Reactive Arthritis (Reiter Syndrome)

Article Author:
Apoorva Cheeti
Article Author (Archived):
Rebanta Chakraborty
Article Editor:
Kamleshun Ramphul
Updated:
12/2/2019 4:52:36 PM
PubMed Link:
Reactive Arthritis (Reiter Syndrome)

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 an aberrant autoimmune response to the 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, Mycoplasma hominis, and Ureaplasma urealyticum) or gastrointestinal (GI) tract (Salmonella enteritidis, Shigella flexneri, and disenteriae, 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].

Rare cases have been reported after administration of Bacillus Calmette Guerin vaccine ( BCG) treatment for bladder cancer.[6]

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.[7]

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.[8]

Histopathology

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

History and Physical

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.

For sexually acquired reactive arthritis, there is a history of sexual intercourse, usually with a new partner, within 3 months of arthritis symptoms. Genital symptoms precede arthritis by about 2 weeks on an average. It may include dysuria, discharge, testicular pain in men, and intermenstrual or postcoital bleeding, or deep pelvic pain apart from vaginal discharge in women. [9]

Reactive arthritis is very common in HIV individuals and hence patients with the 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

Patients typically present with acute onset oligo-arthritis, mainly involving the lower extremities, sacroiliac joint, and the lumbar spine. Not more than 6 large joints are affected at a time and knee and ankle are the most commonly affected. Joint pain is classically nocturnal with early morning stiffness.  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. About 30% of patients suffer from associated enthesitis in the form of Plantar fascitis or Achilles tendinitis.[10]

Extra-articular manifestations 

Extra-articular manifestations may involve 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

Skin and mucocutaneous changes are common and may include hyperkeratotic skin and erythematous dermatitis. Nail dystrophy is common. Other involvements include pustular psoriasis on the sole ( keratoderma blenorrhagica), geographic tongue, circinate balanitis, or oral ulceration.

Eye involvement is common and may include conjunctivitis (30%)  or uveitis. In patients with visual symptoms, recognition of uveitis is of paramount importance as it can rapidly lead to visual loss. 

Rare cases can involve the cardiovascular system causing conduction abnormalities in early-stage and aortic regurgitation when advanced. Myelopathy, as well as non-specific gastrointestinal features of diarrhea and colitis, can also persist.[11]

Evaluation

Reactive Arthritis falls within the subclass of seronegative spondyloarthropathies that affect the axial skeleton. Other members of that group are Ankylosing spondylitis and Psoriatic arthritis. Joint involvement is oligoarticular and asymmetrical. 

American College of Rheumatology came up with diagnostic guidelines for Reactive arthritis in 1999. The criteria were divided into 

MAJOR

- Asymmetric oligo or monoarthritis involving lower extremities

- Either enteritis or Urethritis symptoms preceding the onset of arthritis by a time interval of 3 days to 6 weeks. 

MINOR

- Presence of a triggering infection as evidenced by culture positivity.

- Presence of persistent synovial involvement.

A combination of genitourinary symptoms, metatarsophalangeal joint involvement, elevated C reactive protein and Positive HLA- B27 renders a 69% sensitivity and 93.5% specificity to the diagnosis of reactive arthritis. [12]

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 from an early morning urine sample or urogenital swab are utilized to detect chlamydia trachomatis and Neisseria Gonorrheae. Nucleic acid amplification test for Mycoplasma genitalium is also available nowadays and is relevant in men with urethritis. 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.[13][14]

Certain complications like uveitis are important to identify. Slit-lamp exam is helpful to diagnose cells in the anterior chamber in acute iritis. Presence of ocular symptoms in a suspected patient should, therefore, generate a prompt referral to an ophthalmologist. The usual presentation of uveitis will involve acute pain, photophobia, visual impairment, scleral injection, and hypopyon.

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. Aspiration of the joint is often done to rule out septic arthritis and crystalline 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. It is also important in the localization of arthritis. Sacroiliitis occurs more commonly in HLA B 27 positive patients [15]

In a patient from an endemic population, 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.

