Reactive arthritis – Rheumatic fever, Reiter’s syndrome, Lyme disease

01Definition and overview

Reactive arthritis is an inflammatory arthritis that follows an infection at a distant site, usually the gut or the urogenital tract, in which the joint itself is sterile: no organism can be grown from it. It belongs to the spondyloarthritides, with ankylosing spondylitis, psoriatic arthritis and the arthritis of inflammatory bowel disease, with which it shares the link to HLA-B27, enthesitis, sacroiliitis and uveitis.

The syllabus groups three conditions in which an infection leads to arthritis. They differ in the organism, the genes, the joint and the treatment, and only the first is reactive arthritis in the strict sense.

Reiter's syndrome, and why the name is going

The triad of arthritis, urethritis and conjunctivitis was long called Reiter's syndrome. The eponym is being abandoned, for two reasons. Reiter was neither the first to describe it nor right about its cause, and he was a senior official of the Nazi regime.

1. 1818

   Brodie

   Benjamin Brodie, an English surgeon, describes men with urethritis, conjunctivitis and arthritis.

2. 1916

   Two reports in one year

   Hans Reiter, a German army doctor, describes an officer with diarrhoea followed by urethritis, conjunctivitis and arthritis, and blames a spirochaete. In the same year Noël Fiessinger and Edgar Leroy describe the same picture in French soldiers after dysentery.

3. 1933 to 1945

   Reiter in the Nazi state

   Reiter, a Nazi party member, heads the Reich Health Office, which supported forced sterilisation, and helps design typhus vaccine experiments on Buchenwald prisoners in which hundreds died. After the war he is held and questioned at Nuremberg as a prisoner of war until 1947, but never tried.

4. 1942

   The eponym

   Two American physicians, Walter Bauer and Ephraim Engleman, name the triad Reiter's syndrome, and the name spreads.

5. 2000 to 2007

   Dropping it

   Rheumatologists publish the case against honouring Reiter, journal editors move to reactive arthritis, and Engleman himself withdraws his support for the eponym.

The triad also misleads: only a minority of patients have all three parts, and those who do have no different disease. The old name still appears in older books and exam questions.

02Etiology and pathophysiology

Reactive arthritis

The triggers are intracellular or invasive bacteria of mucosal surfaces:

• enteric: Salmonella (non-typhoidal), Shigella (above all S. flexneri), Campylobacter jejuni, Yersinia enterocolitica and Y. pseudotuberculosis, and more rarely Clostridioides difficile;
• urogenital: Chlamydia trachomatis, the commonest trigger in young adults, and possibly Mycoplasma genitalium and Ureaplasma;
• others: Chlamydia pneumoniae from the airways, and intravesical BCG given for bladder cancer.

Only a minority of people infected in an outbreak of enteric infection develop arthritis, from about 1 to more than 10 per cent depending on the organism and how arthritis is counted, so the host decides. HLA-B27 raises the risk and, above all, the severity and chronicity. It is carried by only a minority of patients found in community outbreaks, but by most of those with severe or chronic disease seen in hospital.

1. 1

   Infection

   The organism invades the gut or urethral mucosa and is taken up by macrophages and dendritic cells.
2. 2

   Carried to the joint

   Bacterial antigens, and the DNA and RNA of chlamydiae persisting in a non-dividing form, reach the synovium inside cells. Nothing can be cultured from the joint.
3. 3

   An inappropriate response

   In a susceptible host, clearance is poor and the response skews towards IL-23 and IL-17. HLA-B27 may present bacterial peptides that resemble self, or misfold and stress the cell; how much each matters is still debated.
4. 4

   Synovitis and enthesitis

   The synovium and the entheses, where tendons and ligaments insert into bone, become inflamed; in chronic disease the entheses grow new bone.

After streptococci

Two arthritides follow group A streptococcal pharyngitis. Acute rheumatic fever is an autoimmune disease, by molecular mimicry between streptococcal and human proteins, and its arthritis is one of several manifestations. Post-streptococcal reactive arthritis is an arthritis alone, without the heart, brain or skin, and whether it is a separate disease or a form of rheumatic fever is still argued. Both are covered in rheumatic fever.

Lyme disease

Lyme borreliosis is a zoonosis caused by spirochaetes of the Borrelia burgdorferi sensu lato complex, kept in small mammals and birds and passed to humans by hard ticks: Ixodes ricinus in most of Europe, I. persulcatus further east, I. scapularis and I. pacificus in North America. Nymphs, the size of a poppy seed, bite unnoticed from spring to autumn. The risk of transmission is low in the first 24 hours of attachment and rises with time, especially after 36 to 48 hours, so prompt removal of a tick helps.

The species explain why European and American Lyme disease look different:

From the bite, the spirochaete multiplies in the skin and spreads outward, giving erythema migrans. It then disseminates through the blood to other skin, nerves, heart and joints, evading the host by changing its surface proteins and inhibiting complement. Much of the late damage is inflammatory. In antibiotic-refractory Lyme arthritis the synovitis continues after the spirochaetes have been killed, linked to certain HLA-DR alleles, to persisting bacterial cell wall fragments and to autoimmune responses in the synovium.

