bubble_chart Overview

Reiter's syndrome is characterized by sterile urethritis, conjunctivitis, and polyarthritis, and may be accompanied by skin and mucous membrane lesions as well as other organ involvement. It is often preceded by fever and is more common in adult males.

bubble_chart Epidemiology

Since the disease cause of this syndrome is unclear, and its name and diagnostic criteria are not standardized, there has been a lack of systematic research on its prevalence and incidence. A few studies suggest that Reiter's syndrome is not a rare wind-dampness disease. Among inflammatory joint diseases in young men, it is the most common cause. It has been reported ^[2] that approximately 1% of nonspecific urethritis patients develop Reiter's syndrome; another report indicates that about 3% of nonspecific urethritis cases lead to reactive arthritis. Noer observed that among 420 patients with Shigella infection, 9 developed Reiter's syndrome, with an incidence rate of 1.5% ^[3]. For HLA-B₂₇-positive individuals with nonspecific urethritis, the incidence is even higher, reaching about 20%.

This syndrome has been more frequently reported in Europe and America. A 10-year survey of U.S. Navy medical personnel found an incidence rate of approximately 4 per 100,000 annually. During World War II, a dysentery epidemic on the Finnish front affected an estimated 150,000 patients, among whom 344 developed reactive arthritis, an incidence rate of 0.23%. In 1980, Kosune reported ^[8] 8 cases of reactive arthritis associated with Campylobacter enteritis: 3 had positive stool cultures, 5 showed reduced antibody titers, and 7 were tested for the histocompatibility antigen HLA-B₂₇

, with 5 testing positive. The incidence of reactive arthritis following Campylobacter enteritis was 2.35%. Since the first domestic case was reported in 1956, over 10 sporadic cases have been documented, though the actual number is likely much higher. Particularly, HLA-B₂₇-positive individuals are more susceptible, suggesting that the syndrome's geographic distribution may be very wide. As diagnosing Reiter's syndrome in women is more challenging, the commonly cited male-to-female incidence ratio is 20:1. However, in a study by FOX^[4] involving 131 cases, women accounted for 15%. Males predominate in Reiter's syndrome following sexually transmitted disease, possibly due to the higher incidence of nonspecific urethritis in men. The syndrome can occur at any age but is most common in individuals aged 20–30. Diagnosing Reiter's syndrome in children is difficult unless a dysentery epidemic affects multiple family members. There are also reports of individuals over 50 developing Reiter's syndrome after sexually transmitted disease or local epidemics ^[2]. Among the over 10 cases reported domestically, the youngest was 17 years old, and the oldest was 38.

bubble_chart Etiology

The disease cause and mechanism of disease of Reiter's syndrome remain unclear to this day, and can currently be roughly summarized into the following hypotheses^{[1, 12, 14, 16, 18]}.

1. Infection Theory Since Reiter first isolated spirochetes from the blood of reported cases, he suspected at the time that this syndrome was an infectious disease caused by spirochetes. Most sufferers of this syndrome are young males, often presenting with symptoms of urethral infection and a history of unclean sexual intercourse or promiscuity, leading later suspicions that the syndrome might be related to gonorrhea or the fourth venereal disease. As mentioned earlier, this syndrome may be secondary to non-bacterial urethritis or dysentery caused by various pathogens. Chlamydia has been isolated from the synovial fluid of several cases with urethritis^[1]

. Some cases transmitted through sexual contact have yielded pathogens such as Bedsonia, Mycoplasma, and Chlamydia from urethral secretions^[14]. Among patients associated with diarrhea, some cases have cultured Shigella flexneri, Salmonella, Yersinia, and Campylobacter from stool samples. Additionally, the incidence of this syndrome is higher during dysentery outbreaks^[1], but it is unrelated to Shigella sonnei, suggesting that reactive arthritis is associated with certain components of specific microorganisms. Currently, it is known that, apart from sexually transmitted diseases, pathogens such as dysentery bacilli, Mycoplasma pneumoniae, Chlamydia, Bedsonia, and even viruses are related to this syndrome, with Shigella flexneri infection showing a particularly close association^{[12, 18]}. However, to date, there is no substantial evidence proving a direct relationship between the syndrome and infection, as not all individuals with related infections develop this syndrome.

