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Reactive Arthritis

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Definition

It refers to an "arthritis that occurs shortly after an infection at another site in the organism, but in which the microorganisms cannot be isolated from the joint" (1). The classic "triad" of post-infectious arthritis, urethritis and conjunctivitis is also referred to today as reactive arthritis. These diseases belong to the "family" of spondyloarthritides, as they have many similarities with undifferentiated spondyloarthritis, ankylosing spondylitis (Bechterew's disease), psoriatic arthritis and the (spondylo)arthritides associated with chronic intestinal diseases.

Frequency and incidence

ReA usually occurs in younger adults and affects women and men in roughly equal numbers.

Pathogenesis

The pathogenesis of joint inflammation is not fully understood. Increased mucosal permeability in the intestine or urinary tract is considered a possible factor. The resulting increased exposure to bacterial or other antigens leads to immune reactions in the joint. Loss of tolerance to the body's own (intestinal) bacterial flora could also play a role.

Tiggers

The infections that trigger ReA characteristically affect the intestines and the urogenital tract. As a result, the following intestinal bacteria are found:

  • Salmonella of different serotypes
  • Yersinia (Y. enterocolitica 0:3 and 0:9, Y. pseudotuberculosis)
  • Shigella (S. flexneri, dysenteriae and sonnei)
  • Campylobacter, in particular Campylobacter jejuni
  • Clostridium difficile

Among the urogenital infection triggers, only Chlamydia trachomatis is recognized beyond doubt as the cause of ReA.

Diagnosis

Identification of such an infection is not always easy, so multiple terms, diagnostic and classification criteria have been proposed for clinical use (2). Unfortunately, none of these criteria sets have been sufficiently validated, so the following characteristics were identified in a consensus process (3):

  • Typical joint pattern
  • Typical ReA is asymmetric and affects a single joint or only a few joints (mono- or oligoarthritis). The large joints of the lower extremities are usually affected; involvement of the spine is common
  • Extra-articular manifestations
  • In addition to the symptoms of the triggering infection, there are usually (although not always) signs of involvement of tendon attachments (enthesitis), skin, eyes, gastrointestinal and urogenital tract
  • Interval between symptoms of infection and the onset of arthritis
  • At least a few days and typically no more than about four weeks
  • Infection with typical triggering germs
  • In addition to classic triggers such as Chlamydia, Yersinia, Salmonella and others, a large number of other germs are associated with ReA.

Clinic

It is characterized by asymmetric oligoarthritis, often in the lower extremities. However, arthritis of the upper extremity and/or polyarthritis of small joints are not uncommon (up to 50%) (4).
Symptoms of enthesitis include swelling of the heels (Achilles tendon bursitis and enthesitis) and the so-called sausage fingers or toes. Other localizations of enthesitis that are more difficult to identify clinically are the symphysis or the iliac crest.


Extra-articular manifestations of ReA include urogenital tract symptoms, conjunctivitis, uveitis, oral ulcers and skin manifestations such as keratoderma blennorrhagicum (hyperkeratotic lesions on palms or soles), balanitis circinata and nail changes similar to those seen in nail psoriasis. Genital lesions are not specific to ReA. Dysuria or pelvic pain may be signs of sterile urethritis.

Diagnostic methods - Infection detection

Laboratory tests can sometimes confirm a previous or ongoing infection with one of the typical germs. However, the hit rate is a maximum of 50%, as the triggering germ has often already been eliminated or the culture or serology shows a ("false") negative result. Stool cultures (possibly also in the absence of gastrointestinal symptoms) and chlamydia tests from urethral and vaginal swabs or urine (based on DNA amplification, such as the ligase reaction) are considered suitable tests.
Serological tests for Yersinia, Salmonella, Campylobacter and Chlamydia can be indicative, but the asymptomatic infestation of the population is very high, so that often no conclusions can be drawn about a recent infection.

Forecast

The prognosis for ReA is generally good. Most patients are largely symptom-free after around 6 months (with or without specific therapy, see below). Only 4-19% of patients with ReA caused by Yersinia, Salmonella, Shigella and Chlamydia in a Finnish study had symptoms after more than 6 months (5), although it is not clear whether this result also applies to other populations. Especially for this minority of patients suffering from chronic ReA (defined by a duration of symptoms of more than 6 months), the initiation of long-term therapy with DMARDs makes sense.

Therapy

Non-steroidal anti-inflammatory drugs (NSAIDs) are the basis of symptomatic therapy in the acute phase of the disease(s). It is recommended to treat with an effective dose (e.g. 500-1500 mg naproxen or 100-150 mg indomethacin/day) for at least 2 weeks before other drugs should be used. Glucocorticoids, especially intra-articular, also have a good effect in a large number of patients.

If the arthritis persists for several weeks despite the non-specific measures mentioned, the use of disease-modifying drugs ("basic therapeutics" or DMARDs) is recommended. The drug of first choice appears to be sulfasalazine, which was significantly better than placebo in a controlled study (6). Remarkably, there are no published results on the value of the other DMARDs or biologics in (chronic) ReA, although most of them are approved for diseases from the group of seronegative spondyloarthropathies such as ankylosing spondylitis or psoriatic arthritis.

In principle, antibiotics have no effect against arthritis, but are recommended if there is evidence of persistence of the infection. In the case of active enteral or urogenital infection, the infectiological recommendations should be followed depending on the local circumstances. In general, uncomplicated enteral infections do not require treatment, except in immunocompromised patients. In contrast, active chlamydial infections should always be treated with the involvement of the partner. This approach could also prevent the development of ReA.


Individual reports postulated favorable effects of tetracyclines on chronic ReA without evidence of active infection. However, these observations have not been clearly reproduced, so antibiotic therapy is currently not recommended in these cases.

Similar to chronic polyarthritis, the number of swollen and painful joints, the patient's assessment of pain and disease activity and the CRP can be used to measure the success of treatment (7).

References

  1. Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 1969; 15(3):232-53.
  2. Hannu T, Inman R, Granfors K, Leirisalo-Repo M. Reactive arthritis or post-infectious arthritis? Best Practice & Research in Clinical Rheumatology 2006; 20(3):419-33.
  3. Braun J, Kingsley C, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000; 27(9):2185-92.
  4. Leirisalo-Repo M. Reactive arthritis. Scandinavian Journal of Rheumatology 2005; 34(4):251-9.
  5. Leirisalo-Repo M, Sieper J. Reactive arthritis: epidemiology, clinical features, and treatment. In: Weisman MH, van der Heijde D, Reveille JD, editors. Ankylosing spondylitis and the spondyloarthropathies. Philadelphia: Mosby Elsevier; 2006. 53-64.
  6. Clegg DO, Reda DJ, Weisman MH, Cush JJ, Vasey FB, Schumacher HR et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome) - A Department of Veterans Affairs cooperative study. Arthritis Rheum 1996; 39(12):2021-7.
  7. Eberl G, Studnicka-Benke A, Hitzelhammer H, Gschnait F, Smolen JS. Development of a disease activity index for the assessment of reactive arthritis (DAREA). J Rheumatol. In press 1998.