Reactive Arthritis (Reiter's disease, Reiter's syndrome, Fiessinger-Leroy disease, venereal arthritis, polyarteritis enterica)

Are You Confident of the Diagnosis?

What you should be alert for in the history

The classic triad of arthritis, urethritis, and conjunctivitis became known as ‘Reiter’s disease’ after a large number of cases were reported during World War I and II. The condition was named for Hans Reiter, who published a case in 1916, but the uncovering of Reiter’s affiliation with the Nazi party led to a change in designation for this condition.

Reactive arthritis, the currently accepted term, is a systemic, seronegative spondyloarthropathy defined by a temporal relationship to a precipitating infection with manifestations not limited to the classic triad. Symptoms of arthritis, ranging from mild arthralgia to severely disabling polyarthritis, begin typically within 1-4 weeks but up to 3 months following an infection.

Ask patients about recent illness, as the diagnosis requires an identified or presumed initiating infection. Many patients may be unaware of recent illness, however, having not had any infectious symptoms prior to arthritis.

There is no universally accepted diagnostic approach to reactive arthritis, but useful parameters in making the diagnosis include identifying a preceding infection with classic causative pathogens, and identifying an appropriate time interval between infection and onset of a typical reactive arthritis pattern. A family history of related disorders, including psoriasis, ankylosing spondylitis, and inflammatory eye or bowel disease, are also valuable clues in making the diagnosis.

The majority of patients actually have little or no extra-articular findings like urethritis and conjunctivitis, but these manifestations represent key diagnostic aids.

Characteristic findings on physical examination

On physical exam, reactive arthritis is characterized by an acute onset mono- or asymmetric oligoarthritis and enthesitis of the lower extremities. Large joints such as the knees and ankles are most often affected, but subtalar and metatarsophalangeal joints are also regularly involved. Large joint effusions are common, may be a presenting feature, and may recur rapidly if drained.

The arthritis may be quite painful and disabling, and can occasionally be erosive in nature. Arthritis of the upper extremities is uncommon, and when present typically involves only one or a few joints, particularly in the hand. Most patients also complain of some degree of back pain, which may be secondary to associated sacroiliitis or lumbosacral enthesitis.

Enthesitis, inflammation at bony insertion sites of ligaments and tendons, is also characteristic of reactive arthritis. Patients frequently complain of heel pain, stemming from enthesitis with or without an associated bursitis at the plantar fascia or Achilles tendon insertion onto the calcaneus. Dactylitis or sausage digit, a diffuse swelling of a single finger or toe, is also characteristic of both reactive arthritis and other spondyloarthropathies like psoriatic arthritis.

Skin findings are present in 5-33% of patients, most often on the extensor surfaces of the legs, dorsal aspects of the hands, penis, fingers, and scalp. These papulosquamous, psoriasiform lesions, more common in disease initiated by urogenital rather than enteric infections, are known as circinate balanitis (Figure 1) when present on the penis
and keratoderma blennorrhagicum when present on the soles and elsewhere (Figure 2, Figure 3).

Figure 1.

Figure 2.

Figure 3.

Keratoderma blennorrhagicum classically is found on the plantar surface of the feet, but palms and other areas may also be involved (Figure 4). Keratoderma blennorrhagicum begins as small vesicles on an erythematous base that soon rupture and form lesions with varying degrees of crusting, exudation, and erosion. Thick yellow scale and hyperkeratosis is common, and pustules are often present.

Figure 4.

Superficial ulcers are common, and are typically painless and transient. These unkeratinized lesions may occur on the buccal mucosa, palate, lips, or tongue (Figure 5).

Figure 5.

Up to one third of patients with reactive arthritis following urogenital infection have skin or mucous membrane pathology, but less so in disease following enteric infection.