Treatment / Management

If an infectious agent has been identified as a trigger for reactive arthritis, antimicrobial therapy is strongly recommended often for a long term of 3 to 6 months. It can significantly shorten the time to remission. [16] 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. [17] Vasey et al reported the results of a double-blinded prospective triple placebo trial in which chlamydia positive patients by PCR were treated for 6 months with a combination of doxycycline and rifampin or azithromycin and rifampin. The treatment arm did achieve statistically significant symptom remission as well as PCR negativity although the study was underpowered for identification of the preferred combination of antibiotics.  

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. Mechanical devices like orthotics and insoles can be useful. Systemic use of glucocorticoids is limited to severe polyarthritis, cardiac and ocular manifestations.  Disease-modifying antirheumatic drugs (DMARDs), mainly Sulphasalazine have been 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 definitive indications.[18][19][20]

All patients should be urged to become physically active. Strengthening exercises are a key component of long term therapy to prevent muscle wasting. 

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 
  • Ankylosing spondylitis
  • Rheumatoid arthritis
  • Immunotherapy/immunization–related arthropathy
  • Secondary syphilis
  • Tubercular arthritis 

Prognosis

Rheumatoid arthritis usually has a self-limited course and the symptoms resolve within 3- 5 months. Symptoms lasting beyond 6 months indicate a chronic element of the disease. Sacroiliitis is the most common chronic joint involvement. 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

The social taboo associated with genitourinary symptoms often becomes a challenge in obtaining a complete and accurate history from patients. Some studies have suggested that appropriate treatment of acute Genitourinary infection with a 3-month course of antibiotics can prevent ReA. However, this is highly controversial.

Similarly from a physician's perspective, identification of the triad of visual, genitourinary and arthritis symptoms to a pattern of unifying diagnosis is time-sensitive. It is even more so when acute uveitis or iritis sets in, as they can rapidly progress to permanent loss of visual function, if not intervened upon in due time. 

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. While evaluating, general physicians should not shy away from exploring the detailed history of sexual contacts and genital symptoms. 

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 to counsel.

Finally, all patients with reactive arthritis should follow up with an ophthalmologist since they remain at high risk for visual problems.[21][22] (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. [23][24](Level V) 


