ODESA NATIONAL MEDICAL UNIVERSITY

Departments of Pediatrics №2

	CONFIRMED by

Vice-rector for research and educational work

____________________ Svitlana KOTYUZHYNSKA

September 1st, 2022	

METHODOLOGICAL RECOMMENDATIONS
on practical classes for students

International Medical Faculty, сourse  4

Educational discipline "PEDIATRICS"

Approved 
at the meeting of the department of Pediatrics №2
Protocol No. 1 dated 28/08/2022

Head of the department of Pediatrics №2    __________________              Tetiana STOIEVA 
                                                                                Signature                                      

Authors: 
Head of the department of Pediatrics №2, MD, PhD in Pediatrics, DM, Professor Stoieva Tetiana
Associate Professor of the department of Pediatrics №2, PhD in Pediatrics Prokhorova Svitlana
Associate Professor of the department of Pediatrics №2, PhD in Pediatrics Titkova O. V. 
Associate Professor of the department of Pediatrics №2, PhD in Pediatrics Portnova O. O. 
Associate Professor of the department of Pediatrics №2, PhD in Pediatrics Vesilyk N. L. 
Associate Professor of the department of Pediatrics №2, PhD in Pediatrics Godlevska T. L.
Assistant of the department of Pediatrics №2, PhD in Pediatrics Fedin M. V.
Assistant of the department of Pediatrics №2, PhD in Pediatrics Jagiashvili O. V.
Assistant of the department of Pediatrics №2, PhD in Pediatrics Reshetilo O.V.
Assistant of the department of Pediatrics №2, PhD in Pediatrics Soboleva H. B.
Assistant of the department of Pediatrics №2 Bratkova L. B.

1.	Topic 19. Practical lesson № 23: « Reactive arthropathies in children» - 2 h.
2.	Background
Diseases belonging to this group are characterized by the similarity of clinical manifestations, especially in the early stages of development, according to laboratory research that requires careful differential diagnosis, in order to verify the diagnosis and individualized therapy appointment.
3. Training goals: 
3.1. Common goals:
- To introduce students to create understanding of the epidemiology, etiology, clinical reactive arthropathy
- The student must know to learn how to establish the diagnosis
- Provide students with the opportunity to master the skills, equipment performance objective examination of the patient
- Provide students with the ability to explore the theoretical, clinical, experimental patients for clinical diagnosis.
3.2. Educational goals:
Demonstrate possession of the moral and deontological principles of a medical specialist and principles of professional subordination in cardiorheumatology childhood
3.3. Specific objectives:
Know:
1. The etiology and pathogenetic factors of a reactive arthropathy in children.
2. Classify acute respiratory infections of the upper respiratory tract, fever, convulsions; to analyze the typical clinical picture of acute respiratory disease.

3.4. Based on the theoretical knowledge with the theme:
- Master the techniques (to be able)
- Make Up a plan of inspection and analyze the data of laboratory and instrumental investigations at reactive arthropathy.
- To put a preliminary diagnosis of reactive.
- Demonstrate ownership principles of treatment, rehabilitation and prevention of reactive arthropathy.

4. Materials for the classroom self-preparation (interdisciplinary integration).

№	Discipline	Know	
1.	Normal human anatomy	Know the structure of the organs of the cardiovascular system and     the musculoskeletal system. 	
2.	Histology and Embryology	Know the histological structure and embryonic development of structures of the cardiovascular system, the connective tissue of various localization. 	
3.	Normal human physiology	To know the basic aspects of the physiology of the functioning of the musculoskeletal system,of cardio-vascular system.	
4.	Pathological physiology	To know the basic aspects of the functioning of the physiology of the musculoskeletal system, the cardiovascular system in pathology	
5.	pharmacology	Know l ikarski drugs affecting the autoimmune and
immunocomplex processes and their application in pediatric practice.	
6.	propedeutics pediatrics	To know the anatomical and physiological characteristics of the musculoskeletal system, the cardiovascular system of children of iznih age groups.	
 
5. Content of the topic 
INTRODUCTION — Reactive arthritis is conventionally defined as an arthritis that arises following an infection, although the pathogens cannot be cultured from the affected joints. It is generally regarded as a form of spondyloarthritis (SpA).
The definition, clinical features, approach to diagnosis and differential diagnosis, and management of reactive arthritis will be reviewed here. Mechanisms that may play a role in reactive arthritis and in other spondyloarthritides are discussed separately
DEFINITION — The term “reactive arthritis” was introduced in 1969 as “an arthritis which developed soon after or during an infection elsewhere in the body, but in which the microorganisms cannot be recovered from the joint”. The original definition did not specify the pathogens that were accepted as causes of reactive arthritis, and, in 1999, a panel of experts determined a specific list of gastrointestinal and urogenital pathogens that could be considered causative. These included Chlamydia trachomatis, Yersinia, Salmonella, Shigella, and Campylobacter. Escherichia coli, Clostridium difficile, and Chlamydia pneumoniae have since been added to the list.
Additional causative pathogens, alternative terms, and diagnostic and therapeutic strategies for reactive arthritis have subsequently been proposed. However, none of the newer diagnostic or therapeutic approaches or alternate names has been adequately validated. Another problem is that many of the studies generating these approaches involved patients seen in rheumatology clinics or followed outbreaks of disease after exposure to a common pathogen; such patients are not likely to be representative of the affected patients in the general community. Thus, the definition of reactive arthritis is still evolving.
Two major clinical features that characterize reactive arthritis were identified:
●An interval ranging from several days to weeks between the antecedent infection and arthritis
●A typically mono- or oligoarticular pattern of the arthritis, often involving the lower extremities, and sometimes associated with dactylitis and enthesitis
By convention, reactive arthritis of more than six months’ duration was regarded as being chronic instead of acute.
The term “reactive arthritis” has sometimes been used historically to refer to the clinical triad of postinfectious arthritis, urethritis, and conjunctivitis, which was formerly called Reiter syndrome. However, these patients represent only a subset of patients with reactive arthritis.
Patients suspected of having reactive arthritis whose features initially or subsequently satisfy the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis (SpA) are also considered as having a form of SpA. A preceding episode of genital or gastrointestinal infection is included among the ASAS criteria that may support a diagnosis of peripheral SpA and the inclusion of a patient with reactive arthritis in this group.
EPIDEMIOLOGY — Reactive arthritis is a relatively rare disease that typically occurs in young adults, affecting both men and women. Studies of the prevalence and annual incidence of reactive arthritis are highly heterogeneous with respect to the size of the cohort, collection of data, the definition of reactive arthritis, and the identification of the inducing pathogens. In a US population-based study in Oregon and Minnesota, the incidence of reactive arthritis following documented enteric bacterial infections ranged from 0.6 to 3.1 cases per 100,000, depending upon the organism. An analysis of the data in a 2013 systematic review found that the incidence of reactive arthritis following infection with Campylobacter, Salmonella, and Shigella, was estimated as 9, 12, and 12 per 1,000 patients, respectively. Similarly, the annual incidence of reactive arthritis among children in three pediatric health networks in the United States with Clostridium difficile infection was estimated at 14 per 1000 patients. Globally, the annual incidence has been reported between 0.6 to 27 per 100,000, and the prevalence is estimated to be 30 to 40 per 100,000 adults.
Among patients with any of the spondyloarthritis (SpA) variants seen by rheumatologists, those with reactive arthritis are a small minority. This was illustrated by two registry-based studies from Spain in which 1.2 to 1.4 percent of all patients with SpA had been diagnosed with reactive arthritis.
Most cases of reactive arthritis appear sporadically, but outbreaks may follow single-source infections. In such outbreaks, the proportion of infected subjects who developed subsequent reactive arthritis has ranged from 0 to 21 percent.
The causative pathogens, incidence, and prevalence of reactive arthritis depend upon the geographic region. In general, among the pathogens, Chlamydia is probably the most endemic. It has been estimated that 4 to 8 percent of patients with chlamydial infection develop arthritis. Some of epidemiological studies include cases in which the preceding enterobacterial and Chlamydial infections are silent.
CLINICAL MANIFESTATIONS — Patients with reactive arthritis typically present with an asymmetric oligoarthritis, usually one to four weeks following the inciting infection.The extent of the interval between infection and the onset of arthritis considered consistent with a reactive arthritis by expert consensus is a minimum of several days and a maximum of several weeks. In at least half of patients, all symptoms resolve in less than six months; in most patients, symptoms resolve within one year. The several types of clinical manifestations of reactive arthritis include:
●Symptoms of preceding enteric or genitourinary infection
●Musculoskeletal signs and symptoms 
●Extraarticular signs and symptoms 
Other than those symptoms due to the infection that has triggered the arthritis, the articular and extraarticular manifestations are similar regardless of the particular enteric or genitourinary organism or species of organism causing the disorder.
Preceding infection — The characteristic symptoms of the enteric or genitourinary infections that can cause reactive arthritis are diarrhea or urethritis. Patients with arthritis induced by enteric bacteria can also develop aseptic urethritis. Many patients have been described in whom the preceding infections are clinically silent and detectable only by laboratory testing. There are no data to indicate whether the disease course or prognosis of reactive arthritis differs between patients with or without an antecedent infection that is symptomatic. 
The enteric bacteria commonly associated with reactive arthritis include:
●Salmonella of various serovars
●Shigella, especially Shigella flexneri, but also Shigella dysenteriae and Shigella sonnei
●Yersinia, including Yersinia enterocolitica 0:3 and 0:9 and Yersinia pseudotuberculosis
●Campylobacter, especially Campylobacter jejuni
●Clostridium difficile
The genital pathogen commonly accepted to be the cause of reactive arthritis is Chlamydia trachomatis.
Other bacteria also reported to cause reactive arthritis include Chlamydia pneumoniae, Escherichia coli, Ureaplasma urealyticum, and Mycoplasma genitalium. Intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer has also been identified as a rare cause of reactive arthritis. 
Reactive arthritis has also been reported in patients with human immunodeficiency virus (HIV) infection, in which it is generally thought to be related to other infections to which patients have been exposed, rather than to HIV itself. An association between reactive arthritis and human leukocyte antigen (HLA)-B27 has been noted in Caucasian HIV-infected patients but not in patients from sub-Saharan Africa, where the prevalence of HLA-B27 is much lower.
Although a large variety of pathogens have been described that may induce musculoskeletal symptoms, an arthritis is conventionally considered to be a reactive arthritis only if some of the typical musculoskeletal features occur. Not infrequently, patients do not volunteer the history of infection until asked about this specifically, since most patients are not aware that the infections can be related to arthritis.
Musculoskeletal signs and symptoms — The musculoskeletal features of reactive arthritis include four major manifestations: arthritis, enthesitis, dactylitis, and back pain.
●Arthritis - The typical picture of arthritis, seen in rheumatology clinics, is an acute-onset asymmetric oligoarthritis, often affecting the lower extremities. However, about 50 percent of patients have arthritis in the upper extremities, and some have polyarthritis in the small joints. Less often, axial arthritis may occur, with areas involved including the spine at any level and also the sacroiliac joints. By convention, the minority of patients with arthritis that does not resolve within six months is defined as having chronic reactive arthritis.
Asymmetical arthritis of the knees

Asymmetrical swelling due to reactive arthritis is apparent in this photograph. The patellar borders are effaced and there is suprapatellar fullness of the left knee.
●Enthesitis - The enthesis is the site of insertion of ligaments, tendons, joint capsule, or fascia to bone; enthesitis (or enthesopathy), the term for inflammation around the enthesis, can occur in patients with reactive arthritis and other forms of spondyloarthritis (SpA). Swelling at the heels is among the most characteristic symptom of enthesitis. Common sites of heel involvement are at the insertions of the Achilles tendon and of the plantar fascia on the calcaneus. Pain, swelling, and local tenderness are suggestive clinical features. Estimates of the frequency of enthesitis in patients with reactive arthritis have ranged from 20 to 90 percent.
In one study in the US of patients with documented enteric infections and a symptom of reactive arthritis, enthesitis was more common than arthritis or inflammatory back pain, occurring in 89 percent of patients.
Enthesitis is discussed in more detail elsewhere. 
●Dactylitis - Some patients also develop dactylitis, which typically presents as sausage digits. The frequency of dactylitis in patients with Chlamydia-induced reactive arthritis may be as high as 40 percent. 

Sausage digit (left 2nd toe)

Sausage like swelling of the left second toe is apparent in this photograph of a patient with reactive arthritis.
●Low back pain Inflammatory low back pain is frequent as an accompanying symptom, but seldom as the only presenting symptom. 
Extraarticular signs and symptoms — Extraarticular involvement in reactive arthritis is associated with a variety of manifestations, which may be present during the acute or chronic phase of illness. The relative frequency of each of these manifestations has not been well-analyzed. In one European cohort of 186 patients enrolled in a clinical trial, the frequencies of eye and skin involvement were approximately 20 and 15 percent, respectively.
Extraarticular manifestations include:
●Conjunctivitis, and less frequently, anterior uveitis, episcleritis, and keratitis. In one report a third of those with conjunctivitis were found to have detectable Chlamydia in scrapings off the conjunctiva.  