03Clinical features

Reactive arthritis

A young adult develops an asymmetric oligoarthritis, typically of the knees, ankles and toes, one to four weeks after diarrhoea or urethritis. The infection can have been mild or silent, especially chlamydial infection in women.

• Enthesitis: pain at the Achilles insertion and the plantar fascia, the heel being the classic site.
• Dactylitis: a whole toe or finger swollen like a sausage, from synovitis and tenosynovitis together.
• Inflammatory back pain from sacroiliitis, often one-sided, more often in HLA-B27 carriers.
• The eye: conjunctivitis, sterile and early, in up to half; acute anterior uveitis, a painful red eye with photophobia, which is less common but threatens sight.
• The urogenital tract: sterile urethritis or cervicitis, which can follow enteric infection too; prostatitis.
• The skin and mucosa: circinate balanitis, painless shallow ulcers with a raised, serpiginous edge on the glans (crusted plaques in the circumcised); keratoderma blennorrhagicum, scaly, pustular, then crusted plaques on the soles and palms that look and read under the microscope like pustular psoriasis; painless oral ulcers; nail dystrophy; erythema nodosum after Yersinia.
• Rarely the heart: conduction block, and aortitis with aortic regurgitation in long-standing disease.

Post-streptococcal arthritis

The arthritis of acute rheumatic fever flits between large joints and settles within a day or two of aspirin or an NSAID. Post-streptococcal reactive arthritis is persistent and additive, reaches small joints and the spine too, responds poorly to these drugs and lasts weeks to months.

Lyme disease

The illness passes through stages, which overlap, and many patients have only the first.

A red patch appearing within a day or two of the bite, and smaller than 5 cm, is usually a local reaction to the bite, not erythema migrans.

• Neuroborreliosis is the commonest disseminated form in Europe. In adults it is Bannwarth syndrome: burning radicular pain, worse at night, with lymphocytic meningitis and often a facial palsy, which can be bilateral. In children it is mostly facial palsy or meningitis. Encephalitis and myelitis are rare.
• Carditis brings atrioventricular block that changes from hour to hour and can become complete, causing syncope, sometimes with myopericarditis. It is uncommon, and rarer in Europe than in the United States.
• Lyme arthritis comes in attacks, weeks or months long, of a large and relatively painless effusion, most often of the knee, sometimes with a Baker's cyst. It is the commonest late feature in the United States and less common in Europe.
• Acrodermatitis chronica atrophicans, mostly from B. afzelii in older women, is a bluish-red discolouration of the extensor skin of a limb that thins over years to wrinkled, translucent skin, often with a neuropathy beneath it.

04Diagnosis and management

The approach to an arthritis after infection

1. 1

   Exclude sepsis and crystals

   Aspirate any hot swollen joint before antibiotics or steroids: cell count, Gram stain, culture and polarised microscopy. Reactive arthritis gives inflammatory fluid with no organisms and no crystals. Disseminated gonococcal infection, with tenosynovitis, pustules and polyarthralgia, is a septic illness that can look reactive.
2. 2

   Find the trigger

   Ask about diarrhoea, sexual contacts, sore throat, tick bites and travel. Test with a NAAT for Chlamydia and gonorrhoea (first-void urine or a vulvovaginal swab), stool culture if diarrhoea persists, ASO and anti-DNase B, and Lyme serology after possible exposure; offer HIV and syphilis tests after a sexual trigger.
3. 3

   Judge the inflammation

   ESR and CRP are raised. Rheumatoid factor and anti-CCP are negative. HLA-B27 helps with prognosis, not diagnosis.
4. 4

   Image

   X-rays are normal early; chronic disease shows periostitis, fluffy heel spurs and asymmetric sacroiliitis. MRI shows sacroiliitis and enthesitis earlier.

There are no validated diagnostic criteria: the diagnosis rests on the pattern, the timing and the exclusion of other causes.

Treating reactive arthritis

• A full dose of an NSAID, such as naproxen 500 mg twice daily, for the arthritis and enthesitis, with rest of the joint in the acute phase and physiotherapy afterwards.
• An intra-articular corticosteroid injection, once sepsis is excluded, and a short course of oral prednisolone for many joints.
• The skin: topical steroids for balanitis and keratoderma.
• The eye: urgent ophthalmology for uveitis, with steroid and mydriatic drops.
• The infection: active chlamydial infection is treated with doxycycline 100 mg twice daily for 7 days, and sexual partners are tested and treated. Uncomplicated enteric infections are not treated for the sake of the joints: antibiotics given after the arthritis has started do not change its course, and in Salmonella infection they can prolong carriage.
• Arthritis lasting more than about six months, or recurring: sulfasalazine or methotrexate, and in refractory disease, outside the licence, a TNF inhibitor after excluding persisting infection, tuberculosis and HIV.

Long courses of combined antibiotics, such as doxycycline or azithromycin with rifampicin for six months, helped chronic Chlamydia-induced arthritis in one small trial. This has not been confirmed and is not standard practice.

