Reactive Arthritis (Reiter Syndrome)


Article Author:
Apoorva Cheeti
Rebanta Chakraborty


Article Editor:
Kamleshun Ramphul


Editors In Chief:
David Wood
Andrew Wilt
Mary Cataletto


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
9/15/2019 5:26:43 PM

Introduction

Reactive arthritis (ReA) is inflammatory arthritis which manifests after several days to weeks after a gastrointestinal or genitourinary infection. It is also described as a classic triad of arthritis, urethritis and, conjunctivitis. However, a majority of patients do not present with the classic triad. It was previously called "Reiter syndrome", named after Hans Reiter, who first described this syndrome. The name, Reiter syndrome was dismissed because it is believed that Hans Reiter was a member of The National Socialist German Workers' Party or the “Nazis” and the director of the Kaiser Wilhelm Institute of Experimental Therapy under whose leadership the war prisoners were subject to many inhumane experiments. Today, it is believed that the disorder is due to autoimmunity in response to an infection from a gastrointestinal infection caused by Salmonella, Shigella, Campylobacter or chlamydia.[1][2][3]

Etiology

Reactive arthritis is known to be triggered by a bacterial infection, particularly of the genitourinary (Chlamydia trachomatis, Neisseria gonorrhea, and Ureaplasma urealyticum) or gastrointestinal (GI) tract (Salmonella enteritidis, Shigella, Yersinia enterocolitica, Campylobacter jejuni, Clostridium difficile). The incidence is about 2% to 4% after a urogenital infection mainly with chlamydia trachomatis and varies from 0% to 15% after gastrointestinal infections with Salmonella, Shigella, Campylobacter, or Yersinia. This might be affected by the epidemiological, environmental factors, the pathogenicity of the bacteria, and differences in the study designs. The enteric ReA occurs commonly following enteric infections. However, chlamydia associated ReA is endemic, especially in developed countries.[4][5]

Epidemiology

Reactive arthritis is relatively rare, and the incidence in population-based studies is reported to be 0.6 to 27 per 100,000. Reactive arthritis is more common in adult males in the second and third decades of their life.[6]

About 1-3% of patients with nonspecific urethritis will develop an episode of arthritis. Overall, higher disease activity and worse functional capacity are seen in the lower socioeconomic populations.

Pathophysiology

Reactive arthritis is an immune-mediated syndrome triggered by a recent infection. It is hypothesized that when the invasive bacteria reach the systemic circulation, T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids. These activated cytotoxic-T cells then attack the synovium and other self-antigens through molecular mimicry. This is supported by the evidence of Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts, enteric bacterial DNA and bacterial degradation products in the synovial tissue and fluid. It is believed that anti-bacterial cytokine response is also impaired in reactive arthritis, resulting in the decreased elimination of the bacteria. It is, however, unclear why such localization of inflammation occurs.

The prevalence of HLA-B27 in reactive arthritis is estimated at 30% to 50% 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% have been reported. HLA-B27 should not be used as a diagnostic tool for a diagnosis of acute ReA. The presence of HLA-B27 is believed to potentiate reactive arthritis by presenting bacterial antigens to T cells, altering self-tolerance of the host immune system, increased TNF-alpha production, promoting invasion of microbes in the gut, and delayed clearance of causative organisms.[7]

Histopathology

Initially, the dermal histopathological features of reactive arthritis are similar to psoriasis. examination of the synovial fluid will reveal large macrophages, reiter cells that have phagocytosed neutrophils, lymphocytes and plasma cells. Extensive pannus formation is very rare.

History and Physical

Patients typically present with acute onset oligo-arthritis, mainly involving the lower extremities, sacroiliac joint, and the lumbar spine. Other extra-articular manifestations such involving the skeletal system (enthesitis, dactylitis), eye (conjunctivitis, anterior uveitis episcleritis, and keratitis), genitourinary (urethritis, cervicitis, prostatitis, salpingo-oophoritis, cystitis or circinate balanitis), mucosal and skin involvement (mucosal ulcers, keratoderma blennorrhagica and erythema nodosum), cardiac (carditis, aortic, conduction and valvular abnormalities), and nail changes (onycholysis, subungual keratosis, or nail pits) also are seen. 