Conjunctivitis and anterior uveitis in reactive arthritis

Conjunctival injection and anterior uveitis (iritis) with hypopyon are noted in the photograph of the eye of a patient with reactive arthritis (formerly Reiter's Syndrome).
●Genitourinary tract symptoms, such as dysuria, pelvic pain, urethritis, cervicitis, prostatitis, salpingo-oophoritis, or cystitis. Urethritis can occur even when the arthritis is induced by enterobacteriaceae.
●Oral lesions, including mucosal ulcers
Oral lesions in reactive arthritis

Gray plaques are present on the tongue.	Palatal erosion in reactive arthritis

A sharply demarcated erosion of the hard palate is shown. This is among the more common of the oral manifestations of reactive arthritis.
	
●Cutaneous eruptions and other skin changes, such as keratoderma blennorrhagica (hyperkeratotic skin lesions on soles and palms) and erythema nodosum
Keratoderma blennorrhagicum

This close-up photograph shows the erythematous, scaly plaques of keratoderma blennorrhagicum in a patient with reactive arthritis (formerly Reiter's Syndrome).	Erythema nodosum

Painful erythematous nodules of erythema nodosum are often found in a symmetric distribution on the legs. The nodules can also appear to be pigmented.
	
●Nail changes that resemble those seen in psoriasis 
Nail changes in reactive arthritis

Subungual hyperkeratosis, onycholysis, and periungual erythematous scaly plaques are present on the hands of this patient with reactive arthritis.
Nail changes in reactive arthritis

Separation of the distal portion of the nails (onycholysis), accumulation of subungual keratotic debris, and periungual scale and erythema can occur in both reactive arthritis and psoriasis.  Arthritis is present in addition to the dystrophic nail changes.

●Genital lesions such as circinate balanitis 
●Cardiac manifestations, which are uncommon, include valve disease, particularly aortic insufficiency, with greater chronicity of illness. Pericarditis has been reported very rarely.
None of the mucocutaneous or other manifestations are specific for reactive arthritis.
LABORATORY AND IMAGING FINDINGS — Several types of findings may be present, including:
●Evidence of antecedent or concomitant infection
●Elevated acute phase reactants
●Positive testing for human leukocyte antigen (HLA)-B27
●Inflammatory synovitis
●Imaging abnormalities consistent with enthesitis or arthritis
Laboratory findings
Antecedent or concomitant infection — Laboratory tests, such as stool cultures to test for Salmonella, Shigella, Campylobacter, and Yersinia, can sometimes confirm a preceding or concomitant infection with one of the pathogens that classically induce reactive arthritis. However, by the time patients develop arthritis, the diarrhea has usually resolved, and the pathogens may no longer be retrievable. Urine and genital swab testing can sometimes detect chlamydial trachomatis infection using nucleic acid amplification techniques. 
Serological testing is used primarily in epidemiologic studies to test for preceding infections but is generally not useful in clinical practice. Infections by Yersinia, Salmonella, Campylobacter, and Chlamydia trachomatis cause strong antibody responses, and the triggering enteric infections can still be identified by serology in more than 50 percent of Yersinia- or Salmonella-infected patients, if such testing is performed. In communities in which these infections are endemic and often clinically silent, serological testing is not specific for recent episodes of infection.
Acute inflammatory changes — Acute phase reactants such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be elevated. In many patients, however, these studies may be normal; elevations in acute phase reactants were found in less than half of patients diagnosed with reactive arthritis in one study.
Genetic predisposition — The prevalence of HLA-B27, which is increased in patients with the various forms of spondylarthritis (SpA), including reactive arthritis, is generally estimated at 30 to 50 percent in patients with reactive arthritis, although values range widely. In hospital-based studies with more severely affected patients, frequencies as high as 60 to 80 percent have been reported; however, estimates in population-based studies and analyses of disease outbreaks are generally much lower and occasionally have shown no increase in HLA-B27 prevalence compared with the general population. 
Inflammatory synovitis — The findings in synovial fluid are nonspecific and are characteristic of inflammatory arthritis, with elevated leukocyte counts, predominantly neutrophils. White blood cell (WBC) counts are typically between 2000 and 64,000 WBC per mm3. 
Imaging abnormalities — There are no specific findings on plain radiographs that can establish a diagnosis of reactive arthritis. Changes are usually limited to those associated with joint swelling if inflammatory arthritis is present. Patients with concurrent or past heel pain may show calcaneal spurs, but such findings are nonspecific and can be seen in other forms of arthritis and in asymptomatic individuals.
Radiographic sacroiliitis, a feature of spondyloarthritis, has been reported. In patients with chronic joint disease, imaging studies such as ultrasonography, scintigraphy (radionuclide bone scanning), or magnetic resonance imaging (MRI) can also identify changes consistent with peripheral synovitis, enthesitis, or sacroiliitis. 
DIAGNOSIS — The diagnosis of reactive arthritis is a clinical diagnosis based upon the pattern of findings. There is no single definitive diagnostic test, nor are there validated diagnostic criteria. The diagnosis can generally be made in patients who exhibit all three of the following:
●Characteristic musculoskeletal findings – Such findings include a combination of oligoarthritis of peripheral joints, most often with asymmetric involvement of the lower extremity, enthesitis, dactylitis, or inflammatory back pain. 
●Evidence of preceding extraarticular infection – The presence of a preceding extraarticular infection may be indicated simply by a history of urethritis or diarrhea. In the case of urethritis, or suspected silent urethritis, chlamydia can usually be identified, if present, by nucleic acid amplification. Stool cultures are usually not done in patients in whom the preceding episode of diarrhea has resolved. 
Inability to identify the causative pathogen does not exclude the diagnosis of reactive arthritis. Even in well-controlled studies, pathogens can be identified in only about 50 percent of the patients. In those cases, the diagnosis of infections would depend entirely upon the history. 
●Lack of evidence for another more likely cause of oligoarthritis, monoarthritis, or enthesitis – Similar musculoskeletal findings may occur in patients with other disorders, such as other forms of spondyloarthritis (SpA); crystal-induced arthritis; other forms of inflammatory polyarthritis, such as rheumatoid arthritis or systemic lupus; septic arthritis; poststreptococcal arthritis; or Lyme arthritis. These alternative diagnoses can usually be excluded based upon the history, physical examination, and laboratory examination. 
Algorithms derived from analysis of available cross-sectional data in the literature provide support for these criteria; although the probabilities described below are estimates, given the lack of a definitive diagnostic test for reactive arthritis:
●In patients with new onset of arthritis in a pattern characteristic of reactive arthritis, in whom alternative diagnoses have been excluded, the probability of reactive arthritis has been estimated to be about 40 percent.
●In a patient with a typical musculoskeletal presentation, in whom other diagnoses have been excluded, plus symptomatic enteritis with a positive stool culture for bacteria associated with reactive arthritis, the probability of reactive arthritis is high.
●In a patient with a typical musculoskeletal presentation, in whom other diagnoses have been excluded, plus a history of proven symptomatic preceding infection by Chlamydia trachomatis, the probability of reactive arthritis is very high (increased to about 90 percent). If the patient does not have a symptomatic Chlamydia trachomatis infection but Chlamydia trachomatis can be detected in the urine, the probability is roughly 60 percent.
The diagnostic values of inflammatory spinal pain and extraarticular features , including conjunctivitis, balanitis, and keratoderma blennorrhagica, have not been systematically evaluated in longitudinal studies.
Diagnostic evaluation — The diagnostic evaluation in a patient suspected of reactive arthritis depends upon the presenting symptoms and likely infectious etiology. In most patients, we do the following:
●A thorough history and physical examination. The history is directed, in particular, at distinguishing musculoskeletal manifestations characteristic of reactive arthritis from those suggesting an alternative diagnosis and at determining whether there are symptoms to indicate a preceding or concomitant infection, especially diarrhea or urethritis. 

The physical examination should include a detailed examination of the joints, including the heels, digits, and spine, as well as the rest of the joint examination. The general examination should aim at excluding other systemic or localized arthritic disorders. 
●Plain radiographs of affected joints and entheses, if necessary to exclude other causes of joint pain, including other forms of arthritis and stress fractures.
We perform the following studies, depending upon the history and findings:
●In patients with a joint effusion, we perform arthrocentesis and examination of the synovial fluid, including total and differential white blood cell counts, crystal search, and examination for bacteria by Gram stain and culture to exclude septic arthritis. Techniques such as polymerase chain reaction (PCR) testing for pathogens in the synovial fluid or tissue are not indicated in the routine clinical evaluation and management of reactive arthritis. 
●In patients with active diarrhea, we obtain stool cultures to test for Salmonella, Shigella, Campylobacter, and Yersinia. Serologic testing for enteric pathogens is generally not indicated because the limited specificity of such testing. 
●In patients suspected of infection with Chlamydia trachomatis and in patients with neither gastrointestinal nor genitourinary symptoms, we may obtain a first-catch urine sample (first portion of the urine specimen) or a vaginal swab, which may be self-administered by the patient or obtained by the clinician, for testing for chlamydia using nucleic acid amplification techniques. Testing for chlamydia is described in detail separately. 
Additional testing which may further increase or decrease support for the diagnosis, but which alone is not diagnostic or exclusionary, includes the following:
●Routine laboratory testing – We obtain a complete blood count and differential, acute phase reactants, renal and liver chemistries, and urinalysis to obtain supportive evidence of acute inflammation and to exclude other systemic disorders. 
●Testing for human leukocyte antigen (HLA)-B27 – We obtain HLA-B27 testing in patients with an intermediate likelihood of reactive arthritis. The prevalence of HLA-B27 in patients with reactive arthritis is generally estimated at 30 to 50 percent. Thus, a positive test would increase the likelihood of reactive arthritis being the correct diagnosis, rather than a different form of arthritis, other than another type of spondyloarthritis (SpA). In patients with an intermediate likelihood of another form of SpA (eg, ankylosing spondylitis), a positive test would increase, and a negative test would decrease, suspicion of that diagnosis. 
●Serologic testing for rheumatoid arthritis – Rheumatoid factor and anticyclic citrullinated peptide antibody testing are obtained in patients with polyarthritis suspected of possible rheumatoid arthritis. At least one of these antibodies is present in over 70 to 80 percent of patients with rheumatoid arthritis, but both are usually absent in patients with reactive arthritis. 
DIFFERENTIAL DIAGNOSIS — Acute inflammatory monoarthritis or oligoarthritis may occur in a variety of disorders. Particularly important and/or common causes of arthritis to differentiate from reactive arthritis include crystal-induced inflammation, which is diagnosed by the history and identification of crystals (typically monosodium urate or calcium pyrophosphate) upon examination of the joint fluid, and bacterial infection (eg, septic arthritis and Lyme disease, which are identified by joint fluid examination and culture and by serologic testing of patients potentially exposed while in an endemic area, respectively). The general approaches to the evaluation of acute monoarthritis and polyarthritis are discussed separately. 
The differential diagnosis of reactive arthritis can be guided, in part, by the pattern of symptoms and findings that are associated with the arthritis and that may suggest a related infectious or other systemic disorder. The following conditions should also be considered in the differential diagnosis:
●Diarrhea and arthritis – Various systemic conditions affecting the gastrointestinal tract and some infectious disorders may cause diarrhea in association with chronic or self-limited arthritis, features that may suggest reactive arthritis. Enteroviral infection-associated arthritis may represent a substantial number of cases of nonspecific, self-limited inflammatory joint disease; although arthritis is an uncommon manifestation of enterovirus infection, viral gastroenteritis is relatively common. Additional symptoms suggestive of a viral etiology include the presence of myalgias, an evanescent rash, and constitutional symptoms such as fever. Both large and small joints may be involved. Sore throat, pleuritic pain, and myocarditis are other features suggestive of enteroviral infection.
Inflammatory bowel diseases (eg, Crohn’s disease and ulcerative colitis), Behçet’s syndrome, celiac (sprue) disease, Whipple’s disease, parasitic infections, and intestinal bypass surgery may cause diarrhea and arthritis. These conditions can usually be differentiated from reactive arthritis by the history, including the chronicity of the gastrointestinal symptoms and other features suggesting the alternative diagnosis; by physical examination; and, as indicated clinically, by serology, biopsy, or culture. These conditions are discussed in greater detail separately. 
●Genitourinary symptoms/disorders and arthritis – Disseminated gonococcal infection (DGI) is the primary cause to consider when urethral, uterine, cervical, or tuboovarian inflammation occurs in a patient with arthritis. The presence of a rash and tenosynovitis are suggestive. However, purulent arthritis due to gonococcal infection can occur in the absence of these findings. Culture of synovial fluid, the urethra, and other potentially infected mucosal sites is helpful in the diagnosis or exclusion of DGI or gonococcal arthritis. Nucleic acid amplification testing may be substituted for culture of genitourinary sites when it is available. The clinical manifestations and diagnosis of gonococcal infection and DGI are discussed in detail separately. 

