Reactive arthritis (ReA) is a joint inflammation developing soon after or during an infection elsewhere in the body, but the organism cannot be isolated or cultured from the joint. Recently, non-infectious components of the infective organism have been demonstrated in the synovium and synovial fluid. It is often termed Reiter's disease after Hans Reiter who described a triad of oligoarthritis, urethritis, and conjunctivitis in a young officer and discussed this as 'treponema arthritides'. However, the first description of the disease is attributed to Benjamin Brodie in 1818. The term reactive arthritis was first proposed by Ahvonen et al and since that time, it has been in common use.

ReA consists of an asymmetrical, predominantly lower limb oligoarthritis often associated with urethritis, conjunctivitis, and sometimes with other articular and extraarticular features. It characteristically follows an infection, usually of the gastrointestinal or genitourinary tract. In 65 percent-85 percent of patients, ReA is associated with the class I major histocompatibility antigen HLA-B. The connection between ReA and antecedent infection has long been recognized, yet the mechanism by which such distant infections trigger arthritis remains unclear. In about 25 percent patients no primary precipitating agent can be recognized. The severity of infection does not necessarily correlate with the subsequent course of arthritis.

Epidemiology
The true incidence of reactive arthritis is difficult to assess due to the wide variation in clinical severity. Increasing awareness of the disease will possibly help better recognition of the spectrum of illness all over the world. According to a Finnish estimate, the incidence of enteroarthritis or uroarthritis per 100,000 adults per year is 30 and that of seronegative arthritis is 40 per 100,0004. Rheumatic fever, also a type of reactive arthritis, often occurs in developing countries but is rare in developed countries.

Reactive arthritis affects males and females with same frequency. However, it was previously claimed to be more common in males. Most patients are aged between 20 to 40 years.In classical Reiter's disease young males are commonly affected (15:1).

Aetiology
Genetic factors play a role in susceptibility to the disease and 65-80 percent of patients a HLA-B is positive in 80 to 90 percent of patients with shigella, 70 to 80 percent with yersinia, 40 to 50 percent with chlamydia, and 20 to 33 percent with salmonella infections. However, the relationship is not absolute and even HLA-B negative patients can develop reactive arthritis6. There is a possibility that the disease is more severe and the tendency to chronic development is greater in HLA-B27positive individuals7. Family clustering has also been observed in HLA-B27 positive individuals.

Many infections may be implicated in the etiopathogenesis of reactive arthritis. Acute enteric infections caused by Salmonella, Shigella, Yersinia, Campylobacter, or Borrelia are often followed by development of this complication. These members of Enterobacteriaceae family are known to share several common antigenic determinants8,8a,9. Interestingly, Chlamydia, frequently found as an etiologic agent for reactive arthritis and Reiter's disease, have similarities in the lipopolysaccharide. The O-polysaccharide of bacterial lipopolysaccharide is often present in inflamed joints of patients of reactive arthritis. No specific arthritogenic antigens however, have so far been found, except the recently described 2-megadalton plasmid in the Shigella flexneri strains10. It is important to remember that Salmonella, Borrelia, and Neisseria can cause true septic arthritis as well as reactive arthritis. Chlamydia trachomatis, besides the microplasma species, presently is recognized as an important triggering agent of post-venereal Reiter's disease as suggested by the observations on electron microscopy of chlamydial inclusions in synovium or synovial fluid, by the demonstration of chlamydial antigens in affected joints by immunohistology and/or immuno electron microscopy and by the recent demonstration of chlamydial RNA in the synovium11.Certain viruses like rubella, hepatitis, and parvovirus may result in reactive arthritis. Besides these infections as triggering agents, reactive arthritis may follow inflammatory bowel disease like Crohn's disease, ulcerative colitis, and ileal bypass operation for morbid obesity12. Reactive arthritis is also a recognized feature of HIV infection where CD4 + cells are depleted with relative predominance of CD8 + cells. Sometimes systemic tuberculosis in tropics can cause sterile synovitis, which is known as Poncet's syndrome.
Generally, reactive arthritis may be either HLA-B related (eg, Reiter's disease) or HLA-B unrelated (eg, Lyme arthritis, Brucellosis, Rheumatic fever, SAPHO syndrome, etc.).

