Introduction

This original article was written by the late Professor WW Buchanan and W F Kean (WFK) in 2004 but was not published. WFK and colleague D MacPherson had previously written on the history, clinical features and management of Reiter’s Syndrome (Kean and MacPherson 1991).

Reactive Arthritis

In 1973, Kimmo Aho and his Finnish colleagues introduced the term "Reactive Arthritis" (Aho et al. 1973) for non-purulent sterile joint inflammation associated with sexually acquired Chlamydia trachomatis urethritis or following dysentery due to a variety of organisms, including Salmonella typhimurium, Shigella flexneri, Yersinia enterocolytica and Campylobacter jejuni. A list of organisms implicated in the causation of reactive arthritis is summarised in Table I. A detailed account of the original descriptions of Reactive Arthritis has been given by Iglesias-Gammara et al. (2005). Arthritis associated with urethritis was described in the sixteenth century by Pieter van Foreest (Forestus) (1522–1597) (van Foreest 2003):and following dysentery by Pierre Martin de la Martiniere (1634–1690) in the seventeenth century (de la Martiniere 1664); and later by others in the eighteenth century (Bazy-Lestrade and Caroit 1986; Iglesias-Gammara et al. 2005). Whether the Urethritis described by van Foreest (van Foreest 2003) was due to gonorrhoea is uncertain, since the organism was only discovered by Albert Ludwig Siegmund Neisser (1855–1916) in 1879 (Neisser 1879). Sir Benjamin Collins Brodie (1783–1862) described patients in 1818 who had the triad of purulent urethral discharge, purulent conjunctivitis and arthritis, particularly involving the knees, ankles and feet (Brodie1818; Buchanan 2003). Some of the patients developed an iritis, and one had a rash which may have been circinate balanitis. Several patients suffered from recurrent relapses which could have been the result of further attacks of gonorrhoea or infection with Chlamydia trachomatis (Csonka 1960). In the absence of laboratory tests for these organisms the diagnosis must however remain uncertain. Markwald in 1904 (Markwald 1904) and Singer in 1916 (Singer 1916) reported patients with the triad of purulent conjunctivitis sicca, purulent urethritis, and arthritis, in whom they were unable to identify the gonococcus or any other pathogen. However, it was later during the first world war in 1916 that the definitive descriptions of Reactive Arthritis were made. The first was by two French doctors, Noel Fiessinger (1881–1946) and Edgar Leroy (d. 1965), who published a 40 page review of dysentery affecting 80 soldiers on the Somme, four of whom developed what the authors described as a "syndrome conjunctivo-uretro-synovial" (Fiessinger and Leroy 1916). They presented their paper at la Societe des Hopitaux-in Paris on the 8th December 1916 (Bazy-Lestrade and Caroit 1986). Four days later on 12th December at the Society of Medicine in Berlin, Hans Conrad Julius Reiter (1881–1968) who was serving with the First Hungarian Army in the Balkans, described a German army officer (Reiter 1916; Benedek 1969; Iglesias-Gammara et al. 2005) with an illness similar to those described in French soldiers by Fiessinger and Leroy (Fiessinger and Leroy 1916). These papers in French and German are of historical importance and were not originally translated into English as indicated in Ralph H. Major's Classic Descriptions of Disease with Biographical Sketches of the Authors (Major 1932). Fiessinger and Leroy's description occupies only three short paragraphs in their 40 page manuscript (Fiessinger and Leroy 1916). Reiter's paper is more frequently cited than that of the French authors, but seems rarely to have been read, since several reviews have cited two patients and attributed the onset to a sexually acquired infection. An English translation of the German is presented in Table II (Reiter 1916; Iglesias-Gammara et al. 2005). Reiter attributed the condition to infection with the Spirochaete forans obtained from a blood culture. A second article by Reiter the following year again gave a description of the spirochaete (Reiter 1917). The finding, however, was never confirmed and now regarded as an artefact. Reiter it should be noted had previously participated in research on the causative agent in Weil's disease, which re-proved to be due to the spirochaete, leptospira icterohaemorrhagiae (Hubener and Reiter 1915). Reiter may have been influenced by his previous discovery of a spirochaetal cause of Weil's disease: a case of Johann Wolfgang von Goethe' s famous dictum: “was man weiss, man sieht” (what one knows, one sees). One of us (W.W.B.) wrote to Reiter in the 1960's and received a prompt reply and list of all publications on "my" disease. Noteworthy was the absence of Fiessinger and Leroy's paper, or any other publication antedating his own. In 1937, Postma in Holland popularized the term "Reiter's Disease" (Postma 1937) which, however, was still referred to in France as the Fiessinger−Leroy syndrome. But why was Reiter's eponym widely accepted and not that of Fiessinger and Leroy? The reason is due to the fact that Reiter continued his interest and to publish reports, whereas Fiessinger and Leroy made no further contributions to the literature. Noel Fiessinger became Professor of Medicine at L'Hotel Dieu in Paris, while Edgar Leroy became a psychiatrist at the asylum of Saint-Remy-de-Provence, where Vincent van Gogh (1853–1890) had previously been a patient. During the Second World War a number of authors described post-dysenteric reactive arthritis (Bazy-Lestrade and Caroit 1986). The first extensive study was reported by Ilmari Paronen and his colleagues in Finland (Paronen 1948; Sairanen et al. 1969; Kean and MacPherson D 1991). Amongst 150,000 soldiers fighting the Russians in the Karelian Isthmus who developed dysentery due to Shigella flexneri: 344 soldiers, (0.2%), developed Reiter's Disease. However, despite an extensive European literature the disease was not reported in the United States until 1942, when Bauer and Engleman (Bauer and Engleman 1942) described 6 patients and attributed the cause to pleuro-pneumonia-like organisms (PPLO). Noer (Noer 1966; Kean and MacPherson D 1991) in Little Rock, Arkansas, USA, reported 602 of 1276 US sailors who contracted salmonella dysentery after a picnic: 9 of the sailors developed the syndrome of Reactive Arthritis. The concept of a venereal origin of Reactive Arthritis took much longer to establish, despite the fact that Chlamydial organisms had been identified as far back as 1903 (Coste et al. 1952, 1953). Gradually it became apparent that infection with Chlamydia trachomatis of venereal origin was another cause of Reactive Arthritis (Bazy-Lestrade and Caroit 1986; Coste et al. 1963; Amor et al. 1972; Smith et al. 1973; Ford 1953; Kean and MacPherson D 1991). Chlamydia infections in animals, such as sheep and cows, have also been noted to result in chronic arthritis, conjunctivitis, bowel infection, orchitis and epididymitis (Milon et al. 1983). The clearest evidence that there was a form of Reactive Arthritis quite distinct from gonorrhoea came from a studies in venereal disease clinics in London, England in 1953 and 1958 (Ford 1953; Csonka 1958). In Csonka’s study, 67 of the patients with gonorrhoea, the gonococci disappeared with penicillin therapy, but urethritis and other features of Reiter's syndrome persisted. This suggested that another organism was involved, and led to the conclusion that it was Chlamydia trachomatis (Csonka 1958).