Arthritis and arthralgias are a rare complication of intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer. Affected patients commonly experience polyarthritis or oligoarthritis, predominantly of the lower extremities, within two weeks after instilling BCG. Approximately 20 percent of reported patients complain of axial pain compatible with spondyloarthritis (SpA), and over one-half of patients are human leukocyte antigen (HLA)-B27-positive. Associated genitourinary symptoms include cystitis, fever, and hematuria 
●Arthritis/SpA/enthesitis without preceding infectious symptoms — Other members of the SpA family, especially peripheral spondyloarthritis unrelated to psoriasis or inflammatory bowel disease (undifferentiated SpA), may present with arthritis and sometimes enthesitis, which are indistinguishable from the musculoskeletal manifestations of reactive arthritis. Such conditions are distinguished from reactive arthritis by the lack of history and laboratory findings to suggest recent infection with the organisms associated with reactive arthritis. 
●Poststreptococcal arthritis – Arthritis is a common manifestation in patients with acute rheumatic fever (ARF) following streptococcal pharyngitis. These patients typically lack features common to the spondyloarthritides (eg, enthesitis), and this condition is generally not considered to be a form of reactive arthritis. Other clinical and laboratory manifestations of rheumatic fever and evidence of recent streptococcal infection distinguish these patients from those with reactive arthritis. A “poststreptococcal reactive arthritis” has been described in adults who have arthritis but do not satisfy criteria for ARF. These issues are discussed in detail separately   
TREATMENT — There are several major aspects to management. In some patients, particularly those with genitourinary infection, treatment of the infection that triggered the arthritis is indicated; arthritis and associated periarticular conditions should be treated in patients with symptomatic joint disease. Additional interventions may also be required for the treatment of extraarticular manifestations. 
Treatment of the infection — Antibiotics are not used to treat the arthritis specifically but may be indicated for treatment of the underlying infection if there is evidence of ongoing genitourinary infection or carriage of potentially pathogenic organisms. A role for antibiotic therapy in the treatment of chronic arthritis has not been established. 
A systematic review and meta-analysis of randomized trials comparing antibiotic therapy with placebo or no antibiotics for treatment of reactive arthritis found that antibiotic treatment did not significantly reduce the likelihood of failing to achieve remission of the reactive arthritis; although results of the studies were very heterogeneous, trial design varied substantially, and many trials were at risk of bias. Rates of remission were able to be analyzed in 7 of the 12 trials included in the review, involving a total of 375 patients. Additionally, there were no significant effects of antibiotic therapy on pain, joint counts, or patient global assessment, but gastrointestinal side effects were nearly twice as likely in the patients receiving antibiotics.
Enteric infection — In general, antibiotics are not indicated for uncomplicated enteric infections, but some patients with active enteric infections may require treatment, depending upon their comorbidities and upon the specific organism. For example, therapy may be indicated in patients with severe gastrointestinal disease, in older adults, or in immunocompromised hosts. Treatment of enteric infections is discussed separately. 
In patients with chronic reactive arthritis induced by enteric bacteria, the available evidence does not support the use of long-term antibiotics.
Genitourinary tract infection — In contrast with most patients with enteritis, patients with acute Chlamydia trachomatisinfection of the genitourinary tract and their sexual partners should receive a standard antimicrobial treatment for chlamydial infection of the genital tract. Treatment regimens are presented elsewhere.
Patients with a history of chlamydia-induced arthritis should be evaluated for recurrent genitourinary infection if arthritis or genitourinary symptoms recur and should be retreated with antibiotics if testing for chlamydia infection is positive. Antibiotic treatment of the infection might prevent relapses of arthritis in patients with recurrent genitourinary tract symptoms alone. Prompt treatment of acute chlamydia infections prior to the development of reactive arthritis, in both patients and partners, may lower the probability of developing reactive arthritis, although this has not been proven.
The approach to the evaluation and treatment of persistent or recurrent genitourinary tract symptoms despite initial antibiotic therapy is discussed in detail separately. 
Chronic Chlamydia-related arthritis — We do not advise the routine use of long-term antibiotics to treat established reactive arthritis. Results are mixed in randomized trials of long-term therapy with single antibiotics, and most do not show benefit.
By contrast, one study (included in the meta-analysis) provides limited evidence to suggest that combination antibiotics might be useful in the subset of patients with polymerase chain reaction (PCR)-proven chlamydia-induced arthritis. This trial involving 42 patients with reactive arthritis of at least six months’ duration, who tested positive for Chlamydia trachomatis or Chlamydia pneumoniae by a special PCR technique in blood or affected synovial tissue. Patients were randomly assigned to receive six months of treatment with rifampin plus either doxycycline or azithromycin or to receive placebo. The composite endpoint for improvement in musculoskeletal signs and symptoms was reached more often by the patients receiving combination antibiotics (17 of 27 [63 percent] versus 3 of 15 [20 percent], p = 0.01). Adverse events were mild and comparable between groups. However, there were limitations to the study: the numbers in each group were too small to compare the different antibiotic regimens, and the study was limited to patients with evidence of persistent chlamydial infection by a special PCR using peripheral blood or synovial samples instead of routine urine samples. Serologic tests did not correlate with these PCR results, and the PCR assays that were used in the study are not yet available for routine clinical use and are not of proven clinical utility. Further studies with larger numbers of patients are required to confirm these findings. There is no evidence of benefit for such treatment in patients with any other form of reactive arthritis.
Treatment of arthritis — The treatment of arthritis with antiinflammatory and immunosuppressive agents can be divided into two stages: the treatment of acute reactive arthritis and the treatment of refractory (chronic) reactive arthritis, usually defined as disease of greater than six months’ duration. 
The initial treatment goal is symptomatic relief of the arthritis, because the disease is self-limited in a substantial majority of patients, and joint injury with significant continued symptoms is infrequent. 
The approach to therapy is based upon both clinical experience in reactive arthritis and upon evidence of benefit for these therapies in other inflammatory arthritides, particularly other forms of spondyloarthritis (SpA), given the paucity of randomized trials and longitudinal observational studies in patients with reactive arthritis. 
In clinical practice, disease activity and the response to therapy are assessed by the swollen or tender joint counts, the intensity of pain and disability, the presence and severity of enthesitis, and global assessments by the clinician and patient. There are no validated indices for assessment of disease activity in reactive arthritis.
Acute reactive arthritis — In patients with acute reactive arthritis, we initiate treatment with nonsteroidal antiinflammatory drugs (NSAIDs), which are usually the principal form of therapy, and may administer intraarticular and/or systemic glucocorticoids in patients with disease resistant to NSAIDs. 
Initial therapy — We suggest treatment with antiinflammatory doses of NSAIDs (eg, naproxen 500 mg two to three times daily, diclofenac 50 mg three times daily, or indomethacin 50 mg three to four times daily) for symptomatic therapy for most patients, unless contraindicated (eg, by a history of gastrointestinal bleeding, allergy, cardiovascular disease, or compromised renal status). Maximum antiinflammatory doses and continuous use may be necessary to control pain and inflammation. An adequate trial of a given NSAID is usually at least two weeks in duration. Individual responses vary, and more than one NSAID may need to be tried before identifying an effective agent. There is no evidence that NSAIDs shorten or otherwise affect the course of the disease.
NSAIDs are used initially because treatment of the infection does not alleviate the signs or symptoms of arthritis, because the disease is most frequently self-limited, and because most patients will not require disease-modifying antirheumatic drugs (DMARDs) to control inflammation or to prevent erosive joint changes. The use of NSAIDs is based upon their ability to provide significant symptomatic relief in other forms of SpA and upon clinical experience with their use in reactive arthritis; there have been few formal trials of NSAIDs in reactive arthritis. 
Patients receiving NSAIDs should be cautioned regarding the risk of gastrointestinal, renal, hepatic, and cardiovascular adverse effects, including the risk of NSAID gastropathy and gastrointestinal bleeding. Complete blood counts, renal function, and hepatic aminotransferases should be measured after two months on a given agent and then every three to six months thereafter in patients continuing to require antiinflammatory dosing regimens of NSAIDs, depending upon the comorbidities present. 
Inadequate response to NSAIDs — Intraarticular glucocorticoids can be administered in patients with persistent symptoms despite treatment with NSAIDs, and oral glucocorticoids may be of benefit in patients who do not respond to these therapies.
Intraarticular glucocorticoids — In patients who do not respond adequately to NSAIDs, we suggest injection of major affected joints with intraarticular glucocorticoids. In our experience, intraarticular injection with triamcinolone acetonide (40 mg for a large joint, such as the knee, and lower doses for smaller joints), or an alternative agent in equivalent doses, is generally effective in reducing joint inflammation and in providing symptomatic relief similar to that seen in other forms of SpA or in rheumatoid arthritis. These may result in symptomatic relief sufficient to avoid the need for oral glucocorticoids or DMARD therapy and the side effects associated with use of these agents. 
There is no evidence in our experience, nor are there any reports, of a greater frequency of adverse events or of disease worsening associated with the use of intraarticular or systemic glucocorticoids, despite the infectious etiology of reactive arthritis and the detection of the causative microbes in the joints of some patients with reactive arthritis. This issue has not been systematically evaluated. Pain and swelling of the plantar fascia can also be relieved by local glucocorticoid injections. 
Systemic glucocorticoids — In patients who do not respond adequately to NSAIDs and intraarticular glucocorticoid injections or in those with a large number of involved joints, we suggest low to moderate doses of oral glucocorticoids (eg, a starting dose of prednisone 20 mg daily), which should be reduced gradually to the lowest dose required to control symptoms. In our experience, use of these agents for a limited period and in a tolerable dose range may preclude need for use of DMARD therapy. There are no randomized trials of systemic glucocorticoids in reactive arthritis. The use of glucocorticoids for inflammatory joint disease, the adverse effects of these agents, and strategies for the prevention of glucocorticoid-induced osteoporosis are described in detail elsewhere. 
Resistant to NSAIDs and glucocorticoids — Treatment with a DMARD is indicated in patients who do not respond adequately to initial therapies. The duration prior to beginning DMARDs depends upon the degree of disease activity and upon the relative risks and benefits of NSAIDs and glucocorticoids in a given patient, given the comorbidities that are present and the dose of glucocorticoids required to control symptoms. We generally use DMARDs in patients who have not responded adequately to at least two different NSAIDs over a total of four weeks and who require ongoing therapy with more than 7.5 mg of prednisone or equivalent for more than three to six months. 
Chronic reactive arthritis — In patients who develop refractory reactive arthritis, usually defined as disease lasting greater than six months, or who are resistant to initial therapy for acute arthritis with NSAIDs and glucocorticoids, we initiate therapy with a nonbiologic (traditional) DMARD, usually sulfasalazine (SSZ) or, alternatively, methotrexate (MTX). In patients with disease that is refractory to a nonbiologic DMARD, we administer therapy with a tumor necrosis factor (TNF) inhibitor. The use of these medications for reactive arthritis is based upon limited data and upon clinical experience. 
Nonbiologic DMARD use
Sulfasalazine — We suggest the use of SSZ in patients with refractory reactive arthritis or with reactive arthritis resistant to initial therapy for acute arthritis. We initiate treatment with 500 mg once daily and increase the daily dose stepwise (in increments of 500 mg each week) to 1000 mg twice daily. The dose can be increased to a maximum of 3000 mg/day (taken in two or three divided doses) if required. 
The use of SSZ in patients with reactive arthritis is based primarily upon one randomized trial in patients with reactive arthritis and is further supported by a meta-analysis and randomized trials comparing it with placebo in patients with ankylosing spondylitis and with psoriatic arthritis; and by randomized trials comparing it with placebo and other nonbiologic DMARDs in rheumatoid arthritis. We prefer SSZ over MTX because of its better documented efficacy in patients with peripheral SpA, including psoriatic arthritis. 
Benefit from SSZ was suggested by a 36-week randomized trial involving 134 patients with chronic reactive arthritis who had not responded adequately to NSAIDs. Response in the trial was defined by a composite measure that included patient self-assessment, clinician assessment, and improvement in joint pain or tenderness and in joint swelling. Results for the primary outcome measure showed a trend toward benefit with SSZ that was not statistically significant but that might be clinically meaningful if real. SSZ was well-tolerated, with minor gastrointestinal side effects in some patients.
In general, the most common adverse effect causing discontinuation of therapy with SSZ is gastrointestinal upset, but central nervous system symptoms, rash, and other infrequent side effects may also occur. The use and monitoring of SSZ, as well as its adverse effects, are discussed in detail separately. 
Methotrexate — MTX may be used as an alternative nonbiologic DMARD for patients who may be allergic to or intolerant of SSZ or who do not respond to SSZ treatment. However, MTX has not been formally studied in patients with reactive arthritis, and there is a lack of evidence to support the use of MTX for axial disease in ankylosing spondylitis, even though clinical experience suggests it may be of benefit for treating peripheral arthritis in such patients. 
The use of MTX is based upon clinical experience with its use for peripheral SpA, including psoriatic arthritis, and upon evidence in meta-analyses and in randomized trials for its efficacy in rheumatoid arthritis. In reactive arthritis, we use MTX in the same fashion and doses (15 to 25 mg given on one day weekly) as are employed in psoriatic arthritis and rheumatoid arthritis. The use and adverse effects of MTX are described in detail elsewhere. 
Duration of therapy — The nonbiologic DMARDs are continued for at least four months (SSZ) or three months (MTX) at the maximally tolerated therapeutic dose (up to 3 g/day SSZ or up to 25 mg/week MTX) to determine if there is a response to therapy and are then discontinued three to six months after the patients have entered into remission, with resolution of clinical signs and symptoms of disease activity. Some patients who do not respond to the initial DMARD therapy may respond to the alternative agent, in our experience; however, whether to use a second nonbiologic DMARD or to proceed directly to the use a biologic agent in such patients has not been formally evaluated. If disease recurs, we resume therapy with the previously effective agent.
Resistant to nonbiologic DMARDs — For patients who have reactive arthritis that is refractory to NSAIDs and glucocorticoids and who do not respond to or have a contraindication to the use of SSZ and MTX, we use an anti-TNF agent (eg, etanercept 50 mg/week administered by subcutaneous injection or infliximab 3 to 5 mg/kg administered intravenously on weeks zero, two, and six and then every eight weeks). In patients who do not respond to an initial trial of one agent after three months of therapy, another TNF inhibitor can be tried instead. An effort can be made to discontinue therapy in patients who have been in remission induced by a TNF inhibitor for at least three months, but treatment should be resumed with the medication if disease then recurs.
The use of TNF inhibitors in patients with reactive arthritis is directly supported only by case reports and by small case series. Their use, rather than the use of other nonbiologic or biologic DMARDs, is also supported by clinical experience and by their effectiveness in the treatment of other spondyloarthropathies, including axial and peripheral SpA and the various forms of psoriatic arthritis. The dosing and agents, the evidence supporting their use in patients with other types of SpA, and the adverse effects of TNF inhibitors are described in detail elsewhere. 
Evidence directly supporting the use of TNF inhibitors in reactive arthritis is illustrated by the following examples:
●A group of patients with reactive arthritis (seven patients) or undifferentiated SpA (nine patients) were treated with etanercept for six months; a treatment response (a composite of pain score and tender and swollen joint counts) was achieved by 9 of the 10 patients who completed the study, including patients from both groups. None of the patients experienced a worsening of arthritis or an exacerbation of any suspected underlying infections.
●An observational study in France reported the efficacy and safety of anti-TNF therapies in 10 patients with reactive arthritis of recent onset (within 12 months). Five, four, and one patient(s) each received infliximab, etanercept, and adalimumab, respectively. Nine of 10 patients met response criteria, with reduction in tender and swollen joint counts, pain score, and serum C-reactive protein (CRP) levels. All eight patients taking glucocorticoids successfully discontinued them after a median of four months. Six patients discontinued the anti-TNF therapy after a median of 7.5 months; three relapsed after stopping but responded to retreatment.
There are no studies of patients with reactive arthritis refractory to the above therapies, although other approaches to the treatment of chronic inflammatory arthritis have been evaluated in SpA, including psoriatic arthritis, and in rheumatoid arthritis. In the very uncommon patients who are resistant to treatment with the agents noted above, including at least two TNF inhibitors, alternative diagnoses such as other forms of SpA or central pain should be reevaluated. 
Treatment of other clinical features — Some extraarticular manifestations, including ocular involvement and mucous membrane and skin manifestations, require additional interventions. The management approaches are based upon the treatments used for these or for similar manifestations in patients with other disorders and upon clinical experience.
None of these interventions has been systematically evaluated in randomized trials or has been the subject of observational studies in patients with reactive arthritis, and most treatment studies of antiarthritic or antibiotic therapy for reactive arthritis and reviews of this disease do not discuss the effects of such therapies on these manifestations or the recommended approaches for their treatment. Extraarticular manifestations that may require treatment include the following:
●Ocular manifestations – Patients with eye pain, visual disturbance, or abnormal eye findings should be referred for ophthalmologic evaluation, as a slit-lamp examination may be required to determine if uveitis is present. The diagnosis and treatment of conjunctivitis and anterior uveitis are discussed separately. 
●Skin and mucous membrane lesions – Patients with very mild skin involvement or oral ulcers may not require intervention. Symptomatic treatment may be sufficient in patients with oral mucosal ulcers, and topical steroids are effective in some patients. The treatment of oral mucosal ulcers is discussed in detail elsewhere. 
More symptomatic involvement with mild to moderate keratoderma blennorrhagica may benefit from the use of topical steroids, and some skin lesions can be treated with topical salicylates . In general, treatment of these manifestations is very similar to the approach in patients with palmoplantar pustulosis from other causes. The treatment of circinate balanitis is discussed separately. 