These symptoms manifest several days to weeks after the initial infection. Diarrhea or other symptoms caused by the offending agents are usually resolved by the time the patient develops arthritis. A detailed history and physical examination to investigate any recent illness such as urethritis, diarrhea, etc, should be performed. ReA can be self-limiting, recurrent or continuous and about 20% to 25% of the patients may progress to have chronic articular, ocular and cardiac complications.

Reactive arthritis is very common in HIV individuals and hence patients with new-onset disease must have HIV ruled out. Individuals with HIV who develop reactive arthritis often develop severe psoriasiform dermatitis on the scalp, soles, palms, and flexures.

The physical exam may reveal:

  • Sausage shaped finger, toe or heel pain
  • Asymmetric oligoarthritis- usually of the lower extremities
  • Conjunctivitis or iritis
  • Acute diarrhea or cervicitis within 4 weeks of the onset of arthritis
  • Urethritis or genital ulcers

Two or more of the above features plus involvement of the skeletal system establishes the diagnosis.

Joint and entheses

The involvement is asymmetric and affects the weight bearing joint. The joints are often warm, painful and swollen. Tendinitis is a common feature of the disease.

Skin and mucocutaneous changes are also common and may include hyperkeratotic skin and erythematous dermatitis. Nail dystrophy is common.

Eye involvement is common and may include conjunctivitis or uveitis.

Evaluation

Although reactive arthritis is a clinical diagnosis, laboratory tests to detect the offending pathogens to confirm concomitant or preceding infections are usually performed to support the diagnosis. Nucleic acid amplification tests to detect early morning urine sample or urogenital swab to detect chlamydia trachomatis. Positive evidence of Chlamydia by polymerase chain reaction (PCR) in the joint is probably strongly diagnostic, but the current methods used for the detection of chlamydia in the urine are not validated for diagnostic purposes for synovial samples. Serological testing for Chlamydia trachomatis is of limited importance due to serological cross-reactivity between Chlamydia trachomatis and Chlamydia pneumoniae, inability to distinguish past and present infection by the persistence of antibodies, lower or absent antibody response in lower urinary tract infections. Serological testing is available for Salmonella, Yersinia, and Campylobacter but is not useful in clinical practice. There are also gastrointestinal infections, for example, Shigella, in which no reliable serological methods exist. A stool culture may be helpful to detect enteric pathogens.[8][9]

Acute phase reactants such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be elevated. Joint aspiration must be performed when possible to rule out other arthritis. The findings in synovial fluid are nonspecific and are characteristic of inflammatory arthritis, with elevated leukocyte counts (typically 2000 to 4000 WBC per ml), with neutrophil predominance.

HLA B 27 can be measured as it correlates with the severity of the disease but is not diagnostic. In immigrants, the tuberculin skin test should be performed.

Plain radiographs may reveal nonspecific inflammatory joint findings, in the acute phase. Ultrasonography or magnetic resonance imaging (MRI) can be used to diagnose peripheral synovitis, enthesitis, or sacroiliitis. Scintigraphy can reveal early stages of enthesitis.

Aspiration of the joint is often done to rule out septic arthritis and crystalline arthritis.

Treatment / Management

The goals of therapy in reactive arthritis is to provide symptomatic relief and prevent chronic complications. Non-steroidal anti-inflammatory drugs are the initial treatment of choice in the acute phase. Intra-articular or local glucocorticoids as in case of enthesitis or bursitis can be used if the patient has mono/oligoarthritis. Systemic use of glucocorticoids is limited to severe polyarthritis, cardiac and ocular manifestations. Treatment of the underlying concomitant infection, if present should be initiated without delay. Patients who do not have active infection do not benefit from antibiotic therapy. Disease-modifying antirheumatic drugs (DMARDs), mainly Sulphasalazine have shown to be effective in both acute and chronic ReA. Other agents such as methotrexate and azathioprine have shown to be useful in chronic arthritis. They are indicated in patients who have failed Nonsteroidal anti-inflammatory drug (NSAID) therapy. Biologicals such as tumor necrosis factor (TNF) blocking agents (e.g., and infliximab and etanercept have been suggested in the treatment of reactive arthritis. However, further studies are needed to determine their role in the treatment of ReA.[10][11][12]

All patients should be urged to become physically active.

Differential Diagnosis

The physician should be able to rule out conditions that present with similar clinical findings.