Patients were described with a hyperkeratotic skin eruption complicating an arthritis attributed to gonorrhoea. A French dermatologist named the condition keratodermia blenorrhagica (i.e. horny skin with urethral discharge) (Vidal 1893; Chauffard 1897). Blenorrhagia was an early synonym of gonorrhoea. In 1939 Kuske (Kuske 1939) in Switzerland proposed that keratoderma blenorrhagica associated with Reiter's Disease was not due to gonococcal infection. Despite this, a major American textbook on diseases of the skin in 1956 still considered keratoderma blenorrhagica, but not Reiter's Disease, was due to gonococcal infection (Sutton 1956). This complication is now recognised as a complication of Reiter's Syndrome (Maxwell et al. 1966; Kean and MacPherson 1991). The clinical features of post-dysentery and sexually acquired reactive arthritis are identical (Keat and Arnett 1998; Kean and MacPherson 1991). However, the latter is almost exclusive to males, as is keratoderma blenorrhagica (Vidal 1893; Chauffard 1897; Boyle and Buchanan1971; Kean and MacPherson 1991). In most forms of Reactive Arthritis the knee joints are usually and often the first to be involved (Boyle and Buchanan 1971; Kean and MacPherson 1991). The arthritis is often associated with severe pain, the overlying skin becoming red (Boyle and Buchanan 1971; Kean and MacPherson 1991). Non-steroidal anti-inflammatory analgesics are often unable to relieve the pain, which may require corticosteroid therapy Boyle and Buchanan 1971; Kean and MacPherson 1991). Antibiotics are of no value for Reactive Arthritis.

Gounelle and Marche (1941) appear to have been the first to describe sacro-iliitis and ankylosing spondylitis developing in patients with Reactive Arthritis, which Marche confirmed in later papers in 1950 (Marche 1950) and 1954 (Marche 1954). In 1947 Marche and Coste described the association with iridocyclitis (Marche and Coste cited Cited by Bazy-Lestrade and Caroit 1986). Sairanen and his colleagues in 1969 (Sairanen et al. 1969; Kean and MacPherson 1991) reviewed 100 of the 344 patients who had developed post-dysenteric reactive arthritis, reported earlier in 1948 by Paronen (Paronen1948; Kean and MacPherson 1991), and found ankylosing spondylitis had developed in 23 people. In the acute illness of Reactive Arthritis (Keat and Arnett 1998; Kean and MacPherson 1991), patients may develop pericarditis, varying degrees of heart block and aortic incompetence (Boyle and Buchanan 1971; Good 1974; Kean and MacPherson 1991). Central nervous system and other organ involvement has been reported (Boyle and Buchanan 1971; Good 1974; Kean and MacPherson 1991). Prostatitis is almost an invariable accompaniment, but only rarely have prostatic abscesses been reported (Boyle and Buchanan 1971; Kean and MacPherson 1991). A haemorrhagic or mucoid cystitis may develop in severe cases, and acute glomerulonephritis has been described (Boyle and Buchanan 1971; Kean and MacPherson 1991). A urethral stricture may develop in the later stages of the disease (Boyle and Buchanan 1971; Kean and MacPherson 1991). Recurrences are common especially following re-infection with Chlamydia trachomatis (Kean and MacPherson 1991). The use of a condom can help prevent the likelihood of such recurrences.