Patients with more severe keratoderma blennorrhagica and pustular lesions who do not respond to topical medications may require systemic DMARDs, such as MTX or a TNF inhibitor. Other treatments that may be of benefit in keratoderma blennorrhagica include topical vitamin D (calcipotriol/calcipotriene) in mild to moderate cases and retinoids in patients with more severe involvement. Therapy of these skin findings and of nail involvement is similar to that used in patients with psoriasis. 
PROGNOSIS — The course of reactive arthritis varies considerably, probably depending upon the triggering pathogen and the genetic background of the host. The typical disease duration is three to five months. Most patients either remit completely or have little active disease within 6 to 12 months after presentation, but 15 to 20 percent may experience more chronic persistent arthritis. After entering remission of peripheral joint arthritis, pain is occasionally still noted in the joints, at entheses, or in the spine. Representative results are illustrated by the following:
●A European League Against Rheumatism (EULAR) study evaluated 152 patients with reactive arthritis who were enrolled within two months of the onset of arthritis. By the end of an additional 24 weeks of observation, almost all patients had very low disease activity as determined by clinician- and patient-global assessments.
●In other studies, reactive arthritis that lasted for more than one year occurred in 4 to 19 percent of patients in Finland whose arthritis was induced by Yersinia, Salmonella, Shigella, and Chlamydia. It is difficult to know whether this proportion of patients who develop chronic disease can be generalized to other geographic regions.
Some patients with chronic reactive arthritis later develop features characteristic of another of the spondyloarthritides, eg, psoriatic arthritis, ankylosing spondylitis, or the arthritis associated with inflammatory bowel disease. Human leukocyte antigen (HLA)-B27 testing has been associated with a worse prognosis in some, but not all studies, with findings suggesting that patients who are HLA-B27-positive are more likely to develop a chronic spondyloarthropathy with radiographic changes. Patients with the triad of postinfectious arthritis, urethritis, and conjunctivitis may also have a poorer prognosis.
SUMMARY AND RECOMMENDATIONS
●Reactive arthritis is a rare disease even among rheumatology practices.
●Reactive arthritis has been defined by consensus as a form of arthritis that is associated with a coexisting or recent antecedent extraarticular infection. Only certain enteric and genitourinary pathogens are conventionally accepted as capable of causing reactive arthritis. These include Chlamydia trachomatis, Yersinia, Salmonella, Shigella, Campylobacter, Clostridium difficile, and Chlamydia pneumoniae. Various other bacterial and viral infections have been suggested as triggers for postinfectious arthritis but they are by convention not considered as “reactive arthritis.” 
●Musculoskeletal features of reactive arthritis typically develop one to four weeks following an acute infection with one of the triggering organisms. At least one of the following is seen in all patients with this condition: asymmetric oligoarthritis (often affecting the lower extremities), enthesitis, dactylitis, and inflammatory back pain. 
●Extraarticular manifestations occur in some patients, but none are specific for reactive arthritis. These include eye involvement, most often with conjunctivitis, but infrequently with anterior uveitis; genitourinary tract symptoms; oral mucosal ulcers; and cutaneous manifestations such as keratoderma blennorrhagica, circinate balanitis, and psoriasis-like nail changes. 
●Laboratory findings may include evidence of the antecedent infection, elevated acute phase reactants, and findings of inflammatory joint fluid in patients with arthritis. Plain radiographs are generally nondiagnostic. 
●The diagnosis is based upon the presence of characteristic musculoskeletal and other clinical features in a patient with a preceding or ongoing enteric or genitourinary infection, in whom other causes of arthritis have been excluded. There is no single definitive test for reactive arthritis. Laboratory testing to confirm infection if feasible may be helpful but is not required to make the diagnosis; such testing may include stool cultures in patients with ongoing gastrointestinal symptoms and testing for Chlamydia trachomatis with a vaginal swab or urine sample for nucleic acid amplification testing in patients with genitourinary symptoms and those without localizing symptoms of infection. Serological testing for preceding infections is used primarily in epidemiologic studies but is generally not useful in clinical care. Human leukocyte antigen (HLA)-B27 testing may be useful in selected patients. 
●The differential diagnosis encompasses disorders that can cause acute mono- or oligoarthritis, particularly those associated with bowel diseases or genitourinary symptoms (eg, enterovirus infection, inflammatory bowel disease, and disseminated gonococcal infection), acute septic or crystal arthritis, undifferentiated spondyloarthritis (SpA), and other postinfectious arthritic disorders. 
●Antibiotic therapy should be used for treatment of active Chlamydia trachomatis infection, if present. In general, antibiotics are not indicated for uncomplicated enteric infections or for treatment of the arthritis itself. 
●We suggest treatment of arthritis in most patients initially with nonsteroidal antiinflammatory drugs (NSAIDs) in antiinflammatory doses (eg, naproxen 500 mg two to three times daily, diclofenac 50 mg three times daily, or indomethacin50 mg three times daily), rather than starting a disease-modifying antirheumatic drugs (DMARD) upon diagnosis (Grade 2B). 
●In patients who do not respond adequately to NSAIDs, we suggest intraarticular glucocorticoids, rather than initiating therapy with daily oral glucocorticoids or a DMARD. (Grade 2C). 
●In patients who do not respond adequately to NSAIDs and intraarticular glucocorticoid injections, we suggest low to moderate doses of systemic glucocorticoids, rather than initiating treatment with a DMARD. (Grade 2C). A typical dose would be prednisone, 20 mg daily, titrated to the lowest dose required to control symptoms 
●In patients who have not responded adequately to NSAIDs over at least four weeks and who require ongoing therapy with more than 7.5 mg of prednisone or equivalent for more than three to six months we suggest a trial of a nonbiologic DMARD, rather than continuing moderate to high dose glucocorticoids without a DMARD (Grade 2B). We usually prescribe sulfasalazine (SSZ, beginning with 500 mg daily and titrating the dose to a maximum of 3 g daily). Methotrexate (MTX, up to 25 mg one day weekly) is an alternative to SSZ. Treatment with a tumor necrosis factor (TNF) blocker may be used in the rare patients who are resistant to NSAIDs and nonbiologic DMARD therapy. 
●The prognosis is good in the majority of patients, with spontaneous remission within 6 to 12 months of onset of arthritis. However, some patients have persistent but mild musculoskeletal symptoms, and others develop radiologic evidence of joint injury and evolve to a more chronic form of SpA.
*************************************************************
Abbreviations ANA: antinuclear antibody 
ARF: acute rheumatic fever 
CRP: C-reactive protein 
ESR: erythrocyte sedimentation rate 
FDA: Food and Drug Administration 
GAS: group A Streptococcus
 HLA: human leukocyte antigen Ig: immune globulin 
JIA: juvenile idiopathic arthritis 
MRI: magnetic resonance imaging 
NSAIDs: nonsteroidal anti-inflammatory drugs 
RF: rheumatoid factor 
SCFE: slipped capital femoral epiphysis