Unilateral or bilateral inflammatory eye lesions, a component of the classic triad of Reiter’s syndrome, are present in up to one third of patients. Ocular disease in reactive arthritis ranges from a transient, asymptomatic conjunctivitis that resolves spontaneously (most commonly) (Figure 6), to an aggressive anterior uveitis or amnio conjunctivitis with severe ocular pain, redness, photophobia, and visual impairment (4-5% of patients).

Conjunctivitis rarely progresses to keratitis, episcleritis, or corneal ulceration, and development of severe pain or redness warrants an urgent ophthalmologic evaluation to prevent permanent disability.

Figure 6.

Onychodystrophy is common and resembles that seen in psoriasis, including onycholysis, distal yellow-brown discoloration, and hyperkeratosis. Nail changes may be severe (Figure 7).

Figure 7.

Urogenital inflammation, represented in the classic triad as urethritis, may occur as part of an initiating sexually transmitted infection, or as an aseptic reactive process at any point throughout the course of the disease.

Patients may have mild or no symptoms, and up to one third of men with chlamydial urethritis are asymptomatic. However, urethritis, whether infectious or reactive, may cause significant pelvic pain or dysuria, and complications include prostatitis in men, and vaginitis, cervicitis, salpingitis, and pelvic inflammatory disease in women. Urogenital inflammation has a tendency to relapse.

As with genitourinary manifestations, enteritis or colitis may occur in reactive arthritis as part of an initiating infection or as part of the reactive process. As in other spondyloarthropathies such as ankylosing spondylitis, ileocolonoscopic studies may show micro- or macroscopic inflammatory lesions resembling ulcerative colitis or Crohn’s disease along intestinal mucosa, irrespective of the presumed precipitating infection. When present, diarrhea and abdominal pain are usually mild.

Rare manifestations of reactive arthritis include pneumonia, pulmonary infiltrates, central or peripheral nervous system deficits, and cardiac abnormalities. Palpitations and conduction defects are not uncommon early in the disease, however, and as in other spondyloarthropathies, aortic root inflammation with or without valvular disease and insufficiency is a rare but important cause of morbidity and mortality. Of the minority of patients with reactive arthritis contracted after Yersinia infection, 10% go on to develop myocarditis.

Expected results of diagnostic studies

Laboratory studies should be directed at ruling out other disorders in the differential and identifying a triggering infection with a typical pathogen. However, by the time the arthritis appears, a pathogen may no longer be retrievable.

Serology may be useful, particularly in enteric infections, but is less likely to be helpful in diagnosing genitourinary infections. A urinalysis with culture may help diagnose chlamydial infections and rule out renal involvement. Stool cultures are recommended as identification of a classically associated pathogen is diagnostically helpful, but the yield is low. In acute patients with significant systemic symptoms, blood cultures may be warranted to rule out sepsis.

Arthrocentesis with aspiration and examination of synovial fluid for crystals or bacteria by Gram stain and culture is important in ruling out septic or crystal-induced arthritis. Mild anemia may be present and acute phase reactants such as C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) are often elevated.

These tests may help corroborate the diagnosis, but they are non-specific and of limited diagnostic value. Genetic testing to determine HLA status is only helpful in patients with moderate probability of having reactive arthritis after all other investigations have been pursued.

Imaging studies may be helpful in identifying and documenting changes consistent with arthritis and enthesitis, but there are no specific findings that firmly establish a diagnosis of reactive arthritis. Moreover, imaging is not necessary in the setting of clinically obvious manifestations, such as dactylitis or heel swelling from Achilles enthesitis. Plain radiography is likely to be normal in early or mild disease, but may help to exclude other conditions like osteoarthritis.

With more long-standing disease, marginal erosions, loss of joint space, periostitis with reactive new bone or spur formation may be seen in affected joints. Radiography may also detect changes consistent with sacroiliitis, although MRI and CT scanning are more sensitive to such changes and should be ordered if this condition is suspected. Ultrasound is a less expensive option that also may demonstrate acute enthesopathic lesions.