2. Genetic and Immunological Theory Patients with this syndrome exhibit increased erythrocyte sedimentation rate, positive C-reactive protein, elevated IgG, IgA, and α₂ globulin levels. Additionally, sterile synovitis can occur after non-bacterial urethritis or enteritis, suggesting that immune factors play a role in the mechanism of disease. However, it has not been confirmed that this syndrome involves widespread humoral or cellular immune abnormalities, as seen in systemic lupus erythematosus. The arthritis in this syndrome may not be mediated by antibodies or T-cell responses. Recently, Chlamydia has been detected in the synovial fluid of some patients, possibly indicating that certain bacterial components hidden within the joints trigger inflammation^[5]

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Early reports on the non-gonococcal nature of the disease showed that the histocompatibility antigen HLA-B₂₇ was significantly elevated in patients with urethritis and reactive arthritis following infections with Shigella, Salmonella, Yersinia, and Campylobacter^[1]. Other reports indicated that individuals with HLA-B₂₇ not only had a higher susceptibility to this condition but also exhibited increased incidence rates of ankylosing spondylitis, acute iritis, and juvenile rheumatoid arthritis^[12], suggesting an association between the occurrence of this disease and HLA-B₂₇. However, some HLA-B₂₇ positive individuals were prone to developing ankylosing spondylitis, while others were more susceptible to Reiter's syndrome. This may be related to the different subtypes of HLA-B₂₇. Studies using monoclonal antibodies and two-dimensional polyacrylamide gel electrophoresis revealed that HLA-B₂₇ consists of at least two subgroups. In HLA-B₂₇ negative patients with Reiter's syndrome, another cross-reactive antigen such as HLA-B₂₇ might be involved, or the arthritis-causing bacteria in this condition may carry components that mimic HLA-B₂₇ antigens, leading to recognition and disease onset^[6].

bubble_chart Pathological Changes

In the early stage of the disease, the histological changes of the synovial membrane resemble those of grade I suppurative infection^[7], with localized inflammatory reactions in the superficial and vascular areas, characterized by marked congestion, edema, and infiltration of neutrophils and lymphocytes. Lesions persisting for more than two weeks may show plasma cell proliferation and hyperplasia of various connective tissue cells, occasionally accompanied by necrosis of synovial membrane cells; most cases exhibit local erythrocyte extravasation.

The pathological features of chronic arthritis lasting several months include villous synovial membrane hyperplasia, vascular nebula formation, and erosion of articular cartilage and bone^[7]. Microscopic examination reveals nonspecific inflammatory reactions with focal infiltration of lymphocytes and plasma cells; some cases may present lymphoproliferative lesions resembling rheumatoid arthritis. The characteristics of skin lesions involve hyperplasia of the stratum corneum, resembling keratosis and acanthosis^[7], with blisters in the epidermis filled with epithelial cells, polymorphonuclear neutrophils, and lymphocytes, often accompanied by microabscess-like changes. The outer dermis shows infiltration of lymphocytes and plasma cells. The pathological changes in mucous membranes are similar to those of skin lesions but lack manifestations of keratosis.

bubble_chart Clinical Manifestations

Reiter's syndrome predominantly occurs in adult males, with rare cases in females. It is often associated with a history of unclean sexual intercourse, promiscuity, or previous urethritis or diarrhea. The syndrome is characterized by the classic triad of urethritis, arthritis, and conjunctivitis. When all three symptoms are present, it is termed the complete type; if only arthritis or arthritis combined with one of the other two symptoms occurs, it is called the incomplete type. This syndrome is a systemic disease, with most patients experiencing fever and weight loss. Some may develop skin and mucous membrane lesions, while a few exhibit extensive involvement, often accompanied by lymphadenopathy and splenomegaly. It can also affect the gastrointestinal tract, cardiovascular system, lungs, and nervous system^{[1, 12, 14]}.