Arthritis is simply defined as inflammation of a joint. Arthritis may affect one or more joints and often is accompanied by swelling, redness, tenderness, warmth, and pain with movement. The pathophysiology of this inflammatory process varies depending on the underlying cause of arthritis. Monoarthritis is inflammation limited to one joint. In the context of juvenile idiopathic arthritis (JIA), oligoarthritis is defined as arthritis involving fewer than five joints, whereas polyarthritis is arthritis of five or more joints. Although there is a broad differential diagnosis, a thorough history and physical examination should provide sufficient information to direct the evaluation and management of the patient with arthritis. An overview of pediatric arthritis as well as a discussion of the most common causes, evaluation, and treatment is offered in this article. 
History and Physical Examination 
It is important to differentiate arthralgia from arthritis. Arthralgia is the presence of joint pain without objective signs of inflammation (warmth, erythema, tenderness, and swelling) on physical examination. Several rheumatologic diseases, such as systemic lupus erythematosus, may present with arthralgia early in the course; it is also important to consider viral as well as other causes of arthralgia. Children who have arthritis may present with pain, limited range of motion, limp, and refusal to use or move the affected joint. Presence of fever, rash, and other constitutional symptoms may suggest an infectious or autoimmune cause. It is important to discern whether the arthritis is migratory and to ascertain the specific joints and number of joints affected. A complete history, including the history of present illness, recent illness, or injury, associated symptoms, prior similar episodes, and prior signs and symptoms, must be elicited. In addition, immunization status and family history of autoimmune disorders must be obtained. Because the causes of arthritis are varied, patients may present with a multitude of other organ system findings suggestive of the underlying cause. Therefore, a comprehensive physical examination is necessary. A toxic or ill appearance may suggest a serious disorder such as pyogenic arthritis. Signs of concurrent upper respiratory infection such as rhinorrhea or pharyngitis may be present in patients who have toxic synovitis. In sexually active patients, reactive arthritis and gonococcal arthritis may occur; hence, a thorough genital and pelvic examination is necessary to evaluate for urethritis or cervicitis. The presence of a rash or a typical lesion may be suggestive of a specific disorder. Table 1 lists several disease processes that present with arthritis and their additional physical findings that may be helpful in narrowing the broad differential diagnoses. On physical examination, the joints must be evaluated for crepitus, warmth, tenderness, swelling, joint effusion, erythema, contractures, or decreased range of motion. The patient’s preferred position at rest must be observed. The joints should be tested for passive and active range of motion. Examination of the contralateral joints is important for comparison purposes. The patient’s gait should be observed carefully.
Differential Diagnosis of Arthritis/Limping 
Commonly encountered causes of arthritis in children include septic arthritis, reactive arthritis, acute rheumatic fever (ARF), Lyme arthritis, toxic synovitis, and JIA. Arthritis may occur in patients afflicted with inflammatory bowel disease, systemic lupus erythematosus, Henoch-Scho¨nlein purpura, Kawasaki disease, sarcoidosis, and other autoimmune and connective tissue disorders. Patients who have arthritis affecting the lower extremities often present with a limp. In a limping child, orthopedic processes such as trauma, slipped capital femoral epiphysis (SCFE), Legg-Calve´-Perthes disease, enthesitis (inflammation of the enthesis, the point at which ligaments, tendons, and fascia attach to bone), and overuse injuries such as Osgood-Schlatter disease must be considered. Leukemia, lymphoma, bone and other soft tissue masses, neuroblastoma, hemarthrosis and sickle cell crisis may present with limping as well. Other infectious causes such as osteomyelitis or a psoas muscle abscess also must be considered in a febrile limping child. Because the differential diagnosis for arthritis is extensive, this article will focus on a few common conditions that affect children and adolescents.
Table 1.
Common Conditions Causing Arthritis and Associated Additional Physical Findings
Underlying condition	Physical examination findings associated with the arthritis	
Disseminated gonorrhea	Fever, new heart murmur (in endocarditis), tenosynovitis, urethral discharge, cervicitis, genital lesions, oral or other lesions, meningismus, impaired mental status, and a maculopapular, pustular, necrotic, vesicular rash	
Juvenile idiopathic arthritis	Fever, uveitis, pericardial rub, lung fields dull to percussion, decreased pulmonary aeration, hepatomegaly, splenomegaly, salmon patch (evanescent, maculopapular, linear rash prominent when febrile)	
Late Lyme disease	Fever, Bell palsy, other cranial nerve palsies, mild meningismus	
Reactive arthritis	Fever, conjunctivitis, uveitis, episcleritis, keratitis, corneal ulcerations, axial spine tenderness, enthesitis (especially of the plantar aponeurosis and Achilles tendon), dactylitis, urethritis, cervicitis, salpingitis, vulvovaginitis, small shallow penile ulcers (balanitis circinata), pustules that coalesce into psoriatic-like plaques (keratoderma blennorrhagica)	
Rheumatic fever	Fever, ill appearance, pericardial rub, new heart murmur, erythema marginatum, subcutaneous nodules (wrist, elbow, knees), choreiform movements	
Septic arthritis	Ill appearance, fever, refusal to bear weight, pseudoparalysis	
Systemic lupus erythematosus	Fever, pallor, pericardial rub, lung fields dull to percussion, decreased aeration, ulcerations, malar rash, discoid rash, other rashes, psychosis	
Toxic synovitis	Low grade fever, rhinorrhea, pharyngitis	

Septic Arthritis 
Septic arthritis, also known as pyogenic arthritis, occurs when there is bacterial invasion of the synovium and joint space followed by an inflammatory process. In the pediatric population, the incidence of septic arthritis peaks between 2 and 3 years of age and has a male predominance (2:1). Except in the neonatal population, Staphylococcus aureus is the most common pathogen implicated in pediatric septic arthritis. The most common pathogens that cause septic arthritis in neonates are group B Streptococcus, Staphyloccus aureus, and gram-negative bacilli. Other common pathogens causing pyogenic arthritis in childhood include Streptococcus pyogenes and S pneumoniae. Kingella kingae is isolated in young children who have a recent history of upper respiratory infection. Because of widespread immunization in the United States, Haemophilus influenzae is no longer a frequent pathogen causing septic arthritis. However, the incidence of community acquired methicillin-resistant Staphylococcus aureus in cases of musculoskeletal infection, including septic arthritis, has been increasing. Other pathogens to consider when more than one joint is involved include Neisseria gonorrhoeae, N meningitidis, and Salmonella species. Table 2 details some common causes of pyogenic arthritis in specific populations and presents treatment options. Because the synovial membrane is vascular in nature, hematogenous seeding of bacteria is the most common mechanism of infection in septic arthritis. Alternatively, septic arthritis may result from the spread of an adjacent osteomyelitis or other infection. The hip and shoulder are particularly vulnerable to contiguous spread. Besides hematogenous and contiguous spread, it is important to consider trauma, instrumentation, and intra-articular injections as potential precursors to arthritis. Patients present often with localized symptoms such as pain, swelling, limp, and refusal to ambulate or to move the affected area (pseudoparalysis). Generalized symptoms such as fever, malaise, fussiness, and decreased appetite are other common manifestations of septic arthritis. The joints of the lower extremities (hips, knees, and ankles) are affected in the vast majority of cases, with the knee being the most commonly affected joint. (1)(2) The patient often is febrile with signs of inflammation and limited range of motion of the affected joint. Patients position the affected limb to optimize intracapsular volume and minimize pain. Therefore, it is important to note the patient’s position at rest. Individuals who have septic arthritis of the knee tend to keep the affected knee moderately flexed. Those with septic arthritis of the hip keep the hips flexed, externally rotated, and abducted.
Table 2.
Pathogens and Antimicrobials in Septic Arthritis Based on Age Group/Risk Factors
Population/Pattern	Organism(s)	Empiric Treatment	
Neonate	Group B Streptococcus, Staphylococcus aureus (MSSA, MRSA), Escherichia coli, and other enteric gram-negative organisms	Nafcillin or oxacillin	
		OR	
		Vancomycin or clindamycin	
PLUS Cefotaxime or gentamicin			
If premature or exposed to broad spectrum antibiotics, intravenous alimentation, intravascular catheter	Candida albicans	Amphotericin B ± Fluconazole	
Children younger than 5 y	S. aureus (MSSA, MRSA), Kingella kingae, Streptococcus pyogenes, Streptococcus pneumoniae,	Nafcillin or oxacillin	
	Haemophilus influenza type b (rare if immunized)	OR	
		Vancomycin or clindamycin if MRSA suspected	
		PLUS third-generation cephalosporin	
Children older than 5 y	S. aureus and S. pyogenes	Nafcillin or oxacillin	
		OR	
		Vancomycin or clindamycin if MRSA suspected	
History of intravenous drug use	Pseudomonas aeruginosa	Antipseudomonal cephalosporin ± aminoglycoside	
	Candida spp.	Amphotericin B ± fluconazole	
Preceding upper respiratory infection	Haemophilus influenzae type b (rare if immunized),	Nafcillin or oxacillin	
	Kingella kingae	PLUS third generation cephalosporin	
Sickle cell anemia	Salmonella spp.	Cefotaxime or ceftriaxone	
History of sexual activity	Neisseria gonorrhoeae	Ceftriaxone	
Contact with livestock	Brucella spp.	Doxycycline or TMP-SMZ	
Ingestion of unpasteurized dairy products or travel to endemic area		PLUS gentamicin	
		PLUS Rifampin	
•	Antibiotic choices, dosing, and duration of therapy should be confirmed because each clinical situation is unique and practice standards may change with time.
•	MRSA=methicillin-resistant Staphylococcus aureus; MSSA=methicillin-sensitive Staphylococcus aureus; TMP-SMZ=trimethoprim-sulfamethoxazole.

Table 3.
Characteristics of Pyogenic Arthritis, Toxic Synovitis, and Lyme Arthritis
Feature	Pyogenic Arthritis	Toxic Synovitis	Lyme Arthritis	
Clinical				
    General Appearance	Generally ill appearing	Generally well appearing	Generally well appearing	
    Fever	Usually present	Low-grade or absent	Low-grade or absent	
    Limp	Yes, if affecting lower extremity	Often	Possible	
    Range of Motion	Markedly decreased	Slightly decreased, limited by pain	Decreased, depending on extent of effusion	
Laboratory				
    Serum WBC count	Elevated with left shift	Usually normal	Usually normal	
    ESR	Elevated (usually >40 mm/h)	Normal to mildly elevated (<40 mm/h)	Elevated	
    CRP	Greater than 1 mg/dL (modest to significant increase)	Less than 1 mg/dL	Greater than 1 mg/dL (modest increase)	
Synovial Fluid Results				
    Color	Yellow, white, gray	Yellow	Xanthochromic, white	
    WBC (WBC/mm3)	>50,000	5,000–15,000	∼25,000 (wide range reported)	
    Culture	Positive 50%–80% of the time	Negative	Negative	
Imaging				
    Plain radiograph	Early soft tissue swelling, subchondral bony changes (2–4 wk later), obliteration or lateral displacement of the gluteal fat planes and capsular swelling	Usually normal	Usually normal, soft tissue swelling	
    Ultrasonography	Joint effusion always present	Joint effusion may be present but small	Joint effusion often present	
    MRI	Abnormalities of soft tissue, bone, and cartilage damage. Low signal on T1 weighted and a high signal on T2 weighted	Normal or thickening of the articular surface	Often normal, limited data	
•	CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; MRI=magnetic resonance imaging; WBC=white blood cell.