A skin biopsy is usually not necessary as the cutaneous findings are rarely the presenting feature and the arthritic component allows the diagnosis to be made in confidence. In those equivocal cases where a biopsy is deemed necessary, the histologic picture of keratoderma blennorrhagicum is indistinguishable from that of pustular psoriasis.

Lesions are characterized by a broad neutrophilic infiltration and microabscess formation with general epidermal hyperplasia, elongation and hypertrophy of rete ridges, as well as hyper- and parakeratosis (Figure 8). Histologically, circinate balanitis has a similar picture, with the exception that the moist lesions in uncircumcised males are not keratinized.

Figure 8.

Diagnosis confirmation

Reactive arthritis shares many overlapping features with other members of the spondyloarthropathy family:

1. Psoriatic arthritis: While reactive arthritis may represent a variant of psoriatic arthritis, psoriatic arthritis is typically more gradual in onset and less commonly associated with urethritis, bowel symptoms and oral ulcers.

2. Pustular psoriasis: Keratoderma blennorrhagicum may resemble pustular psoriasis both grossly and histologically. In many respects, reactive arthritis with skin manifestations is a variant presentation of pustular psoriasis.

3. Psoriasis vulgaris: Nail lesions in reactive arthritis are very similar to those in psoriasis vulgaris, but the cutaneous lesions can usually be readily distinguished between reactive arthritis and the classic form of psoriasis. As noted above, the skin lesions of reactive arthritis most closely resemble the pustular variant of psoriasis. Triggering infection is also not as readily associated with psoriasis.

4. Ankylosing spondylitis: Lumbosacral involvement in reactive arthritis is characteristically unilateral and asymmetric, and progression to spinal fusion is rare. The pattern of ankylosing spondylitis is classically bilateral and symmetric, and progression to spinal fusion is common.

The differential diagnosis also includes the following entities:

5. Gout: Dactylitis or sausage digit, a commonly seen feature of reactive arthritis and other peripheral spondyloarthropathies, is also seen in polyarticular gout and sarcoidosis. The presence of negatively birefringent needle-shaped crystals in joint fluid is diagnostic of gout.

6. Septic arthritis: Septic arthritis needs to be excluded, particularly in children. Gram stain and culture of joint fluid will accomplish this.

7. Sepsis: Patients with a significant systemic component, potentially due to the triggering infection, may be septic and blood cultures should be drawn.

8. Disseminated gonococcal infection: This venereally acquired disorder may have a component of arthritis and tenosynovitis, but is more likely to affect both upper and lower extremities equally and have no back symptoms. The associated rash of vesicular skin lesions is characteristic and distinct from that of reactive arthritis.

A positive culture from skin, joint fluid, or blood is diagnostic of disseminated gonococcal infection, but a positive culture from the urethra or cervix does not rule out reactive arthritis. A therapeutic trial of antibiotics may be needed to distinguish infection of Neisseria gonorrhoeae from Chlamydia trachomatis.

9. Intravesical BCG: Bladder instillation of Bacillus Calmette-Guerin (BCG) may be used in the treatment of bladder cancer, and oligo- or polyarthritis, particularly in the lower extremities, has been reported as a rare complication. These patients typically complain of axial pain consistent with spondyloarthritis, and in the literature many of these patients are HLA-B27 positive.

10. Acute rheumatic fever: The rare cases of reactive arthritis and carditis following Yersinia infection may be confused with acute rheumatic fever; however, the clinical picture of arthritis following streptococcal pharyngitis in patients with ARF is quite different.

11. Rheumatoid arthritis: Joint disease in rheumatoid arthritis can be differentiated from reactive arthritis by the more erosive nature, and a predominance for symmetric, upper extremity disease.

12. Enterovirus (viral gastroenteritis) infection: While arthritis is an uncommon manifestation of viral gastroenteritis infections, the disease is fairly common and, as such, these patients may represent a significant portion of those with nonspecific, self-limited arthritis in both small and large joints. Myalgias, transient rash, and more constitutional symptoms suggest a viral rather than bacterial etiology.