1. Joints Joint involvement is typically the second or third manifestation of the syndrome, usually appearing 2–4 weeks after urethritis, diarrhea, or conjunctivitis, or concurrently with these symptoms. It commonly affects weight-bearing large joints such as the knees, ankles, and wrists, but small joints of the fingers and toes may also be involved. The arthritis is polyarticular and asymmetric, varying in severity, often accompanied by significant redness, swelling, heat, and pain. In some cases, joint inflammation may persist for weeks or longer. During the acute phase, a few patients may experience back pain, sacroiliac joint tenderness, or spinal tenderness. Spinal involvement often follows a "skip pattern," moving from one segment to another. Prolonged or recurrent acute arthritis may progress to chronic arthritis. One reported case with a 20-year disease course^[20] showed significant knee and surgical joint deformities, along with atrophy of the thenar and hypothenar muscles. Inflammation at tendon insertion sites, known as enthesopathy, may be a prominent feature of Reiter's syndrome. In plantar fasciitis, marked tenderness of the Achilles tendon is observed, with X-rays revealing fluffy calcification at the calcaneal attachment of the plantar fascia. Due to periostitis, scattered linear swelling may occur. Enthesopathy can also develop at the lower end of the tibia or at the insertion sites of the tibial and plantar tendons.

2. Genitourinary System Most cases involve male urethritis, presenting with dysuria, difficulty urinating, and mucopurulent urethral discharge. A few patients may exhibit erythema and edema at the urethral orifice, though urethritis can sometimes be asymptomatic. In cases related to unclean sexual intercourse, urethritis typically develops within a few days to about a month after exposure. Besides urethritis, prostatitis is a common complication, with the prostate often enlarged, soft, and tender; prostatic secretions may contain numerous pus cells, and occasionally, prostatic abscesses may form. In females, urethritis, cervicitis, or cystitis may occur, usually with mild symptoms such as dysuria or slight vaginal discharge.

3. Ocular Manifestations Conjunctivitis is usually the initial ocular symptom, generally mild and accompanied by a slight burning sensation, with morning eyelid adhesion. Most cases are bilateral. About 5–10% of first-time sufferers may develop iritis, while 20–50% of those with disease progression or recurrence experience iritis. A few cases may present with uveitis, episcleritis, or corneal ulcers. Rare reports include optic neuritis, retinitis, and macular retinal edema. Approximately 3% of cases may result in permanent vision impairment^[5].

4. Skin and Mucous Membranes Superficial ulcers on the penis, particularly around the urethral meatus, are most common. Lesions on the glans penis may coalesce to form annular or circinate balanitis with a serpiginous border. Painless, shallow ulcers with an erythematous base may appear on the buccal and lingual mucosa, ranging from a few millimeters to over 1 cm in diameter. These ulcers often go unnoticed, though oral ulcers due to Campylobacter infection may be painful.

Skin lesions most commonly occur on the palms and soles, but can also appear on any part of the limbs, trunk, or scalp. The skin disease initially manifests as small papules, which quickly develop into pustular blisters. However, when these ulcers rupture, they contain only keratinized material. A single blister is typically a few millimeters in diameter, and when multiple blisters appear, they may cluster together and cover a larger area with a thick layer of keratinized crust. Eventually, the skin scabs over and sheds without leaving scars. Skin keratinization can also occur on the fingers and toes, potentially leading to the loss of nails. The aforementioned skin disease is known as keratoderma blennorrhagicum, which often appears several weeks after the onset of other symptoms of Reiter's syndrome and usually resolves spontaneously after a few weeks. A domestic case report described a chronic patient who developed atrophic scars after the scabs fell off^[20], while connective tissue nevi with mild itching appeared on the skin of the chest and back on the other side^[19].