In the early 1970's patients with Reactive Arthritis were found to have a high prevalence of HLA-B27 (Brewerton et al. 1973). This is present in 8% of healthy Caucasians but is rare in Africans (Al-Jarallah et al. 1993). Up to 90% of patients with reactive arthritis have been reported to be HLA-B27 positive (Al-Jarallah et al. 1993). Using fluorescent monoclonal antibodies, electron microscopy and/or molecular probes fragments of Chlamydia trachomatis, Yersinia enterocolitica, and Salmonella typhimurium have been identified in synovial tissue which could provoke an inflammatory response (Nanagara et al. 1995; Toivanen 2001). It is of interest that all of the bacteria responsible for reactive arthritis are gram-negative facultative or obligate intracellular organisms, thus, enabling them to enter cells, and survive, and even multiply, so that antibiotic therapy is ineffective Sieper and Braun 1995; Toivanen 2001). The exact molecular role of HLA-B27 in the pathogenesis of reactive arthritis has not been defined, but is clearly complex probably involving molecular mimicry and autoimmunity or both (Bragado et al. 1990; Stieglitz and Lipsky 1993; Tsuchiya et al. 1990; Inman et al. 2000). T Cells play an important role, as shown from studies in transgenic rats (Breban et al. 1996), and on cytotoxic T cells (Geczy et al. 1986). However it is also shown that it is HLA-B27 and not some closely linked gene which is involved (Geczy et al. 1986; Bragado et al. 1990; Tsuchiya et al. 1990; Stieglitz and Lipsky 1993; Inman et al. 2000).

Patients who are severely immunocompromised with acquired immunodeficiency syndrome (AIDS) can develop Reactive Arthritis, suggesting a possible role of CD8 + (cytotoxic or suppressor) T lymphocytes (Winchester et al. 1987; Cush and Lipsky 1993; Kean and MacPherson 1991; Schwartz 1997. It has been identified that patients with AIDS and Reactive Arthritis have increased severity and degree of joint pain not responsive to standard analgesics like non-steroidal anti-inflammatory drugs (Winchester et al. 1987; Forster et al. 1988; Kean and MacPherson 1991).

Hans Reiter's Tainted Legacy: Statement by Professor W Watson Buchanan 2004.

Hans Reiter had a distinguished career in medicine, and received many awards including the Robert Koch medal, the Great Medal of Honour of the Red Cross, and affiliate member of the Royal Society of London. As an octogenarian he received a signal mark of honour when he was invited to present a keynote address at the International Congress on Rheumatism in Rome in 1961, in which he said:

"In the field of rheumatology, which overlaps with the so-called Reiter's disease, dermatology and venereology, we have not found the real solution. We must avoid any limitation of our scientific thinking…if we really want to help the sick people" (Gerhard and Heights 1970).

Reiter was one of a number of University professors who signed an oath of allegiance to Adolf Hitler in 1932 (Keitel 2004; Iglesias-Gammara et al. 2005). He was appointed president of the Reich Health Office and proclaimed that amongst his goals was "to ensure that inferior genetic material will be excluded from further transmission" (Wallace and Weisman 2000). Reiter must have been aware of the Nazi programme during the 1930's of sterilisation and euthanasia of the mentally retarded, and of the experiments carried out on concentration prisoners (Iglesias-Gammara et al. 2005), although he stoutly denied this at the Nuremberg trial 57 (Wallace and Weisman 2003). Although found not guilty by the court it is worth noting that he had been made an honorary member of the SS (Zaller 2003). It remains an ethical dilemma whether Reiter's eponym should be abolished in view of his tainted legacy of support of national socialism (Gottlieb and Altman 2003; Gross 2003; Panush et al. 2003; Iglesias-Gammara et al. 2005).

Comment by KD Rainsford, Colin A Kean and Walter F Kean

This original article was written by the late Professor WW Buchanan and W F Kean (WFK) in 2004 but was not published. WFK and colleague D MacPherson had previously written on the history, clinical features and management of Reiter’s Syndrome (Kean and MacPherson (1991). Readers are encouraged to search the article by Keat (1983) on the clinical features of Reactive Arthritis: and the article by Iglesias-Gammara et al. (2005) to review further detail on the history and clinical issues of Reactive Arthritis and Hans Reiter’s original descriptions.

For historical clinical reasons and socio-ethical reasons, Reiter’s Syndrome is now known as Reactive Arthritis. It classically occurs after a genito-urinary or gastrointestinal infection in genetically predisposed individuals (Brewerton et al. 1973; Kean and MacPherson 1991). It is most common in the 20–50 year age group. The acute form is characterised by a large joint asymmetrical polyarthritis and sometimes spinal involvement. The chronic form has a similar pattern (Kean and MacPherson 1991). The treatment of the acute form is with topical and oral NSAIDs, and selected corticosteroid injections: the chronic form is managed by education, exercises, Physiotherapy, NSAIDs, selected corticosteroid injections and Biologic agents (NICE UK 2021).