13. DVT: Enthesitis behind the knee may cause the formation of a Baker’s cyst, which may rupture, giving the impression of a DVT. The surrounding clinical picture is quite distinct, and the two are easily differentiated on ultrasound.

14. Osteoarthritis: Osteoarthritis is more gradual in onset, and the characteristic joint changes can readily be seen with plain radiography.

15. Sarcoidosis: Dactylitis may also be seen in sarcoidosis. The clinical picture is also quite distinct from that of reactive arthritis.

16. Lyme Disease: This diagnosis can best be made through careful history and high levels of positive antibodies in synovial fluid compared to serum.

Who is at Risk for Developing this Disease?

Reactive arthritis is an uncommon disorder, with a reported annual incidence ranging from 3-30/100,000 adults worldwide and 3.5/100,000 in the US, with an overall prevalence reported at 30-40/100,000. Epidemiologic patterns vary by triggering infection and genetic susceptibility between different populations, as do typical causative pathogens.

Urethritis-associated reactive arthritis, occurring in 1-3% of patients with nongonococcal urethritis, has a strong male bias. Enteritis-associated reactive arthritis, occurring in approximately 2% of patients with enteric infections, affects both genders equally. Reactive arthritis of all origins is most common in young adults 10-20 years old but may occur at any age.

Most episodes resolve spontaneously or with NSAID therapy within 6 months, but some residual symptoms may persist for years and up to 50% of patients may have one or more recurrences, particularly in Chlamydia-associated disease.

The course varies considerably depending on the genetic background of the patient and the triggering pathogen, and patients rarely develop a chronic persistent arthritis, (more than 6-month duration) or other spondyloarthropathies such as psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease. Most cases are sporadic, but familial clustering has been noted and outbreaks of enteritis-associated disease have been reported with Shigella, Campylobacter, Salmonella, and Yersinia.

It is well-documented that prevalence is strongly correlated with exposure to known triggering pathogens and HLA-B27 positivity. Populations with higher rates of HLA-B27 positivity are associated with higher rates of reactive arthritis, although HLA-B27 is not essential for disease. HLA-B27 is present in 7-9% of healthy Caucasian populations, for example, with 45-80% of those with reactive arthritis having the gene.

Positivity for this gene is also associated with a more prolonged course, more severe symptoms and joint disease, and a greater risk for developing chronic joint disease, ankylosing spondylitis, and other peripheral spondyloarthropathies.

Reactive arthritis is also strongly associated with HIV irrespective of genetic status. The relationship between the two remains unclear however, as in the US amongst HIV-infected individuals with reactive arthritis; the majority of non-Caucasians are HLA-B27 negative, while the majority of Caucasians are HLA-B27 positive.

What is the Cause of the Disease?

The etiology of reactive arthritis has not been fully elucidated, but it is clear that a triggering infection with certain pathogens in genetically susceptible individuals induces the disease. Reactive arthritis thus depends on both infectious and genetic factors.

Pathophysiology

While the exact pathophysiologic mechanism has not been elucidated, it has been shown that an aberrant, exaggerated cell-mediated and humoral immune response to particular antigens leads to inflammation at target organs in genetically susceptible individuals, with Chlamydia, Salmonella, Campylobacter, Shigella, and Yersinia infections as the most commonly reported triggering bacteria.

It is unclear whether the pathogenic mechanism is the same for each organism, but common features amongst them include an ability to invade mucosal surfaces, the presence of lipopolysaccharide (LPS) in their outer membrane, and an ability to invade host cells and survive intracellularly, particularly in macrophage endosomes.

Of infectious agents, Chlamydia trachomatis is the most reported triggering pathogen and the bacterium has been recovered from the urethra of up to 70% of men with reactive arthritis and concurrent urethritis. Chlamydia trachomatis, Salmonella of various serotypes, Campylobacter of various serotypes (but especially jejuni), Shigella flexneri (and less so dysenteriae and sonnei), and Yersinia enterocolitica (and less so pseudotuberculosis) are the most well documented triggering pathogens.