References

[1] Arévalo M,Gratacós Masmitjà J,Moreno M,Calvet J,Orellana C,Ruiz D,Castro C,Carreto P,Larrosa M,Collantes E,Font P, Influence of HLA-B27 on the Ankylosing Spondylitis phenotype: results from the REGISPONSER database. Arthritis research     [PubMed PMID: 30285828]
[2] Picchianti-Diamanti A,Panebianco C,Salemi S,Sorgi ML,Di Rosa R,Tropea A,Sgrulletti M,Salerno G,Terracciano F,D'Amelio R,Laganà B,Pazienza V, Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept. International journal of molecular sciences. 2018 Sep 27     [PubMed PMID: 30261687]
[3] Houzou P,Fianyo E,Kakpovi K,Koffi-Tessio VS,Tagbor KC,Oniankitan O,Mijiyawa M, Panorama of inflammatory arthropathies in rheumatologic consultations in Northern Togo. Medecine et sante tropicales. 2018 Aug 1     [PubMed PMID: 30270840]
[4] Generali E,Bose T,Selmi C,Voncken JW,Damoiseaux JGMC, Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory. Autoimmunity reviews. 2018 Sep     [PubMed PMID: 30005857]
[5] Spyridakis E,Gerber JS,Schriver E,Grundmeier RW,Porsch EA,St Geme JW 3rd,Downes KJ, Clinical Features and Outcomes of Children with Culture-Negative Septic Arthritis. Journal of the Pediatric Infectious Diseases Society. 2018 Apr 30     [PubMed PMID: 29718310]
[6] Kim PS,Klausmeier TL,Orr DP, Reactive arthritis: a review. The Journal of adolescent health : official publication of the Society for Adolescent Medicine. 2009 Apr     [PubMed PMID: 19306788]
[7] Muilu P,Rantalaiho V,Kautiainen H,Virta LJ,Eriksson JG,Puolakka K, Increasing incidence and shifting profile of idiopathic inflammatory rheumatic diseases in adults during this millennium. Clinical rheumatology. 2018 Sep 26     [PubMed PMID: 30259249]
[8] Protopopov M,Sieper J,Haibel H,Listing J,Rudwaleit M,Poddubnyy D, Relevance of structural damage in the sacroiliac joints for the functional status and spinal mobility in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis research     [PubMed PMID: 29065931]
[9] Carlin E,Flew S, Sexually acquired reactive arthritis. Clinical medicine (London, England). 2016 Apr;     [PubMed PMID: 27037393]
[10] Stavropoulos PG,Soura E,Kanelleas A,Katsambas A,Antoniou C, Reactive arthritis. Journal of the European Academy of Dermatology and Venereology : JEADV. 2015 Mar     [PubMed PMID: 25199646]
[11] Wu IB,Schwartz RA, Reiter's syndrome: the classic triad and more. Journal of the American Academy of Dermatology. 2008 Jul     [PubMed PMID: 18436339]
[12]     [PubMed PMID: 24418301]
[13] Shohat N,Goswami K,Fillingham Y,Tan TL,Calkins T,Della Valle CJ,George J,Higuera C,Parvizi J, Diagnosing Periprosthetic Joint Infection in Inflammatory Arthritis: Assumption Is the Enemy of True Understanding. The Journal of arthroplasty. 2018 Jul 24     [PubMed PMID: 30100134]
[14] Pavic K,Pandya J,Sebak S,Shetty A,Spencer D,Manolios N, Acute arthritis: predictive factors and current practice in the approach to diagnosis and management across two hospitals in Sydney. Internal medicine journal. 2018 Sep     [PubMed PMID: 29756282]
[15]     [PubMed PMID: 9766487]
[16]     [PubMed PMID: 25151762]
[17]     [PubMed PMID: 20155838]
[18] Glintborg B,Lindström U,Aaltonen K,Kristianslund EK,Gudbjornsson B,Chatzidionysiou K,Askling J,Nordström D,Hetland ML,Di Giuseppe D,Dreyer L,Kristensen LE,Jørgensen TS,Eklund K,Grondal G,Ernestam S,Joensuu J,Törmänen M,Skydsgaard H,Hagfors J,Kvien TK,Lie E,Fagerli K,Geirsson AJ,Jonsson H,Provan SA,Krogh NS,Jacobsson L, Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries. Scandinavian journal of rheumatology. 2018 Aug 2     [PubMed PMID: 30070923]
[19] Bhutia E,Kumar D,Kundal M,Kishore S,Juneja A, Atypical Articular Presentations in Indian Children With Rheumatic Fever. Heart, lung     [PubMed PMID: 28528779]
[20] Sieper J,Hu X,Black CM,Grootscholten K,van den Broek RWM,Kachroo S, Systematic review of clinical, humanistic, and economic outcome comparisons between radiographic and non-radiographic axial spondyloarthritis. Seminars in arthritis and rheumatism. 2017 Jun     [PubMed PMID: 27855973]
[21] Maravic M,Bozonnat MC,Sevezan A,Gasqueres D,Pastor J,Péré M,Neil V,Roch-Bras F,Daures JP,Sany J, Preliminary evaluation of medical outcomes (including quality of life) and costs in incident RA cases receiving hospital-based multidisciplinary management. Joint, bone, spine : revue du rhumatisme. 2000     [PubMed PMID: 11143909]
[22] Ahlmén M,Bjelle A,Sullivan M, Prediction of team care effects in outpatients with rheumatoid arthritis. The Journal of rheumatology. 1991 Nov     [PubMed PMID: 1787485]
[23] Deminger A,Klingberg E,Geijer M,Göthlin J,Hedberg M,Rehnberg E,Carlsten H,Jacobsson LT,Forsblad-d'Elia H, A five-year prospective study of spinal radiographic progression and its predictors in men and women with ankylosing spondylitis. Arthritis research     [PubMed PMID: 30075808]
[24] Kullich W,Neff H,Pöllmann G,Machreich K,Schwann H, [Adhesion molecule ICAM-1 in patients with chronic polyarthritis--effects of inpatient rehabilitation]. Wiener medizinische Wochenschrift (1946). 1999     [PubMed PMID: 10637965]