Laboratory Testing 
Arthrocentesis is mandatory for any patient in whom septic arthritis is considered strongly. Arthrocentesis can serve both diagnostic and therapeutic purposes. Laboratory tests most useful in diagnosing pyogenic arthritis are culture, Gram stain, and white blood cell counts of the synovial fluid (Table 3). Synovial fluid cultures are positive in 70% to 80% of cases; (3) however, a negative culture does not exclude the diagnosis of pyogenic arthritis. A complete blood count may indicate leukocytosis with a left shift. A blood culture may be positive in approximately one third of septic arthritis cases. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration also are supportive of this diagnosis. If N. gonorrhoeae is suspected in sexually active patients, pelvic, urethral, throat, skin, and rectal cultures should be obtained Imaging Plain radiographs in patients who have septic arthritis may reveal widened joint spaces or bulging of the soft tissues. Soft tissue swelling may be identified in radiographs as early as 48 hours into the infection. Plain radiographs also may reveal subchondral bony changes after 2 weeks of onset of the illness. (4) It is important to bear in mind that a normal plain radiograph does not rule out a pyogenic joint. Ultrasonography is a fast and noninvasive test that is useful in identifying and quantifying the joint effusion, as well as aiding in needle aspiration of the joint. In contrast to plain radiographs, magnetic resonance imaging (MRI) with gadolinium contrast is more sensitive for early detection of a septic joint. Because MRI gives reliable soft tissue and bone contrast, this modality is effective in identifying cartilaginous involvement. MRI may reveal abnormalities in surround ing soft tissue and bone and delineate the extent of cartilaginous damage. A low signal on T1 weighted studies and a high signal on T2 weighted studies are indicative of active inflammatory or infectious processes.  Making the diagnosis of septic arthritis requires a high degree of suspicion while evaluating the constellation of symptoms, physical findings, and laboratory and imaging results.
Septic Arthritis in Neonates and Infants 
Clinically, septic arthritis is more challenging to diagnose in neonates, infants, and young children. Because neonates and infants have less mature inflammatory and immune responses, they may present with only vague symptoms. There may be no obvious joint involvement or fever. Pseudoparalysis is observed often. The hip is the most common joint affected in the neonatal population.  Infants have a higher rate of coexisting osteomyelitis and septic arthritis because the spread of infection from the metaphysis to the joint space is enhanced by the unique transphyseal vasculature in this age group.  Unique risk factors predisposing patients in this age group to the development of septic arthritis include a history of urinary infection, prematurity, and umbilical catheterization.  Young infants may not show an elevation in inflammatory markers such as white blood cells, ESR, and CRP. Due to the decreased overall muscle tone in neonates, widening of the hip space may lead to upward displacement or lateral subluxation of the femoral head being evident on plain radiograph.
Treatment 
Ideally, empiric antimicrobial therapy should be initiated promptly after joint aspiration is completed and cultures are obtained. However, antibiotic therapy should not be delayed while waiting for arthrocentesis. Immediate aspiration of the synovial fluid is essential to decompress the intracapsular space, remove infected fluid, and provide specimens for Gram stain, cell count, and culture. Although some patients respond well to needle aspiration and antibiotics, specific joints such as the hips and shoulder require open drainage. Many cases necessitate repeat needle aspiration, arthroscopic drainage, or even arthrotomy. Age, risk factors, and Gram stain (when positive) should direct initial antibiotic choice. Ultimately, positive synovial fluid or other culture and sensitivity results (as from blood, cerebrospinal fluid, cervix, and urethra) should dictate antibiotic selection. Antibiotics generally are administered for 2 to 6 weeks, depending on the organism and clinical resolution of signs and symptoms However, it is important that parenteral antibiotic therapy be administered at least for the first week. A downward trend in ESR and CRP concentrations is reassuring evidence of the effectiveness of ongoing therapy in reducing inflammation. When patients are not improving clinically, additional or alternate antibiotic regimens should be considered. Especially in community acquired methicillin-resistant Staphylococcus aureus infection, input from infectious disease specialists must be obtained to tailor therapy specifically to the results of local antibiotic susceptibility testing. Ultimately, the management of a pediatric patient who has septic arthritis is accomplished best by using a multidisciplinary approach with input from the orthopedic surgeon and the infectious disease specialist.
Complications and Pitfalls 
Pyogenic arthritis affecting the hip is particularly challenging to diagnose because frequently there is no apparent joint swelling. However, it is critical to make a timely diagnosis of septic arthritis, especially of the hip, because pressure on the precarious vascular supply to the femoral head makes it susceptible to long-term sequelae such as avascular necrosis, limb length disparities, pseudarthrosis (false joint), joint dislocations, and other bony or joint deformities. (4) Risk factors for long-term complications include age younger than 6 months, concomitant osteomyelitis, involvement of high risk joints such as the hip or shoulder, and delay in appropriate initial management (decompression and initiation of antibiotics) by 4 days or longer.
Reactive Arthritis 
Reactive arthritis is a type of arthritis associated with an infection at a distant site, distinct from that of the affected joints. Reactive arthritis is more common in the adult population than in children. However, it is an important entity to consider, particularly in adolescence. There is a 3:1 male predominance. Male patients and those who are human leukocyte antigen-B27 (HLA-B27) positive tend to have more severe disease. The pathogenesis of reactive arthritis is understood poorly. Although commonly associated with sexually transmitted pathogens such as Chlamydia trachomatis and N gonorrhoeae, reactive arthritis can be associated with other genitourinary, gastrointestinal, and upper respiratory pathogens. The most common pathogen associated with reactive arthritis in the United States is Chlamydia trachomatis. Gastrointestinal infections caused by Shigella species, Salmonella species, Yersinia species, or Campylobacter species potentially can lead to reactive arthritis. Among respiratory pathogens, S pyogenes has been known to cause reactive arthritis. N meningitidis can be associated with reactive arthritis as well. Clinically, patients who have reactive arthritis present with monoarthritis or oligoarthritis, frequently accompanied by other musculoskeletal inflammatory changes, as well as ophthalmologic, dermatologic, and genitourinary changes. One well-known presentation of reactive arthritis (previously known as Reiter syndrome) is the triad of arthritis, urethritis, and bilateral mucopurulent conjunctivitis. Other manifestations include pain, enthesitis, dactylitis, urinary symptoms, urethral discharge, cervicitis, uveitis, photophobia, and skin findings. In the presence of HLA-B27, reactive arthritis typically presents with calcaneal and plantar pain and tenderness. Systemic symptoms that can accompany reactive arthritis include arthralgia, fever, weight loss, and malaise. Reactive arthritis is asymmetric and often involves large joints such as the knee, hip, ankle, and sacroiliac joint. The joints of the lower extremity are implicated more often than those of the upper extremities. Symptoms start from a few days to 6 weeks after infection. According to one study, reactive arthritis should be diagnosed clinically based on two major criteria: 1) the presence of mono or oligoarthritis of the lower extremities, and 2) exclusion of other causes of arthritis, such as septic arthritis, Lyme arthritis, ARF, and trauma. (5) If both criteria have been met in a patient who has a history of preceding Chlamydia infection, the diagnosis of reactive arthritis is highly probable (up to 90%). If both criteria have been met, and the patient has a positive stool culture, the diagnosis of reactive arthritis is highly probable also (up to 70%). (5) Because reactive arthritis can be triggered by a multitude of pathogens, there is no single gold standard diagnostic test. However, this diagnosis is supported by an elevated ESR and CRP concentration or positive urine, cervical, or urethral culture for C. trachomatis. Synovial fluid tests can be helpful in excluding other disease processes. HLA-B27 positivity is supportive of the diagnosis of reactive arthritis in a patient who has a consistent history and physical findings. Antinuclear antibody (ANA) and rheumatoid factor (RF) should be considered in a patient who has a history or physical finding consistent with an autoimmune process. Imaging studies often are normal, but should be obtained particularly if other disorders such as pyogenic arthritis or osteomyelitis are considered. Treatment is primarily supportive and involves giving nonsteroidal anti- inflammatory drugs (NSAIDs), local cold treatment, and avoidance of overuse of the affected joints. A positive genitourinary culture requires treatment of the patient and sexual partners with appropriate antibiotics. The beneficial effects of treatment of gastrointestinal infections accompanying reactive arthritis are unclear. Certain musculoskeletal manifestations can be treated with local corticosteroid injections. Symptoms of reactive arthritis may last weeks to months. If the arthritis fails to resolve in 6 months, it is categorized as chronic reactive arthritis. This outcome occurs in approximately 4% to 19% of patients for whom a rheumatology referral is warranted. In this subset, diseases modifying antirheumatic drugs may be used to manage the patient’s symptoms.
Table 4.
Treatment Approach to Common Causes of Pediatric Arthritis
Disease Process	General Treatment Approach	
Septic arthritis	• Arthrocentesis/drainage	
	• Obtain cultures	
	• Immediate administration of antibiotics	
Reactive arthritis	• Supportive care: NSAIDs, cold packs, rest	
	• Antibiotics and treatment of sexual partners when indicated	
	• Chronic reactive arthritis: possible DMARDS	
Rheumatic fever	• Penicillin	
	• Anti-inflammatory drugs	
	• Cardiac medications if indicated	
	• Medications to control chorea if needed	
	• Rest	
	• Antibiotic prophylaxis	
Lyme arthritis	• First line: doxycycline or amoxicillin	
	• Second line: ceftriaxone	
Toxic synovitis	• Supportive care: rest, NSAIDs	
Juvenile idiopathic arthritis	• NSAIDs	
	• Local and systemic steroids (selective cases)	
	• DMARDs	
	• Biologics	
•	DMARD=disease-modifying antirheumatic drug; NSAID=nonsteroidal anti-inflamatory drug.
Acute Rheumatic Fever 
ARF is an inflammatory process involving many organ systems precipitated by preceding group A Streptococcus (GAS) pharyngitis. In the United States, the incidence of ARF has declined in the past several decades; however, focal outbreaks occur periodically. ARF is diagnosed clinically using the well-established Jones criteria. The major Jones criteria are polyarthritis, carditis, subcutaneous nodules, chorea, and erythema marginatum. Erythema marginatum is a rash that involves the extremities and trunk in a serpiginous fashion with central clearing and salmon-colored margins. The minor criteria are fever, arthralgia, prolonged P-R interval on electrocardiogram, and elevated acute phase reactants. Confirmation of an antecedent GAS infection plus two major criteria or one major and two minor criteria must be fulfilled to make the diagnosis of ARF. Prior GAS infection can be confirmed by positive throat culture, positive rapid streptococcal antigen test, and elevated titers of anti- streptolysin O or other streptococcal antibodies. The arthritis of ARF is a nondeforming migratory polyarthritis usually involving large joints such as the knees, wrists, elbows, or ankles. Most experts recommend a single dose of intramuscular benzathine penicillin G or 10 days of oral penicillin to eliminate any remaining GAS infection regardless of throat culture results. The other mainstays of treatment are anti-inflammatory drugs, restriction of activity, and antibiotic prophylaxis. Antibiotic prophylaxis is critical in the prevention of future streptococcal infections, which potentially may worsen the cardiac disease. The arthritis in ARF tends to be exquisitely responsive to aspirin. In patients afflicted with carditis, cardiology consultation is helpful in determining the role of diuretics (in those who have secondary heart failure) and for the follow-up of potential longterm cardiac sequelae.
Lyme Arthritis 
Lyme arthritis is the most common late manifestation of Lyme disease, a tick-borne disease caused by Borrelia burgdorferi. Although early Lyme disease tends to occur more in the late spring or early summer, late disease has no true seasonality. The Borrelia organisms residing within the digestive tract of the Ixodes ticks migrate to the salivary glands after the tick bites and attaches to the victim’s skin. Approximately 48 hours post bite, the organisms are transmitted to the bloodstream of the victim. Seeding the synovium hematogenously, the Borrelia induces mononuclear cell infiltration and stimulates complement, cytokines, neutrophils, and immune complexes to accumulate within the joint space, leading to inflammation and pain. In contrast to septic arthritis, B burgdorferi does not produce proteases that are responsible for rapid joint destruction. (6) A history of a rash consistent with erythema migrans is supportive but not required for the diagnosis of Lyme arthritis. In about 30% of patients given a diagnosis of Lyme disease, this rash is not identified. (3) Patients may experience migratory arthralgias, myalgias, or fatigue early in the course. Occasionally, patients who have Lyme arthritis have fever or other systemic symptoms. Lyme arthritis usually presents as an asymmetric mono or oligoarticular arthritis. Typically, a single knee joint is affected. However, other joints, such as the shoulder, ankle, elbow, temporomandibular joint, and wrist, are affected commonly. Unlike a patient who has pyogenic arthritis in which pain is severe and constant, the pain of Lyme arthritis waxes and wanes and is of lesser severity. In fact, this joint involvement tends to resemble the symptoms experienced by children who have oligoarticular juvenile arthritis and was misdiagnosed historically as JIA before the epidemiologic and basic science research that elucidated the etiology of Lyme disease. Physical examination reveals a mild to moderately in- flamed joint with an effusion. Range of motion is not decreased significantly. Lyme arthritis occasionally is confused with trauma because it may present with remarkable joint effusion and no fever. Confirmation of B burgdorferi infection requires a two-step process. The first step involves a sensitive enzyme immunoassay for serum antibodies. The second step is a confirmatory result on a Western immunoblot for specific bands of antibodies in the immune globulin G (IgG) or IgM classes, depending on the stage of the disease. Synovial fluid testing may reveal a white blood cell count around 21,000 to 24,000 cells/ microliter (6) (can vary significantly), with a neutrophil predominance. ESR rates usually are about 20 to 30 mm/hour. Soft tissue changes and joint effusions are noted on imaging studies. However, imaging generally is not helpful. If treated adequately, early Lyme disease does not progress to arthritis or other manifestations of late disease. Once arthritis develops, generally 28 days of appropriate oral antibiotic therapy is required. Treatment options include doxycycline (for children older than 8 y) 4 mg/kg per day divided in two doses (maximum 100 mg/dose) or amoxicillin 50 mg/kg per day divided in three doses (maximum 500 mg/dose). Cefuroxime 30 mg/kg per day divided in two doses (maximum 500 mg/dose) is the second line treatment. The vast majority of patients respond to a single course of oral antibiotics. If the patient experiences minimal improvement of symptoms, a second course of oral antibiotics is recommended. In those who exhibit minimal or no response despite an additional 4 weeks of oral antibiotics, parenteral antibiotic therapy for 1 month (usually employing ceftriaxone) is warranted. (6) Adjunctive use of NSAID therapy can be helpful in controlling symptoms of some patients who have Lyme arthritis. If Lyme arthritis is accompanied by neurologic symptoms, disease should be treated as per the management of the neurologic disease. Although the prognosis for those who have Lyme arthritis is good, a small subset of patients has symptoms lasting months to years after given a diagnosis of Lyme disease. Immunogenetic factors have been implicated in the variation of the clinical course of Lyme disease
Other Infectious
 Etiologies Nonbacterial pathogens implicated in arthritis include viruses and fungi. Viral pathogens commonly implicated include rubella, parvovirus B19, arboviruses, and hepatitis B. Other viral pathogens less commonly associated with arthritis are coxsackie, Epstein-Barr, herpes simplex, varicella-zoster, and mumps virus. Mycobacterium species, Candida species, and other fungi are rare but are potential pathogens that may cause arthritis in children and should be considered, particularly if any risk factors exist 
Toxic Synovitis and Hip Pain 
Toxic synovitis, also called acute transient synovitis, is a relatively common cause of sudden onset of hip pain and limping and is frequently considered in the differential diagnosis of septic arthritis of the hip. Hip pain can be due to a variety of disease processes depending on the age and sex. SCFE, Legg-Calve´-Perthes disease, and osteoidosteoma all can result in significant hip pain. In SCFE, disruption of the proximal femoral growth plate results in varying degrees of displacement of the femoral head. This entity typically presents in the obese peri-pubertal patient, with boys being affected almost twice as often as girls. Legg-Calve´-Perthes disease is an osteonecrosis of the capital femoral epiphysis. This disorder occurs in younger children but with an impressive male predominance (4:1 male-to-female ratio). Often affecting the upper femur, osteoid osteoma may present with hip pain. The pain associated with this benign tumor is localized to the lesion, is worse at night, and often improves with oral salicylates. Osteoid osteoma affects individuals of all ages but occurs most frequently in the second and third decades after birth. Toxic synovitis is a relatively benign entity that is characterized by inflammation of the synovium, most frequently of the hip joint. Often there is a joint effusion as well. Toxic synovitis commonly affects children 3 to 10 years of age. The male-to-female ratio is about 2:1. The exact pathophysiology of this process is uncertain. However, most children who have toxic synovitis have had a prodrome of upper respiratory or gastrointestinal symptoms or have a concurrent infectious process. This process often presents as an acute onset of hip, thigh, or knee pain or limp. Patients often are not ill appearing and are afebrile, although low-grade fevers may be present. The patient may be uncooperative because of pain when eliciting range of motion of the knee or hip, making the range of motion appear more limited than it actually is. Often there is decreased internal rotation and adduction of the affected hip. Distinguishing transient synovitis from septic arthritis is critical because clinical presentations may overlap. Often patients who have toxic synovitis are not as irritable or ill appearing, may have bouts of improved pain (in contrast to the constant pain of septic arthritis), and although they may limp, often can bear weight. In one pediatric study, four independent multivariate predictors were found to be useful in distinguishing septic arthritis from toxic synovitis. (7) These variables are a history of fever, inability to bear weight, ESR over 40 mm/hour, and white blood cell count higher than 12,000/mm3 . Presence of all four variables had a 99.6% predictive probability of septic arthritis. In toxic synovitis, the white count often is normal, with normal to mildly elevated ESR and CRP. Another study revealed a CRP concentration 1.0 mg/dL as an excellent negative predictor for septic arthritis. (8) If clinical presentation and blood tests are reassuring (afebrile, full range of motion in the joint, and low risk ESR, CRP, and white blood cell count), the patient may be watched without further testing. If the clinical picture is not reassuring, a synovial fluid aspirate is required to rule out septic arthritis. The synovial fluid in toxic synovitis often is yellow and clear or slightly turbid, has a normal to slightly elevated white blood cell count, and usually is small in volume in contrast to septic arthritis. Table 3 compares the clinical features and diagnostic test results of septic arthritis, toxic synovitis, and Lyme arthritis. Synovial fluid testing is by far the most reliable way to distinguish toxic synovitis from septic arthritis, and one should never be reluctant to proceed with hip aspiration if there is any question as to the presence of a septic process. Radiographs may reveal capsular distension, widening of the joint space, and distortion of soft tissue planes. Ultrasonography and plain radiography may not help differentiate toxic synovitis from septic arthritis because children who have toxic synovitis often have joint effusions. However, MRI may be helpful. MRI usually is normal or may show thickening of the articular surface or joint effusion in toxic synovitis. The usual treatment for toxic synovitis is antiinflammatory medication and limitation of activity. Most commonly, symptoms resolve within days; occasionally, it may take up to 2 weeks from the onset of symptoms for the patient to return to baseline. Overall, this condition is self-limited; however, a small percentage experience recurrences. The risk of future development of Legg-Calve´-Perthes disease in those who have a history of toxic synovitis may be slightly higher than in the general population.
Juvenile Idiopathic Arthritis 
Previously known as juvenile rheumatoid arthritis, JIA is a term used to label a wide spectrum of arthritides that occur before the age of 16 years, last longer than 6 weeks, and do not fulfill the diagnostic criteria of other known entities. JIA is the most common pediatric rheumatic disease; however, it is a diagnosis of exclusion. Although the pathophysiology is not fully elucidated, evidence suggests an autoimmune process. Both genetic and environmental components have been implicated. For many years, T lymphocytes have been thought to be central to the pathogenesis of JIA. New research reveals that innate immunity, specifically neutrophils, may play additional important roles in this disease process. The International League of Associations for Rheumatology has classified this heterogeneous group of arthritides into seven subgroups. These groups are oligoarthritis (40% of cases), RF positive polyarthritis (5%), RF negative polyarthritis (20%), systemic arthritis (10% of cases), enthesitis related arthritis (5%), psoriatic arthritis (5%), and undifferentiated arthritis (15%). Children afflicted with oligoarthritis have arthritis limited to four or fewer joints within the first 6 months of onset of the disease. Iridocyclitis, inflammation of the iris and ciliary body, occurs in about one third of patients who have oligoarthritis and potentially can lead to loss of vision. Typically, patients have asymptomatic iridocyclitis; therefore, regular screening for this condition should be part of their routine care. There is a strong female predominance in those who have oligoarthritis who present at less than 6 years old (early onset). Individuals who have oligoarthritis have a positive ANA about 70% of the time, normal complete blood count resul results, and normal to mildly elevated acute phase reactants. RF positive and negative polyarthritis involve a minimum of five joints being affected during the first 6 months after onset. RF positive polyarthritis requires two positive IgM RFs documented at least 3 months apart. Typically, these patients have an insidious onset of in- flammation in the small joints of the hands and feet. Both RF positive and negative polyarthritis have a female predominance. A slight elevation in ESR is likely for both groups. Systemic arthritis is the most serious of the JIA subtypes. This variation classically presents with fever, rash, and arthritis. Frequently evaluated for infectious diseases, these children typically have quotidian spiking high fevers (39°C) that defervesce quickly. A salmoncolored migratory rash, typically accentuated by showering, often accompanies this fever. Fever must persist for at least 2 weeks to meet the diagnostic criteria. Fever and rash can precede arthritis by several weeks, making the diagnosis difficult. Contrary to a septic child, children who have systemic arthritis usually are well appearing between their febrile episodes. Although initially the arthritis involves only a few joints, chronic polyarthritis eventually ensues in most cases. Lymphadenopathy, hepatosplenomegaly, and serositis also are potential manifestations of systemic onset JIA. Boys and girls are affected equally. Leukocytosis, anemia, thrombocytosis, and elevated ESR and CRP are supportive laboratory findings. However, these test results, along with the nonspecific initial presentation, may make it challenging to differentiate early systemic arthritis from infectious and malignant causes. Patients who have systemic arthritis are at risk for developing macrophage activation syndrome, which presents with an acute onset of persistent fever, hepatosplenomegaly, neurologic changes, hematologic symptoms, and pancytopenia. This fatal complication requires early diagnosis and aggressive immediate treatment. Enthesitis-related and psoriatic arthritis have more elaborate criteria than what is mentioned here. However, simply stated, enthesitis-related arthritis is a form of JIA in which patients present with both arthritis and enthesitis; this subtype is most common in boys older than 6 years. Psoriatic arthritis is characterized by the presence of arthritis with psoriasis. Those affected by this subtype of JIA may have chronic and erosive disease, making early aggressive therapy necessary. Patients who have psoriatic arthritis often are ANA positive. Finally, undifferentiated JIA captures those patients who do not meet the criteria of the other subtypes.
An interdisciplinary approach addressing physical and occupational therapy, psychosocial support, and pharmacologic treatments must be utilized for optimum management of JIA. (9) NSAIDs serve as the initial treatment for patients who have JIA. Triamcinolone hexacetonide intra-articular injections may be used in addition to or instead of NSAIDs in patients who have a limited number of affected joints. Rheumatologists may use systemic corticosteroids in specific situations (eg, acute flares); however, corticosteroids are not considered the treatment of choice for long-term management. Methotrexate is used as a second-line agent to treat persistent and active arthritis. Etanercept and adalimumab are the only anti-tumor necrosis factor agents approved by the Food and Drug Administration (FDA) for use in children over 4 years of age with JIA. (10) Abatacept, an interleukin 6 blocker, is the first of a new class of biologic agents approved for severe polyarticular JIA in children older than 6 years of age. (10) Recent clinical trials suggest other biologics may be effective as well and are used currently by rheumatologists in the treatment of JIA. Other drugs may be beneficial, depending on the JIA subtype and individual patient. Long-term prognosis has been affected favorably by the advances in pharmacologic therapy and better utilization of multidisciplinary teams.
Summary 
• Arthritis can be a manifestation of multiple disease processes. Therefore, the clinician must consider a broad differential diagnosis, keeping a high degree of suspicion for diseases that may have serious consequences. Although this article reviews more common disease processes that present with arthritis, it is imperative to think outside of the scope of infectious and musculoskeletal entities and consider autoimmune, oncologic, and other processes as well. 
• The diagnostician should use a complete history and physical examination to determine further evaluation. In most cases, the diagnosis can be confirmed by the constellation of supporting historic features, examination findings, and laboratory or imaging results. 
• Appropriate diagnosis and management of pediatric arthritis can facilitate prompt recovery and prevent debilitating consequences. Table 4 offers a brief summary for treatment management. 
• Strong research evidence suggests that delay in decompression of infected joints, especially the hips and shoulders, and delayed initiation of antibiotics are poor prognostic factors. 
• Moderate research evidence indicates that the presence of fever, inability to bear weight, ESR >40 mm/hour, and a white blood cell count >12106 is highly suggestive of pyogenic arthritis. 
• Some evidence exists regarding safety and efficacy of the use of biologic agents in treating children who have JIA. 
• Based on expert opinion, an interdisciplinary approach to the treatment of JIA results in improved quality of life.
6. Materials of methodical maintenance of employment. 
1.      The child 8 years febrile fever, accompanied by small spotty pink rash on the trunk and extremities, swelling interphalangeal joints of hands. In addition, there are "morning stiffness" signs of exudative pericarditis, increased lymph nodes, liver and spleen. What disease should assume the child?
A. Rheumatism
* B. juvenile rheumatoid arthritis
C. Osteomіlіtis, septic form
D. systemic connective tissue disease
E. infectious allergic polyarthritis
 