Clostridium difficile has also been reported as a potential triggering pathogen, and other less validated and disputed bacteria include Mycoplasma genitalium, Ureaplasma urealyticum, Chlamydia pneumoniae, Β-hemolytic streptococci and Neisseria gonorrhea, but this arthritis is generally not consistent with spondyloarthritis or considered a reactive arthritis.

An abnormal immune response to antigenic triggers has been proposed as sensitized antigen presenting cells and T lymphocytes, (mostly CD4+ but also CD8+), have been found in the synovium and synovial fluid of patients with reactive arthritis.

Antibodies to chlamydial heat-shock proteins have been shown to cross-react with human heat-shock proteins, supporting this theory of dysregulation.

Whether a bacterium can induce reactive arthritis may also depend on the presence of particular plasmids, demonstrated in Salmonella and Shigella infections. Bacterial antigens and DNA for Chlamydia, Yersinia, and Salmonella have also been isolated from synovium and synovial fluid in patients with reactive arthritis, suggesting that viable organisms may spread directly from genital to joint tissue, perhaps in macrophages.

This idea has not been proven definitively, and the infectious and arthritic picture of reactive arthritis is usually distinct from that of septic arthritis, where overt organisms are more easily detectable in the joint.

The relationship between the HLA-B27 molecule and the development of reactive arthritis is complex and has not been fully established. B27 homodimers are seen on cell surfaces of patients with spondyloarthritis where they are involved in antigenic binding and presentation to T lymphocytes or natural killer cells, particularly when the ordinary antigen presenting functions of the cell are impaired.

While a specific arthritogenic peptide has not been identified, it has been proposed that HLA-B27 binds unique bacterial or self-derived antigenic peptides that may be found only in joints, and in turn, alternative recognition of different B27 forms by leukocyte receptors then leads to spondyloarthritis development.

This theory is supported by evidence of B27-restricted peptides and T cells with a unique, conserved antigen receptor sequence isolated from the synovium of patients with post-chlamydial reactive arthritis, as well as molecular mimicry between bacterial antigens and B27 peptides. Additionally, compared to other HLA molecules, B27 has an increased tendency to misfold due to the location of disulfide bonds, and the misfolded protein could potentially induce a proinflammatory immune response

Furthermore, compared to controls, in vitro HLA-B27 positive monocytes kill Salmonella less efficiently and show increased production of proinflammatory cytokines IL-10 and TNF-alpha. This effect on the local cytokine milieu may also be important in the pathogenesis of reactive arthritis and is supported by the success of biologic therapeutics that specifically inhibit these cytokines.

Systemic Implications and Complications

Systemic manifestations such as malaise, fatigue, low-grade fever, and chills are common, with high temperature and marked acute phase response resembling sepsis a rare occurrence. Reiter’s classic triad of commonly seen findings, urethritis, conjunctivitis, and arthritis are usually mild and self-limiting, but rarely may progress to prostatitis, cervicitis, salpingitis and pelvic inflammatory disease, iritis, glaucoma, keratitis and severe anterior uveitis and chronic, potentially disabling arthritis.

When present, abdominal pain and diarrhea are usually mild. Symptomatic aortic insufficiency is seen in 1% of patients with reactive arthritis, and prompt cardiovascular evaluation is necessary in any patient with suspected heart disease. Anecdotal reports have also mentioned amyloidosis, peripheral neuropathy, pulmonary parenchymal disease, IgA nephropathy, and glomerulonephrosis as potential complications of the reactive process, but these have not been well-validated.

Treatment Options

As wide variability exists in the presentation, the treating clinician’s specialty, and the affected populations, there is no definitive treatment strategy for reactive arthritis.

Treatment depends on presenting symptoms, and the discussion centers on the central arthritic component. The goal remains primarily to prevent complications and reduce morbidity, especially considering that the natural course of the disease for many patients is spontaneous remission (Table I.).