Female Reiter's syndrome is rare, and vulvar skin and mucous membrane rashes are even rarer. Edwards (1992) reported ^[11]one case of a female patient who initially presented with redness, tenderness, and onycholysis of the fingertips, along with vaginal discharge, mucous membrane lesions, and axillary pustules, with a positive Candida albicans culture. Four years later, she developed vaginal discharge accompanied by painless oral ulcers, followed by the appearance of red, crusted patches on the vulva and perineum. After treatment with MTX, the skin lesions gradually subsided, but the rash recurred upon dose reduction. Pink, scaly papules, 1–2 mm in diameter with well-defined borders, appeared on the vulvar skin, and scattered white circular and annular papules, 2–4 mm in diameter with clear edges, were also observed on the labia minora and vestibule. Scattered, well-demarcated, erosive-topped papules were visible throughout the external genitalia. Skin and labia minora biopsies were consistent with Reiter's syndrome.

bubble_chart Auxiliary Examination

1. Peripheral blood leukocyte count is often elevated, generally (10–18)×10⁹/L (10,000–18,000/mm³), and may exceed 20×10⁹/L (20,000/mm³) in some cases; a few patients may not show an increase in leukocyte count. Anemia may occur in cases with a prolonged course; most patients exhibit an elevated erythrocyte sedimentation rate.

2. Urethral secretions contain a large number of leukocytes, mostly polymorphonuclear leukocytes, often presenting with pyuria; hematuria may also be observed.

3. Synovial fluid is turbid, and in some cases, markedly purulent. The leukocyte count is typically (2–5)×10⁹/L (2,000–5,000/mm³), occasionally reaching up to 10×10⁹/L. In the early stages, most cells are polymorphonuclear leukocytes, but as the inflammatory response subsides, the proportion decreases, shifting to a lymphocyte predominance. Synovial fluid glucose levels are normal, though they may decrease when leukocyte counts are exceptionally high. Synovial fluid complement levels are usually higher than in other exudates; protein content is elevated. The protein-complement binding ratio resembles that seen in degenerative joint disease, wind-dampness, and rheumatoid arthritis.

4. Gonococcal cultures of urethral and prostatic secretions are negative; no bacteria are detected in blood or synovial fluid; synovial membrane exudates are sterile or contain only non-pathogenic bacteria.

5. The leukocyte histocompatibility antigen HLA-B₂₇ is mostly positive.

bubble_chart Diagnosis

The diagnosis of typical cases is generally not difficult, but atypical or incomplete cases present certain diagnostic challenges. The key diagnostic points of this syndrome include: (1) The triad of urethritis, arthritis, and conjunctivitis occurring simultaneously or in quick succession. (2) Characteristic lesions of the skin and mucous membranes. (3) Fever, leukocytosis, elevated erythrocyte sedimentation rate, increased serum immunoglobulins, positive C-reactive protein, and positive human leukocyte antigen HLA-B₂₇. (4) Pathogen examination of urethral discharge, conjunctival secretions, synovial fluid, and stool. (5) Characteristic X-ray findings. (6) Exclusion of rheumatoid arthritis, ankylosing spondylitis, gonococcal arthritis, psoriatic arthritis, enteropathic arthritis, and Behçet's syndrome.

bubble_chart Treatment Measures

There is no specific treatment for Reiter's syndrome, and the general treatment principles are as follows:

1. Supportive therapy During the acute phase, ensure bed rest, limit weight-bearing, and maintain hygiene. Provide easily digestible, high-calorie meals and supplement with vitamins.

2. Symptomatic treatment Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first choice during the acute phase or for arthritis. Examples include: - Aspirin 0.3–0.6g, 3 times daily - Indomethacin 25–50mg, 3 times daily - Piroxicam 20mg, once daily - Ibuprofen 0.2g, 3 times daily Additionally, physiotherapy such as ultrashort wave, infrared, wax therapy, mud therapy, and tuina may be beneficial. For urethritis, apply a hot compress to the lower abdomen or alkalize the urine. Conjunctivitis can be treated with medicated rinses and common eye drops. Severe eye disease may require corticosteroid eye drops. Keratoderma blennorrhagicum can be managed with keratolytics and low-dose corticosteroids, such as topical 1% hydrocortisone.

3. Antibiotics to eliminate pathogens Antibiotics may be used in the initial stage of the disease, but the dose should not be excessive. This may benefit urethritis but has little effect on arthritis or the disease course.