Immunopathogenesis
Microbe - host interaction:
The joint inflammation in reactive arthritis develops sometime after the triggering infections and the causative agents cannot be isolated from the site of inflammation. Microbial components have been identified from the synovium/fluid by immunofluorescence, immune electron microscopy, immunoblotting, and PCR techniques. The following bacterial products have been found in synovial fluid/biopsy:

Chlamydia - DNA, RNA, Antigen
Yersinia - Antigen
Salmonella - DNA, Antigen

The causative infections of reactive arthritis invade the mucosa and replicate in nonprofessional phagocytes. Then they pass through the intestinal epithelial layer due to increased permeability and enter the reticuloendothelial system to activate the immune system. Interesting findings in HLA-B positive subjects include enhanced neutrophilic chemotactic response and poor elimination of arthritis causing microorganisms.

A. Role of immune system:
Though the initiating microbe-host interaction is somewhat uniform, the immune response is variable in different subjects. The humoral immune response is characterized by microbe-specific IgA response following continuous antigenic stimulation in the intestinal mucosa in yersinia or shigella infections. In salmonella-triggered reactive arthritis, antibodies of all three immunoglobulin classes persist for long periods of time, suggesting that salmonella may hide in the mucosa as well as in other sites in the patients. The picture of cell-mediated immune response in patients developing reactive arthritis is not so clear. However, the T-cell response against yersinia antigens is weak in peripheral lymphocytes. At the synovial level, a strong but relatively nonspecific T-cell response is seen. It seems that T-cells with slightly different specificities can be cloned from the synovial fluid, indicating that local stimulation may play a role. Yersinia infection always causes formation of immune complexes in blood and synovial fluid.

B. Currently it seems that reactive arthritis involves persistence of the triggering microorganisms in the host and the spread of its components either as parts of immune complexes or within phagocytosing cells into the joints where they finally activate the inflammatory cascade.

C. Immunogenetics:
Reactive arthritis develops in HLA-B positive subjects based on following hypothesis.

• Arthritogenic peptide hypothesis: This is mediated by activation of cytotoxic CD8+cells by self peptide derived from articular tissue, which is bound to HLA
• Molecular mimicry hypothesis: It develops as a result of sharing of antigenic epitopes between the host tissue and certain arthritogenic microorganisms. Amino acid sequence of HLA-B has sequence homology to yad A protein of yersinia and other membrane protein (OmpH) of Salmonella.

Clinical features
The most important symptom for which a patient seeks medical advice is joint discomfort or pain. History of enteric (enteroarthritis) or urogenital infection (uroarthritis) in the preceding few days may be commonly obtained. However, often the triggering infection may be mild and in about 10 percent of cases the infection may pass unnoticed, especially in women. Reactive arthritis is a systemic disease with variable severity. General symptoms like fatigue, fever, and malaise are commonly seen. However, reactive arthritis combines four syndromes:

• peripheral arthritis syndrome
• enthesopathic syndrome
• pelviaxial syndrome
• extramuscular skeletal syndrome

A. Joint and musculoskeletal features
The most prominent symptoms are usually those in joints and they vary from mild arthralgias to severe disabling polyarthritis. Typically, there is asymmetric monoarthritis or oligoarthritis and most commonly weight bearing joints like knees, ankles, and hips are affected. However, elbows, wrists, and shoulders may also be sparingly involved. There may be fleeting arthritis. Reactive arthritis may also affect small joints of hands and feet and dactylitis is not uncommon. Sausage shaped digits may be present. There might be heel pain or enthesitis. In the later stages patients often complain of sacroiliac joint pain. It is very difficult some times to clinically distinguish between reactive arthritis, gout, and septic arthritis.