2.      The girl of 3 years with rheumatic diseases ' appeared signs that indicate eye disease in the form of uveitis. What disease characterized by the development of uveitis?
A. Juvenile rheumatoid arthritis, joint-visceral form
*B. juvenile rheumatoid arthritis, mainly articular form
C. Systemic lupus erythematosus
D. dermatomyositis
E. Systemic sclerodermіa
 
3.      As a 10 year boy entered the clinic, which on the basis of clinical examination put a preliminary diagnosis: juvenile rheumatoid arthritis. What is the most significant symptom for the diagnosis of this disease?
A. Disease of large joints
B. Zone joint hyperemia
* C Morning stiffness of movement in joints
D. Enlargement of the heart
E. Increased heart rate
 
4.      The boy of 11 years, who suffered two weeks ago, tonsilitis;, arthritis of elbow and ankle joints, involuntary movements of facial muscles, round rash on the abdomen and thighs, dullness of heart tones, subfebrile. What is the most likely diagnosis?
A. Movement neurosis
B. Reactive arthritis
C. Allergic carditis
* D Rheumatism
E. Rheumatoid Arthritis

5.      The girl of 4 years with juvenile rheumatoid arthritis, blood revealed normochromic anemia reticulocytosis. Over the past year took nonsteroidal anti-inflammatory drugs. What is the most likely cause of anemia?
A. Intravascular hemolysis
B. Vitamin B-12
C. Iron deficiency
* D Hidden ulcer bleeding
E. Inhibition of bone marrow

6.      The boy 7 years.History marked the peak temperature to 40˚C for three months is a fusiform swelling of the joints of the fingers, knee and ankle joints, pain in the upper part of the sternum, cervical spine. What is the most likely diagnosis?
* A juvenile rheumatoid arthritis
B. Rheumatism
C. Toxic synovitis
D. Septic arthritis
E. Osteoarthritis
 
7.      Girl 12 years, complains of shortness of breath on exertion, weakness, fatigue, skin rash. Three weeks ago, suffered tonsilitis. After 10 days there was a sharp pain in the right and then the left knee joints, swelling, limitation of movement, increased   t body to 39˚C. The treatment appeared rash on the trunk, limbs as pink spots round. Objectively: pale skin, single annular elements on the limbs,  breathing hard. Borders of heart shifted to left side. Heart sounds are muffled. Pulse - 96 / min. Long blowing systolic murmur at the apex of the heart, which is held to the axillary region. Liver +2 cm. Set preliminary diagnosis:
A. Reactive arthritis
B. Infective endocarditis
S. Anular eritema
D. Rheumatoid Arthritis
* E Rheumatism
 
8.      Patient '10 complaining of shortness of breath when walking, fever 38˚C, pain and swelling of both knee joints. Two weeks ago, suffered Tonsillitis. On examination: swelling, redness, limitation of motion in the knee joints, expanding the boundaries of the left heart, tachycardia, muffled heart tones, systolic murmur at the apex. What is the most likely diagnosis?
A. Nonrheumatic carditis
*B. Rheumatism
C. Stіll syndrome
D. Systemic lupus erythematosus
E. Infectious-allergic arthritis
 
9.      Boy 8 years with a group of children, which often suffer from SARS and tonsillitis complains of periodic rises in body temperature to 37,5˚C, pain in the joints. Objectively: pale periorbital cyanosis, cardiac muted, functional systolic murmur at the apex. ENT Physician diagnosed  decompensated chronic tonsillitis. It is best to put this baby at risk for development:
A. Systemic lupus erythematosus
B. chronic bronchopulmonary pathology
C. respiratory allergies
D. Rheumatoid Arthritis
*E. rheumatism
 
10.  The boy is 10 years, the third day of illness, complaints of abdominal pain, the pain and the inability to movements in the left knee and right elbow. Two weeks ago was ill with tonsillitis. On the 1st day of illness - fever 38,5˚C, ankle joint involved. The observed expansion in the boundaries of cardiac dullness 2 cm Tachycardia - 120 / min., Weakened I tone gallop, "soft" systolic murmur at the apex of the heart. Which diagnosis most consistent to clinical picture described?
A. Reactive arthritis
B. Systemic lupus erythematosus
C. Infectious-allergic arthritis
D. Juvenile rheumatoid arthritis
* E Rheumatism

11.  In the girls 12 years within two months marked by periodic fever to 39˚C, fusiform swelling of interphalangeal joints and pain in the upper part of the sternum and neck, stiffness in the morning. The most likely diagnosis?
A. Osteoarthritis
B. Rheumatism
C. Toxic synovitis
D. Septic arthritis
*E. Juvenile rheumatoid arthritis
 
12.  A child 5 years old hospitalized with complaints of fever to 38˚C. In history marked the peak temperature to 40˚C, during the inspection - spindle-shaped swelling of the fingers and pain in the upper part of the sternum. Your preliminary diagnosis?
A. Septic arthritis
B. Rheumatic Fever
C. Toxic synoviitis
D * Juvenile rheumatoid arthritis
E. Osteoarthritis
 