Treating arthritis after streptococci

Rheumatic fever is diagnosed by the Jones criteria and treated with penicillin, anti-inflammatory drugs and years of prophylaxis. Post-streptococcal reactive arthritis is treated with NSAIDs; because carditis has occasionally appeared later, patients are watched with echocardiography, and American guidance gives penicillin prophylaxis for up to a year, stopped if no carditis has appeared. In a moderate- or high-risk population, an arthritis after streptococci is treated as rheumatic fever. The details are in rheumatic fever.

Diagnosing Lyme disease

• Erythema migrans is diagnosed clinically and treated without testing; antibodies are often still absent at that stage.
• For other presentations, serology is done in two tiers: a sensitive enzyme immunoassay first, and if it is positive or equivocal, an immunoblot to confirm. A newer American approach uses two different immunoassays in sequence. A negative first test early in the illness is repeated after 4 to 6 weeks if the suspicion remains.
• IgM alone is meaningful only in the first weeks of illness; an isolated IgM after that is likely a false positive. Patients with Lyme arthritis almost always have high IgG titres.
• Antibodies persist for years after cure, so serology cannot test for cure and a positive IgG may mean only a past infection. Testing people without symptoms after a tick bite is not useful.
• Neuroborreliosis: lumbar puncture shows a lymphocytic CSF with raised protein, and antibodies made inside the nervous system (a raised CSF to serum antibody index) confirm it.
• Lyme arthritis: synovial fluid is inflammatory, and PCR for Borrelia DNA is positive in most untreated cases.
• Carditis: an ECG for every patient with disseminated disease, chest symptoms or syncope.

Treating Lyme disease

UK guidance treats adults and young people with these regimens:

American guidance uses shorter courses: 10 days of doxycycline (or 14 of amoxicillin or cefuroxime) for erythema migrans, 14 to 21 days for neuroborreliosis and carditis, and 28 days for arthritis. Oral doxycycline works as well as intravenous ceftriaxone for meningitis, cranial neuritis and radiculitis. Amoxicillin is used in pregnancy; azithromycin is avoided in carditis because it lengthens the QT interval. A Jarisch–Herxheimer reaction, a day of fever and aches, can follow the first doses.

Lyme arthritis that does not improve after a first oral course is treated, in American guidance, with 2 to 4 weeks of intravenous ceftriaxone; a mild residual swelling can simply be watched. Arthritis that persists after this is antibiotic-refractory and goes to a rheumatologist: NSAIDs, intra-articular steroid, methotrexate or a biologic, and arthroscopic synovectomy. More antibiotics do not help it.

Preventing Lyme disease

Long clothing, repellents such as DEET, a skin check each evening after time outdoors, and prompt removal of ticks with fine tweezers, gripping close to the skin. UK guidance gives no antibiotics after a tick bite; American guidance offers one 200 mg dose of doxycycline within 72 hours of removing a high-risk tick in highly endemic areas. The vaccine against tick-borne encephalitis, a viral infection, does not protect against Lyme disease, and no Lyme vaccine is yet licensed for people; one candidate finished its phase 3 trial in 2026 but has not been approved.

05Epidemiology

Reactive arthritis affects mostly adults aged 20 to 40. Estimates of its incidence vary widely, from under 1 to about 30 per 100,000 a year, because mild cases are missed and there are no agreed criteria. The sexually acquired form is diagnosed far more often in men, partly because chlamydial infection in women is often silent; the enteric form affects both sexes equally, occurs in children too, and comes in clusters after outbreaks of food poisoning. It is commoner and more severe in HIV infection.

Post-streptococcal reactive arthritis has two peaks, in children aged about 8 to 14 and in adults in their twenties and thirties. In Europe, where rheumatic fever has become rare, it is the more likely diagnosis after streptococcal pharyngitis in an adult.

Lyme borreliosis is the commonest tick-borne infection in the northern hemisphere. National surveillance in Europe records about 130,000 cases a year, and many more go unreported; incidence is highest in central Europe and the Baltic states, and ticks are spreading north and to higher ground. Since 2018 Lyme neuroborreliosis has been on the European Union's list of diseases under surveillance, with one case definition. Children aged 5 to 9 and adults aged 50 to 70 are most affected.

06Prognosis

Most reactive arthritis settles within 3 to 12 months. About a quarter of patients, more of them HLA-B27 carriers, have recurrent attacks or chronic arthritis, and a minority develop spondylitis that progresses like ankylosing spondylitis. Chronic heel pain, recurrent uveitis and, rarely, aortic regurgitation are the lasting problems. A new infection can bring a new attack.

Post-streptococcal reactive arthritis heals without joint damage, though it can last months. Whether it carries a real risk of later valve disease is uncertain; the watch for carditis reflects that uncertainty.

Treated early, Lyme disease is cured in almost all patients. Facial palsy recovers in most, and carditis usually resolves completely. Most Lyme arthritis clears with antibiotics, and even refractory arthritis usually burns out within a few years. A minority of patients have fatigue, pain or poor concentration for months after correct treatment, a post-treatment Lyme disease syndrome; trials show that longer antibiotic courses do not improve it. So-called chronic Lyme disease, a label given to long-standing symptoms without evidence of infection, is not a recognised diagnosis, and the long antibiotic courses given for it cause harm.