4. Corticosteroids For persistent monoarthritis, metatarsal fasciitis, or Achilles tendonitis, local injection of methylprednisolone 40–80mg/day may be effective. Systemic corticosteroids were once thought beneficial, but it is now established that systemic use, regardless of dose, does not provide long-term benefits for arthritis.

5. Other immunosuppressants For severe cases unresponsive to NSAIDs, azathioprine, cyclophosphamide, methotrexate, or 6-mercaptopurine may be used. Azathioprine is commonly administered at 1–2mg/(kg·d), with effects seen in 4–8 weeks. Other drugs may be selected based on patient tolerance, and they may help refractory or prolonged cases, but these medications have significant side effects^[10] and require close monitoring. Recently, sulfasalazine has been found effective in treating Reiter's syndrome and may be considered.

bubble_chart Prognosis

In some patients, the condition resolves within approximately 3 to 4 months, but in some cases, the reactive episode can progress to a chronic sexually transmitted disease course, with reports of durations as long as 20 years ^[20]. Most cases may relapse ^[9]. Follow-up observations over 5 years show that about 20% of patients recover completely after the acute phase without any symptoms, 20–30% retain mild symptoms that affect their work, 40–60% develop chronic or recurrent arthritis, and 15–25% of patients ultimately have to change or cease work due to disability. The hallmark of this syndrome is the recurrence of single or multiple symptoms, with arthritis being the most common, followed by ocular and skin lesions.

During the second or third episode, the condition often manifests as chronic arthritis. Persistent periarticular inflammation can lead to joint deformity, flexion contractures, and extensive bone erosion, sometimes resulting in significant bone destruction, particularly in the small joints of the hands and feet. Bony ankylosis is rare. One report with a follow-up of 14.5 years noted that 8 out of 26 cases developed spondylitis. Chronic back pain and progressive spinal stiffness are common. Radiographic findings may include ligamentous ossification, widespread bony ankylosis, and vertebral calcification, with dense spinal bridging observed in about 25% of cases. Sacroiliitis also occurs in some patients.

bubble_chart Differentiation

1. Rheumatoid arthritis The arthritis manifestations and even X-ray findings are similar to those of this syndrome, so Cecil once classified Reiter's syndrome as a clinical variant of rheumatoid arthritis. However, general wind-dampness arthritis does not simultaneously present with urethritis, conjunctivitis, and skin mucosal lesions.

2. Ankylosing spondylitis Chronic spinal lesions in this syndrome must be differentiated from ankylosing spondylitis. There is little difference in ocular symptoms and X-ray findings between the two, but if there is a history of periarthritis accompanied by urethritis, especially with the manifestation of keratoderma blennorrhagicum, it supports the diagnosis of Reiter's syndrome.

3. Gonococcal arthritis Gonococcal arthritis is limited to the synovial membrane and does not invade the joints, so joint fluid cultures for gonococci are negative, but urethral purulent secretion cultures are positive. In contrast, this syndrome does not show the presence of gonococci. Although this syndrome presents with circinate balanitis, it differs from the balanitis and urethral orifice redness and swelling seen in gonorrhea. ^[13] The skin lesions of this syndrome, particularly keratoderma blennorrhagicum, are distinctive, whereas gonorrhea is characterized by pustular vasculitic skin disease. ^[1].

4. Pustular psoriasis Pustular psoriasis and the keratoderma blennorrhagicum of Reiter's syndrome are clinically and histologically very similar. If psoriasis involves the conjunctiva, it can be even more confusing. ^[1] However, psoriasis lacks a history of urethritis and dysentery.

5. Behçet's syndrome Reiter's syndrome presents with urethritis and arthritis, whereas Behçet's syndrome does not. The oral and genital lesions in this syndrome are erosions with crusting after blister rupture, whereas Behçet's disease presents with deeper ulcers. This syndrome rarely occurs in women, whereas the latter is more common in females. This syndrome is rare in China, whereas Behçet's disease is not uncommon. ^[13]