13.  The child 7 years complaining of pain and swelling of the right knee and elbow joints. Two days marked by pain and swelling of the left knee. Two weeks before the baby was ill with tonsillitis hospitalization. The child's condition is heavy. Both knee and left elbow swollen, hyperemic.  Heart margin expanded. Cardiac impulse poured. Cardiac  tone at the top of the heart is weakened, blowing systolic noise accompanied with irradiation under the left armpit. What is the diagnosis?
A. Reactive arthritis
B. Infectious-allergic arthritis
C. Juvenile rheumatoid arthritis
* D Rheumatism, rheumatic endomіocarditis, polyarthritis
E. Systemic lupus erythematosus
 
14.  The child '10 complaint of pain and swelling of the right and left knee, two days marked by pain and swelling of the ankles, itchy rash, fever. Joint pain occurred immediately after SARS. Body temperature - 38˚C. Both the knee and ankle joints swollen and hyperemic. Margins of heart are not extended. Cardiac impulse localized. Cardiac not altered functional nature systolic murmur at the apex of the heart. Putv diagnosis.
A. Rheumatic fever, rheumatic myocarditis, arthritis
*B. Postіnfectious artropathy
C. Juvenile rheumatoid arthritis
D. Stіll Syndrome
E. Systemic lupus erythematosus

Task 1. Patient '12 complains of fever to 39-40˚C, intense pain in the ankle, especially at night, morning stiffness in the joints, which disappears in the afternoon. OBJECTIVE: soft tissue in the area of both ankles swollen, rough determined moderate local hyperthermia. Active and passive movements are limited in size, difficult, sharply painful. On the surface straightening both legs palpable painless, the size of a pea, soldered to the aponeurosis nodules.   In the analysis of blood marked leukopenia, increased erythrocyte sedimentation rate of 40 mm / h, CRP ++, RF missing increased to 15% content of α -2-globulins. In Rh-gram both ankle joints - there are signs of effusion in the joint cavity sealing and periarticular tissues.
Task:
•	Formulate nosological diagnosis
•	List the indicators of process activity
•	What is the degree of compliance with the process Rh-signs?
•	Describe the clinical diagnosis
•	Assign pathogenetic therapy.
 
Key answer:
 Rheumatoid arthritis, joint form (oligoartritis) RF negative . Activity process and the degree of arthritis patient functional ability is disturbed. 

Task 2. A child of 9 years got ill in the winter. Appeared headache, arthralgia fever on the background   to 39˚C and diarrhea. From history we know that the child eat fresh, not thermally processed vegetables. Objectively, at the peak temperature - chills of heavy sweats. On the skin - erythema nodosum, eyes conjuctiva is inflamed. The boundaries of the heart are  not extended, slightly muted tones. Auscultated functional nature systolic murmur at the apex of the heart. Liver + 1cm, elastic consistency, painless. Joints (right knee and left ankle) are swollen, painful. Volume of passive and active movements saved. Laboratory: leukocytosis - 12 X 10³ / l, ESR - 40 mm / h, CRP + RF negative. Rh-gram affected joints without pathology.
Task:
•	Formulate nosological diagnosis
•	Describe joint damage in this patient
•	List the diagnostic criteria for the disease
•	Give prognosis relatively joints in this case,
•	What pathology on which develops consolidation periarticular tissues and synovial membranes?
 
Key answer:
Reactive arthritis (yersiniosis).
Task 3. Boy '16 helped parents during calving. A month later, he increased body temperature to 40˚C. The overall health had suffered, was marked moderate headache, chills, increased sweating. Did not apply the doctor. Six weeks later, again body temperature rised to febrile digits, was pain throughout the body, increased all of the lymph nodes, and liver and spleen.  arthralgias sometimes joined, and right knee became globular shape, flushed skin over it, the local temperature increased, passive and active movements restricted, painful. Checked pain over the right sciatic nerve.
Task:
•	Formulate nosological diagnosis
•	Describe joint damage in this patient
•	List the diagnostic criteria for the disease
•	What are the diseases to the differential diagnosis?
•	Assign a topical therapy with juvenile rheumatoid arthritis.
 
Key answer:
Reactive arthritis (brucellosis).

6.2. The information necessary for the formation of knowledge, skills can be found in textbooks:
- basic:
1.	Kliegman, R.M., St Geme, J.W., Blum, N.J., Shah, S.S., Tasker, R.C., Willson, K.M., & Behrman, R.E. (Eds.). (2019). Nelson Textbook of Pediatrics (21st ed.). 4264 p.
2.	Ghai ”Essential pediatrics ” 9th Edition. 2019. 814  p.
3. Bănicioiu-Covei  S., Vreju A. F., Rosu A., Ciurea P. L. The Importance of HLA-B27 in the Evolution of Reactive Arthritis // Current  Health  Sciences  Journal.  ‒  2019.  ‒ V. 45, № 4. ‒ P. 
345-352.
- additional:
1.	Antoniou A. N., Lenart L., Kriston-Vizi J., Lwawaki T., Tur-maine M., McHugh K., Ali S., Blake N., Bowness P., Bajaj-El-liott M., Gould K., Nesbeth D., Powis S. J. Salmonella exploits HLA-B27 and host unfolded protein responses to promote intra-cellular replication // Annals of the Rheumatic Diseases. ‒ 2019. ‒ V. 78, № 1. ‒ P. 74-82.

6.3. The estimated card for independent work with literature
N	Main Task	Recommendation	Answers	
1	2	3	4	
1	Acquaint with literature and educational goals	Give information about epidemiology of the disease
Give the definition of the disease studied.		
2	Etiology	Fill the scheme of etiological factors
…%	
	
…%	
	
…%	
	
…%	

3	Pathogenesis	Fill the scheme of pathogenetic factors
Pathogenesis	

	

	

		
4	Clinical data	Make differential diagnosis of this disease and similar to its condition		
5	Diagnosis	Make and explain diagnosis according to the results of clinical, laboratory and instrumental data.		
6	Treatment	Make program of treatment. Write prescription of preparations which is used for the treatment of this disease
Rp…	
	
Rp…	
	
Rp…	
	
Rp…	

7	Prophylaxis and rehabilitation 	Fill the scheme of dispensary control
N	
Specialist	
Time	

	

	

	

		

7. The quality of self-training materials. 
A. Questions for self-control 
- The relevance and prevalence of RA; 
- Features of clinical picture, depending on the causative agent of RA; 
- diagnosing problems; 
- Modern approaches to RA therapy 
- etiology and pathogenesis of RA in children 
- Differential diagnostic of RA; 
- Emergency treatment at RA.

B. Tests for self-control
1.  The child '10 complaints of swelling of the knee, ankle pain and cervical spine. Morning stiffness. Assinged inflammatory therapy gave positive effect. What kind of diseases we talk about?
* A juvenile rheumatoid arthritis
B. osteochondrosis
C. Rheumatism
D. Infectious-allergic arthritis
E. Systemic lupus erythematosus

2.  The 12-year-old girl who suffers from juvenile rheumatoid arthritis for 7 years, the disease runs as oligoartritis I type. In ophthalmology examination of the child found iridocyclitis in connection with what the appointed steroids. Therapy of them within three months was ineffective. What treatment tactic you choose?
A. Appointment of gold drugs 
B. Continue local steroid therapy
C. Appointment maximum dose aspirin
D * Appointment of systemic corticosteroids
E. Appointment of chloroquine

3.  The boy 8 years for three weeks, there are intermittent fever with chills; febrile periods in increasing manifestations of arthritis, there are spotty, papular rash on the trunk and face. Tachycardia, loud tones. Hepatolienal syndrome.   Antibiotic therapy for two weeks did not produce the effect. What is the most likely causes of pathology described in the picture?
A. System sclerodermy
B. Rheumatism
C. Sepsis
D. Systemic lupus erythematosus
E * Juvenile rheumatoid arthritis
 
4.  Patient Boy '13 complaint of pain and swelling of the ankle joints, cramps and frequent urination, redness of the conjunctiva of the eye. Your preliminary diagnosis.
A. Infectious-allergic arthritis
B. Juvenile rheumatoid arthritis
* C.  Reiters disease
D. Systemic lupus erythematosus
E. System sclerodermy
 
5.  The child is 4 years. Ill for three weeks. Acutely ill with the rise in temperature to 39˚C. During the day the temperature was changed to 2 - 2,5˚C, accompanied by a reduction in heavy sweats.Periodically appear pink rash of different shapes and locations. Swollen an ache of joints (knee, ankle, wrist, radial). The child was not rested on his legs, could not take the items. Objectively: temperature - 39˚C, liver +3 cm Spleen +2 cm, All of palpable lymph nodes. Ankle swollen, painful, their contours are smoothed. Blood test: Hb 112 g / L, Er-X 3.9 10¹² / l L-12.9 X 10³ / L, E-6% p / I-1% s /% i-48, l- 35% of 10%. ESR - 54 mm / h. Indicate the most likely diagnosis.
A. Systemic lupus erythematosus
* B. juvenile rheumatoid arthritis
C. Reactive arthritis
D. Rheumatism
E. Sepsis
 
6.  In the emergency department the 7 years boy's parents told the fact that for three months the child concerned about pain in the right knee. Recently have noticed restriction of movement in his right leg and morning stiffness which disappears in the evening. What disease is likely the case with your child?
A. Rheumatism
C. Osteomyelitis of knee joint
C. Reactive arthritis
D * Juvenile rheumatoid arthritis
E. Traumatic arthritis
 
7.  The boy 4 years , for four months there is swelling of the knee joint, early stiffness, increased body temperature. In synovial fluid revealed a significant number of mucin and phagocytes. What is the most likely diagnosis?
A. Reactive arthritis
B. Osteomyelitis of knee joint
C. posttraumatic synuviitis
D * Juvenile rheumatoid arthritis
E. Revmatichny arthritis
 
8 . The girl in '11 marked the destruction   of articular cartilage granulation tissue. Which of these diseases is typical?
A. Rheumatism
B. Systemic lupus erythematosus
C. System sclerodermy
D. Reactive arthritis
E * Juvenile rheumatoid arthritis
 
9. 14 year boy developed amyloid degeneration od parenchymal organs? If any of the diseases that possible?
A. Rheumatism
B. Systemic lupus erythematosus
C. System sclerodermy
D. Reactive arthritis
E * Juvenile rheumatoid arthritis
 
10. Patient 9 years found damage of   the hip and temporal- mandibular joints. In what disease the severity of the process is the condition?
A. Rheumatism
* B. juvenile rheumatoid arthritis
C. Reactive arthritis
D. System scerodermy
E. Systemic lupus erythematosus
 
C. Tasks for self-control.
1. The boy is 15 years old, suffers from 3 years of age when set against low-grade fever   was symmetric polyarthritis joints - metacarpofalangeal, small joints of the hands, elbows. At the end of the first year when the disease developed structural changes in the formation of joint ankylosis of small joints of wrist.   Today noticeable lag in growth (personally upper extremities). Affected joints deformed spindle available flexion contracture. From internal organs pathology is not installed. The skin is clean, pale. The feeling of morning stiffness persists until noon. Body temperature varies from 37.4 to 37,6˚C. Laboratory data show moderate hypochromic anemia and slight neutrophilic leukocytosis up to 10 X 10³ / L, erythrocyte sedimentation rate accelerated to 15 mm / h, CRP + RF positive, high content of α-2 globulin to 12%.
Task:
•	Formulate nosological diagnosis
•	What panus?
•	Describe articular syndrome in this disease
•	Describe the clinical diagnosis
•	List the indications for oral corticosteroids.

8. Materials for the classroom self-study: 
8.1. List of educational practical tasks which must be performed in the practical (lab) classes:
            -When the first time  the term "reactive arthritis" appeared;
            -What viruses often cause RA in children;
            -in which  genes carriers RA often develop;
            -What is the interval between infection and the development of acute RA;
            -Duration of joint syndrome at RA.
9. Instructional materials for learning professional skills, skills: 
9.1. Methods of work, perform the steps
I stage. Establishing the diagnosis: 
1. identify a complaint, analyze the history data, to find the typical clinical symptoms characteristic of RA. 
2. evaluate radiological, spirographic data, if available. 
3. conduct a differential diagnosis. 
4. formulate the main clinical diagnosis, comorbidities, complications.
II of I of phase. Destination therapy. 
10. Materials for self-control of mastering knowledge, skills, abilities
Task
The 11 year girl suffers from  4 years of age at disease, the main feature of which is the articular syndrome. This affected her pathological process of left elbow and right ankle, and 5 years of age and joined another eye disease - uveitis. Objectively: asymetry growth of left hand and right leg. Developed complications of uveitis, cataracts. Pale skin clean. The body temperature is not increased. Morning stiffness persists for 2-3 hours. Internaql orgsns pathology is not installed.  affected joints deformed spindle, active and passive movements in them are limited, skin  over them is not changed, the local temperature is slightly elevated above them, the muscles atrophied. In Rh-grams joints, embroiled in the pathological process determined by osteoporosis, the presence of a small cartilage destruction, joint space narrowing. Laboratory findings: group of α-2 globulin increased to 13%, ESR - 13 mm / h, CRP + RF negative, mild hypochromic anemia. 
Task:
•	Formulate nosological diagnosis
•	List the indications for hospitalization in this case,
•	The extent to which the process responsible Rh-listed signs?
•	Describe the clinical diagnosis
•	Assign glucocorticoid topical therapy.