. They concluded that incident RA presents mainly as symmetric arthritis, with higher disease severity in ACPA-negative patients. . This is not surprising, since as the authors themselves mentioned, the current classification criteria gives weight to seropositivity and, in negative patients, to the number of joints. On the other hand, it was surprising that ACAP-pos patients had a longer delay in diagnosis than ACPA-neg, when we know that ACPA is correlated with disease severity. For me, this suggests that there may be present a recruitment bias in this study: the ACPA-neg patients recruited could be representative of a more severe spectrum, while patients with milder forms are being left undiagnosed as RA, perhaps receiving other labels, such as "undifferentiated arthritis". The authors should discuss that possibility since it can have a great bearing on the main conclusions of the study.

Other issues/recommendations:

1. The authors should comment on the criteria for the request of ACPA, since about 11% of incident RA patients were not included in the analysis because they did not have ACPA available in their records. Could all these patients be RF positive, with high disease activity and, therefore, ACPA was forsaken because of obvious diagnosis? This could alter some of the conclusions that ACPA-neg patients have higher disease activity and shorter diagnostic delay.

2. The variables in Methods should be presented in full sentences, with better descriptions, and not by hyphenated-items. Particular confusing are the variables used to represent the duration of disease: "duration of symptoms", "fulfillment of ACR/EULAR 2010-criteria" and "diagnostic delay". These terms should be standardized throughout the text.

3. In terms of disease duration, the median (IQR) of 4 (2,10) months is very short, indicating that most (if not all) patients have relatively early (< 1y) disease. This should be discussed: is it true that very few patients in Finland are being diagnosed with longer than 1 year disease duration? Perhaps the ranges of disease duration could be presented, particularly for the groups by diagnosis delay.

4. Tables 3 and 4 are supplementary - this should be indicated in the main text when they are referred to.

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Reviewer #1: No

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Author response to Decision Letter 0

24 Apr 2023

Dear Sadiq Umar

We have now made all the corrections you suggested to us for the manuscript called ''initial presentation of rheumatoid arthritis''. I hope this is now acceptable for your paper.

B.R Dr Weman

Submitted filename: Response_to_reviewers_ March10,2023 .docx

Decision Letter 1

12 Jun 2023

PONE-D-22-32344R1

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Additional Editor Comments (optional):

The Manuscript looks good after revision though need some minor changes as suggested by Reviewer 3.

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Reviewer #1: All comments have been addressed

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Reviewer #3: (No Response)

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Reviewer #3: Yes

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Reviewer #3: N/A

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

6. Review Comments to the Author

Reviewer #1: The revised manuscript shows substantial improvement. The authors adequately answered to my concerns.

Reviewer #2: (No Response)

Reviewer #3: The manuscript has been written well, but I have some minor suggestions: (Please look at comments on pdf form). I suggest talking about the relation between cardiovascular risk factors and metabolic diseases with early rheumatoid arthritis in your manuscript.