The most common differential diagnosis should include:

  • Gonococcal arthritis 
  • Gouty arthritis 
  • Still's disease 
  • Septic arthritis
  • Rheumatic fever 
  • Psoriatic arthritis 
  • Rheumatoid arthritis
  • Immunotherapy/immunization–related arthropathy
  • Secondary syphilis

Prognosis

Rheumatoid arthritis usually has a self-limited course and the symptoms resolve within 3- 12 months. Patients who are HLA-B27 positive have a higher risk of recurrence of ReA. 15-30% of patients with ReA can develop long-term arthritis or other joint abnormalities.  The presence of hip involvement, unresponsiveness to NSAIDs and ESR greater than 30 portend a worse outcome.

Complications

Complications of ReA include:     

  • Recurrent arthritis (15-50%)    
  • Chronic arthritis or sacroiliitis 
  • Ankylosing spondylitis (30-50% if the patient is also HLA-B27–positive)    
  • Urethral Stricture
  • Aortic root necrosis 
  • Cataracts    
  • Cystoid macular edema

Consultations

The patient is advised to have regular follow-ups with his primary physician and orthopedic physician to assess for any level of damage caused by the infection.

Deterrence and Patient Education

Some studies have suggested that appropriate treatment of acute GU infection with a 3-month course of antibiotics can prevent ReA. However, this is highly controversial.

Enhancing Healthcare Team Outcomes

Reactive arthritis is a multiorgan disorder that is best managed by a team of healthcare professionals that includes a rheumatologist, ophthalmologist, gastroenterologist, physical therapist, nurse, and pharmacist.

There is no cure for reactive arthritis and the treatment is supportive. All patients should be encouraged to become physically active and a physical therapy consult should be obtained.

The pharmacist should educate the patient on the types of drugs used, their benefits and side effects. If patients are prescribed steroids, the side effects must be closely monitored and the drugs tapered as soon as the clinical symptoms subside.

A consult with a dermatologist is recommended to assess skin lesions and recommend treatment.

The key feature is patient education to help improve physical conditioning, function, and quality of life. The patient should participate in regular exercises to improve exercise endurance and prevent joint stiffness. In addition, the nurse practitioner should educate the patient about safe sex practices to prevent STDs. Because the disorder can induce anxiety and depression, a mental health nurse should follow these patients and offer counseling.

Finally, all patients with reactive arthritis should follow up with an ophthalmologist since they remain at high risk for visual problems.[13][14] (Level V)

Outcomes

The progression of reactive arthritis is variable, but in most people, the disorder is self-limited with the resolution of the symptoms occurring by 6-18 months. Mortality is very rare today and is usually due to the treatments. In general, causes related to sexually transmitted infections have a worse outcome than those caused by gastrointestinal infections. Despite a cure, recurrences are known to occur in 25-50% of cases, especially those who are HLA-B27 positive. Reactivation may signal a new infection or stress. About 20% of patients will have a long-term disease that results in enthesitis and destructive arthritis. Elevation of ESR, lack of response to NSAIDs and involvement of the hip joint usually is indicative of poor outcome. [15][16](Level V) 

 

 


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Reactive Arthritis (Reiter Syndrome) - Questions

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Which gastrointestinal tract microorganism has been associated with reactive arthritis?



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A 17-year-old presents with left ankle and lower back pain which started 3 weeks ago. He denies any injury and states he has been healthy except for a severe case of traveler's diarrhea that resolved without treatment two months ago. Exam reveals tenderness and decreased range of motion of both ankles and the lumbar spine. There is also evidence of mild bilateral conjunctivitis. What is the next step in his management?



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A 19-year-old male has complaints of pain in the mouth, wrists, and ankles. Exam is remarkable for oral ulceration, tenderness in the wrist and ankles, balanitis, and a thick, scaly rash of the palms and soles. What is the most likely infectious cause?



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A young man complains of severe pain in his elbows, knees, ankles, and hands. He had unprotected receptive oral sex with a man 10 days ago and has had fevers and a sore throat. The patient's pharynx is erythematous with pustular exudative tonsillitis, and he has anterior cervical lymphadenopathy. A cardiovascular exam shows regular heart tones with a II/VI systolic ejection murmur. His skin is clear, and there are no genital lesions. There is redness, increased warmth, bogginess, and tenderness of multiple joints. There is pain with both active and passive movement. Complete blood count and comprehensive metabolic panel are normal but C-reactive protein is 11mg/dL, and erythrocyte sedimentation rate is 90 mm/hour. Select the most likely diagnosis.