Reactive arthritis is not limited to the joints; various tendinitides, tenosynovitis, and peritendinitides are present in most cases. Enthesopathy leading to plantar fasciitis and tenosynovitis of the ankle can result in difficulty in walking, and ultimately may lead to severe disability. However, the ultimate outcome is not related to the severity of disease in the initial phase. Highly distinctive features are inflammatory dorsal or low back or buttock pain as observed in 50 percent patients. Intestinal and genitourinary symptoms are not only diagnostic but also of pathophysiological and therapeutic importance.

B. Muco-cutaneous features
The typical skin lesion is keratoderma blennorrhagicum or pustulosis palmoplantaris which is clinically and histologically similar to psoriasis. Circinate balanitis is classically seen as painless, erythematous lesion of glans penis. Cystitis, prostatitis, and mouth lesions like painless shiny patches on tongue and/or palate are also observed. Erythema nodosum is not associated with HLA-B related reactive arthritis.

C. Ocular lesions
Various ocular inflammations (unilateral or bilateral) form a classical part of the clinical picture. Sterile conjunctivitis, iritis, and occasionally episcleritis, keratitis, or even corneal ulceration may occur. Patients with reactive arthritis most commonly complain of redness, photophobia, and pain in the eyes.

D. Miscellaneous
Carditis in common in rheumatic fever with sequelae of valvular disease but is uncommon in other reactive arthritis. In early phase of carditis, prolonged PR interval, and in late phase aortic insufficiency are characteristic. Mild to moderate proteinuria, microhematuria, and aseptic pyuria are seen in about 50 percent patients of reactive arthritis.

Laboratory investigations
Erythrocyte sedimentation rate is markedly elevated in most cases and values above 60-mm/1st hour are commonly seen as a biological marker of inflammation. C3, C4, and C-reactive protein (CRP) are elevated at the onset of the disease. Later ESR and CRP may become normal in the chronic stage of the disease. There may be mild leukocytosis and anemia in the early phase. However, rheumatoid factor is consistently negative.
Urinalysis is necessary to detect aseptic pyuria due to urethritis.

Joint fluid should be aspirated, whenever possible. Gram staining and bacterial culture should be performed to differentiate from septic arthritis. Observations of microbial components in the synovial membrane or in the synovial fluid may be obtained utilizing special techniques not suitable for routine clinical work, e.g., immuno-electronmicroscopy, immunoblotting, and polymerase chain reaction24. A recent study has demonstrated that in an early stage of reactive arthritis the cell count in synovial fluid can be quite high and polymorphonuclear leukocytes (more than 2,000 cells/cmm) may dominate the picture but later lymphocytosis may develop. Microscopy under polarized light should be performed to exclude gout or pseudogout. Radiology of peripheral joints may show fluffy periosteal new bone formation, linear periosteitis, exuberant periosteal spurs, calcification, and ossification of tendons. Seventy percent of patients show sacroiliitis (usually unilateral). Non-marginal, asymmetric, comma shaped syndesmophytes are seen over lower thoracic and upper lumbar vertebrae.

Efforts should be made to isolate the causative organism from the throat, faeces, or urogenital tract by microbiologic and serologic studies, but they are often noncontributory. Radiographic studies on symptomatic joints help in ruling out a differential diagnosis in the acute phase. In recurrent and chronic cases there may be erosions. Often periosteal reaction and proliferation, especially at insertion sites of tendons leading to spurs are seen in chronic cases with heel pain. Chronic or recurring reactive arthritis often leads to sacroiliitis indistinguishable from ankylosing spondylitis. Radionuclide scintigraphy is a sensitive method to demonstrate inflammation and it is even better than radiography. Enthesopathic lesions can be visualized at an early stage by focal uptake of 99Tcm - methylene diphosphonate.

Detection of HLA-B is helpful for screening of families and also in cases of diagnostic difficulties.