Submitted filename: PONE-D-22-32344_R1.pdf

Acceptance letter

19 Jun 2023

Dear Dr. Weman:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

Dr. Sadiq Umar

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855-695-4872 Outside of Maryland. +1-410-502-7683 International. Find a Doctor. Juvenile idiopathic arthritis (JIA) is a form of arthritis in children. Arthritis causes joint swelling (inflammation) and joint stiffness. JIA is arthritis that affects 1 or more joints for at least 6 weeks in a child age 16 or younger.
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Juvenile rheumatoid arthritis. Juvenile idiopathic arthritis. Minimum duration. ≥6 wk. ≥6 wk. Age at onset < 16 y < 16 y. ≤ 4 joints in first 6 mo after presentation. Pauciarticular juvenile rheumatoid arthritis. Oligoarticular juvenile idiopathic arthritis: (A) Persistent < 4 joints for course of disease; (B) Extended >4 joints after 6 mo
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Diagnosis. In order to be diagnosed with juvenile rheumatoid arthritis, a child must have started showing symptoms before the age of 16 or 17 years old. Children as young as two years old can be diagnosed with juvenile rheumatoid arthritis. Juvenile rheumatoid arthritis is difficult to diagnose because many children do not complain of the ...
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Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16 years of age and lasting six weeks or longer. The terminology of chronic arthritis in children has evolved from juvenile chronic arthritis (JCA) and juvenile rheumatoid arthritis (JRA) to JIA since 1995. According to the consensus conference of the International ...
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Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is the most common type of arthritis in children under the age of 16. Juvenile idiopathic arthritis can cause persistent joint pain, swelling and stiffness. Some children may experience symptoms for only a few months, while others have symptoms for many years.
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Introduction. Juvenile rheumatoid arthritis (JRA) is a generic term for arthritis that has an onset before the age of 16 and persists for more than 6 weeks. The JRA nomenclature represents an exclusion diagnosis that includes all forms of chronic childhood arthritis of unknown origin. JRA is the most common chronic rheumatic illness in children ...
2021 American College of Rheumatology Guideline for the Treatment of
Data on tofacitinib was not part of the initial literature review ... Quiroga S, Arnal C, et al. Juvenile rheumatoid arthritis of the knee: evaluation with US. Radiology.1994; 190 (2):403-6. [Google Scholar] 69. Berrington de Gonzalez A, Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries.
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Juvenile rheumatoid arthritis. Juvenile rheumatoid arthritis (JRA) is a form of arthritis in children ages 16 or younger that causes inflammation and stiffness of joints for more than six weeks. Unlike adult rheumatoid arthritis, which is chronic and lasts a lifetime, children often experience periods of remission of juvenile rheumatoid arthritis.
JRA Symptoms: What are Early Signs and Symptoms?
If you notice your child has any of the common arthritis symptoms, you should speak with their doctor or pediatrician immediately. Common JRA symptoms include: High fevers. Loss of appetite. Joint swelling. Anemia. Rashes. If your child is experiencing stiff joints in the morning, especially in their hands and knees, you should speak with a ...
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JRA is not simply rheumatoid arthritis (RA) in children. It is also not a single disease. It is a group of arthritis conditions with a wide variety of manifestations occurring in about 1 in 1,000 children. Although less common than the adult form of RA, JRA is as common in this age group as juvenile diabetes and more common than cystic fibrosis.
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Rheumatoid Arthritis (RA) is a progressive autoimmune disease. It is among the most widespread chronic illnesses in children, with an annual incidence of 1.6 to 23 new instances per 100,000 adolescents. About 1 child in every 1000 develops Juvenile Idiopathic Arthritis (JIA) type of chronic arthritis.
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The management goal of juvenile rheumatoid arthritis (JRA) is to achieve early diagnosis and treatment so that arthritis can be resolved at an early stage, which avoids long-term damage and provides a good outcome of the affected inflammatory joints. This article describes presentation, classificati …
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Introduction. Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis or juvenile chronic arthritis, is the most common rheumatic disease in children. 1 JIA is defined as persistent arthritis for ≥6 weeks if certain exclusionary conditions have been eliminated. 2 The disease onset subtype is defined by clinical symptoms in the first 6 months of the disease.
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At initial presentation, ... Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum. 43, 2402-2409 (2000).
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The terms 'juvenile rheumatoid arthritis' and 'juvenile chronic arthritis' are now discarded for the single term of 'juvenile idiopathic arthritis' (JIA). This term of 'JIA' indicates a disease of childhood onset characterised primarily by arthritis persisting for at least 6 weeks with no known cause. Once the aetiology becomes ...
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Introduction. Juvenile idiopathic arthritis (JIA) is a group of heterogeneous inflammatory diseases that are classified by the International League Against Rheumatism (ILAR) into seven subtypes according to their clinical manifestations and laboratory tests, namely, systemic, rheumatoid factor rheumatoid factor (RF) + polyarticular, RF- polyarticular, oligoarticular, enthesitis-associated ...
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Systemic Juvenile Idiopathic Arthritis (sJIA) At initial presentation with a clinical suspicion of sJIA, NSAIDs are usually started till the diagnostic workup is complete. ... Guzmán J, Burgos-Vargas R, Duarte-Salazar C, et al. Reliability of the articular examination in children with juvenile rheumatoid arthritis: interobserver agreement and ...
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Juvenile idiopathic arthritis is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age. This term encompasses several disease categories, each of which has distinct presentation, clinical manifestations, and, presumably, genetic background and etiopathogenesis.
Oligoarthritis: Symptoms, causes, and treatment
Early treatment may help improve a person's outlook and result in higher remission rates. ... Juvenile rheumatoid arthritis, which is also called juvenile idiopathic arthritis or JIA, is an ...
Initial presentation of early rheumatoid arthritis
Reviewer #1: The authors describe the initial presentation of early rheumatoid arthritis patients in Finland, using national databases. The result may be of interesting to readers, however, I have a couple of concerns. Specific comments are listed below: 1. The authors compare clinical items between ACPA-positive RA patients and negative ...

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Distinguishing Septic Arthritis from Juvenile Idiopathic Arthritis at Initial Presentation

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Lauri Weman

Laura Kuusalo

Johanna Huhtakangas

Johanna Kärki

Paula Vähäsalo

Maria Backström

Tuulikki Sokka-Isler

Demographic variables

Disease characteristics

Joint counts

Methods to study the effect of duration of symptoms on disease activity

Statistical methods

Ethical issues

Swollen- and tender joint counts

Pattern and symmetry of joint involvement at the initial presentation

Disease activity measures

Patient reported outcomes

Initial medication

Effect of duration of symptoms on the clinical picture

Disease activity

Clinical variables between ACPA-positive but RF-negative and RF-positive but ACPA-negative patients

Clinical measures and medication

Comparison to other studies

The effect of duration of symptoms on the initial presentation

Strengths and limitations