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A 25-year-old sexually active female presents to the clinician with new-onset urethral discharge which she says has been present for four weeks. She decided to seek medical attention after noticing pain in her left knee joint, right wrist, and lower back a week ago. She adds that there has also ben some itching and redness of the eye and a low-grade fever. Upon further evaluation of her sexual history, it is revealed she has had a new sexual partner for four months now and admits to having several partners in the past year. Vitals include a blood pressure of 115/78 mmHg, a temperature of 99 degrees Fahrenheit, a pulse of 78 beats per minute and respiration of 15 breaths per minute. Infection with which organism could be responsible for her ongoing clinical presentation?



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What percentage of Reiter syndrome (RS) patients show radiographic changes of the spine or sacroiliac joints?



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A 25-year-old sexually active male presents to the clinician with new-onset urethral discharge which has been ongoing for three weeks now. He had been ignoring it for a while but decided to seek medical attention since he started having pain in his ankle joint, wrist, and lower back a week back. He has also been noticing a thick plaque-like change in his soles along with a similar lesion in his scalp. He has had a low-grade fever. He denies any rash in his genital area. His sexual history reveals that he has had a new sexual partner for four months now and admits to having several partners in the past year. Which blood test in his most likely clinical condition has a greater than 90% specificity for the diagnosis?



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A 26-year-old male presents with a 6-week history of pain and swelling in several joints including his right wrist and left ankle. He also complains of right eye pain and has had some trouble walking. He does admit to several unprotected sexual encounters in the past several months. On physical exam, vital signs are normal. The sclera of the right eye is injected. His right wrist and left ankle are noted to be slightly swollen, warm, and tender to palpation. There is also tenderness in bilateral Achilles tendon. What is the most likely diagnosis?



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A young male was recently treated for a gastrointestinal infection 3 weeks ago. Now he presents with vague joint pains, red eyes, and general malaise. Two days ago, he was in the emergency department complaining of low back pain. On physical, he had tenderness in his right knee and ankle. He also had marked tenderness at the back of the ankle and low back. He has obvious conjunctivitis. The blood work and imaging tests are all normal. How is the disorder managed?



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A 26-year-old male presents to the clinician with an 8-week history of pain and swelling in several joints, including his right wrist and left ankle. His initial presentation also included right eye pain and difficulty walking. On physical exam, vital signs are normal. The sclera of the right eye is injected. His right wrist and left ankle are noted to be slightly swollen, warm, and tender to palpation. During the examination, he also mentions about some ongoing urethral discharge and burning sensation. He does admit to several unprotected sexual encounters in the past several months. Based on the diagnosis, he is initially treated with ibuprofen. After failing to respond, he received two injections of corticosteroids in his spine. He still has not responded. What is the next choice of treatment for the patient's peripheral arthritis?



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A 24-year-old male presents to the clinician with complaints of vague joint pains, red eyes, and general malaise. Two days ago, he was in the emergency department complaining of low back pain. Further evaluation of history reveals that he was recently treated for a gastrointestinal infection three weeks ago. On physical exam, he had tenderness and swelling in his right knee and ankle. He also had marked tenderness at the back of the ankle and low back. Examination of the eyes reveal redness of the eyes, swollen eyelids, and discharge present near the inner canthus of the eye. Laboratory test of blood and radiological imaging are all unremarkable. He is treated with a combination of ibuprofen and corticosteroid injection in the knee joint. He would like to know when the disorder will resolve. Within what time frame is the disease process expected to resolve?



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A 31-year-old female presents to the emergency department complaining of redness in the eye and pain in her joints over the past week. She has also been having some painful discharge from her vagina. She adds that her right knee and both ankles have been stiff, and she is now having trouble walking at her usual pace. She is sexually active with multiple partners and was recently tested negative for human immunodeficiency virus (HIV). She also admits to recently being treated for a sexually transmitted disease about 6 weeks ago. Serum uric acid levels are within the normal range while C reactive protein is elevated. What is the current consensus of the use of antibiotics for the management of patients with chronic reactive arthritis?