Management
There is no cure for reactive arthritis, but symptomatic treatment will reduce discomfort. In the acute phase, NSAIDs form the basis of therapy and should be used judiciously to achieve maximum anti-inflammatory effect. Since patients' responses differ, there is no definite drug of choice.
Physical therapy using cold may alleviate the pain and edema of an inflamed joint. Rest and splinting also help to alleviate nocturnal pain. Corticosteroids are a valuable asset in the treatment of reactive arthritis. In many cases, intra-articular administration gives prompt relief, after strictly excluding purulent arthritis. This may be particularly effective in plantar fasciitis or tendinitis. Topical steroids and keratolytic agents are used for keratoderma blennorrhagicum. Weak topical steroids like hydrocortisone valerate are useful for circinate balanitis. Systemic treatment with corticosteroids has also been proved to be effective but should not be used for more than 2 to 4 months. The initial dose may be 1 mg/kg body weight.

Antibiotic treatment should be given if microbe is identified but this does not alter the course of reactive arthritis24a. Ciprofloxacin, trimethoprim-sulfamethoxazole, and tetracycline have been tried in the early phase of illness only to diminish the spread of infection25. Recently, lymecycline administered for 3 months is found to be effective in chlamydia-triggered disease.

Patients with chronic or recurrent reactive arthritis pose difficult therapeutic problems, because with time, the patients often derive less and less benefit from NSAIDs. In chronic cases, corticosteroids are not advisable, as their therapeutic effect is not well defined and prognosis is good in most cases.

Sulfasalazine is of interest and in most instances may give good results. The drug should be started in low dose and increased to 2g or 3g as tolerated by the patient. The common side effects like skin rash, gastrointestinal upsets and abnormal liver enzymes need to be monitored. Parenteral gold has also been used with some success. Long-term studies on methotrexate and azathioprine are under investigation. The possibility of microbial persistence has opened up the question of whether long-term antibiotic treatment should be used in chronic reactive arthritis27. For rheumatic fever, long-term penicillin prophylaxis is recommended to prevent relapse. In Reiter's disease, oral methotrexate in the dose of 7.5 mg to 12.5 mg per week under supervision has been found to be a useful disease-modifying agent. In some resistant cases this may be combined with sulfasalazine 1.5 to 2 gm per day to induce remission.

Ocular inflammation must be diagnosed and treated promptly to avoid irreversible damage and morbidity. Therapy consists of local or systemic corticosteroids and mydriatics.

The skin lesions are usually treated with keratinolytic agents such as salicylic acid ointment or topical corticosteroid as in the treatment of psoriasis. In more severe cases, the patient may require retinoids or systemic methotrexate.

Prognosis
The prognosis of reactive arthritis is generally good with disease duration varying from few days to several weeks. Even patients who are severely disabled and incapacitated in acute stage of the disease may look forward towards full recovery. However, recurrences are common and can be triggered by infections and nonspecific stress factors. Urogenital and ocular inflammations particularly have a tendency to recur. Many patients complain of abdominal pain and diarrhea for months and even years after the initial attack. Residual back pain and arthralgia are common. Risk factors for severity are HLA-B positivity, frequent recurrences and chronic heel involvement.

Follow up studies of reactive arthritis suggest that 20-70 percent of patients later suffer from some joint discomfort or other symptoms. However, in spite of discomfort severe destructive disease as a sequelae of reactive arthritis is extremely rare. About two thirds of patients have persistent mild symptoms in peripheral joints, low backache, or enthesopathy and 15-30 percent of the patients develop chronic peripheral or axial arthritis.

Conclusion
The decline in the incidence of acute rheumatic fever has led to HLA-B related arthritis either post dysenteric or post-venereal variety dominating the clinical scenario of reactive arthritis. Inspite of the variety of triggering infections, the clinical picture of the disease shows considerable uniformity suggesting common pathogenetic pathways. Host microbial interaction in a genetically susceptible individual induces humoral and cellular immune responses to result in aseptic asymmetrical oligoarthritis. The current understanding of immunogenetics may give insight to plan strategy of ideal therapy for remission, but till that time we can offer only palliative therapy to these group of patients.