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A 35-year-old man presents to the office complaining of redness of the eye and discharges over the last few days. He has also been experiencing pain with urination. His knees and ankles have been stiff, and he is now having trouble taking part in his morning runs. He is sexually active with multiple partners and was recently tested negative for HIV. He denies the use of condoms during intercourse. He also admits having been recently treated for a sexually transmitted disease about 6 weeks ago. On physical exam, discharge from the urethral meatus is also noted along with his other chief complaints. There is tenderness and swelling over his left knee. Serum uric acid levels are within the normal range. The presence of which human leukocyte antigen increases the risk of developing this patient's current condition?



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A 65-year-old male presents to the clinician with complaints of stiffness and pain in his left ankle and right knee joint on waking up every morning for the past three weeks. It is progressively getting worse. He has been having subjective fever and malaise and also mentions that he has pain followed by minimal discharge at the end of urination. He recently gained a new sexual partner three months back. On exam, he has normal vitals except for a mild fever. He has normal-appearing oral mucosa with no palpable lymphadenopathy. Conjunctiva is congested bilaterally. Knee and ankle joints are tender but do not appear to have an effusion. A urethral swab is collected and sent for sexually transmitted disease screen by polymerase chain reaction (PCR). It comes back positive for chlamydia. Blood culture is negative. What should be the best management strategy for the remission of symptoms?



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A 65-year-old female presents to the healthcare provider with complaints of stiffness and pain in her back, left ankle, and right knee on waking up every morning for the past month. It is progressively getting worse. She has been having fever and malaise and also mentions that she has pain followed by minimal discharge at the end of urination. She recalls having an episode of diarrhea after a camping trip four weeks ago. Since yesterday she has been having some pain in her left eye too. She has a low-grade fever but is otherwise hemodynamically stable. The ankle joint appears warm and tender. There is some effusion in the knee joint. Ultrasound-guided aspiration of joint space is done which shows 4000 WBCs with a neutrophilic predominance. RBC is minimal, and there are no crystals. A slit lamp exam of the eyes is also done, which reveals increased cells in the anterior chamber. What should be the best treatment strategy for her underlying condition?



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A 52-year-old gentleman presents to the clinic with a 4-week onset of progressive pain in the lower back, both knees and left ankle, low-grade fever, malaise, and a 1-week history of dysuria. Dysuria is not uncommon for him as he has been diagnosed with transitional cell carcinoma of the urinary bladder and has received treatment with a vaccine of which he cannot remember the name. For the past 2 weeks, he has also been noticing some redness of eyes, although vision is not impaired. He has had no preceding diarrhea or travel in the past few months. He has been sexually inactive for more than 2 years. On exam, the lower back is very tender. His fingers and wrist appear swollen and stiff. The genital exam is unremarkable, and the prostate is not tender. What is the best initial therapy for this patient?



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A 65-year-old man presents with a 4-week history of progressive pain in the lower back, both knees and left ankle, low-grade fever, malaise and a 1-week history of dysuria. For the past two weeks, he has also been noticing some redness of eyes, although vision is not impaired. He has had a recent trip to New Mexico six weeks back with his new girlfriend but does not recall having any major health issues there other than a brief bout of diarrhea. On exam, the lower back is very tender. His fingers and wrist appear swollen and stiff. The genital examination shows no ulcers. He also has a scaly rash on his skin crease around elbow, scalp, and palm. Routine blood work is unremarkable. Blood culture sent two days back is negative on admission. What should be the most important investigation to consider at this phase of work up?



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A 65-year-old male presents to the healthcare provider with complaints of stiffness and pain in his lower back, left ankle, right knee, and index finger of the right hand. The pain starts at night and is accompanied by stiffness on waking up every morning for the past month. It is progressively getting worse. He also mentions that he has pain and burning with urination along with minimal discharge. Before the symptoms started, he had diarrhea after a camping trip four weeks back, which was treated with antibiotics. He notes that the symptoms started soon after that. Since yesterday, he has had some pain and redness in both of his eyes. He is afebrile and is otherwise hemodynamically stable. The ankle joint appears warm and tender. There is some effusion in the knee joint. Ultrasound-guided aspiration of joint space is done, which reveals 4000 white blood cells with a neutrophilic predominance, minimal RBCs, and no crystals. He has a scaly rash on his elbow skin crease in the flexor surface as well as scalp and palm. He does not have any genital ulcers. At the cellular level, which phenomena are responsible for the disease manifestations described above?



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Reactive Arthritis (Reiter Syndrome) - References

References

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