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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0000000000000107
Rheumatology Retrospective

Max Schüller and an Alleged Microbial Cause of Rheumatoid Arthritis

Benedek, Thomas G. MD

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From the Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

All translations are by the author.

No funding was obtained for this study.

The author declares no conflict of interest.

Correspondence: Thomas G. Benedek, MD, Department of Medicine, University of Pittsburgh School of Medicine, 1130 Wightman St, Pittsburgh, PA 15217. E-mail: benedek@pitt.edu.

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Abstract

Abstract: Max Schüller (1843–1907) was a German surgeon and microbiologist. From 1884 to 1905, he published histopathologic and bacteriological research on bacterial infection of human joints. Beginning in 1892, he focused on a bacterium he had identified in joints of patients with rheumatoid arthritis and surmised that he had discovered the cause of this disease. He persisted in conducting various experiments, some original at the time, with which he convinced himself of the validity of his discovery, without considering the possibility that he was working on contaminants. Contemporaneous attempts to confirm Schüller’s findings gave inconsistent results. A century of microbiological research with ever more sensitive techniques has not definitively answered the etiologic question. This history is a cautionary tale of the difficulty of disproving an erroneous premise.

This article reviews the bacteriologic research into the etiology of rheumatoid arthritis (RA) of a distinguished German surgeon at the turn of the 20th century. His conclusions were entirely incorrect but initiated a century of technically varied investigations. Schüller’s 20 years of scientific misadventure deserve to be recounted because investigators remain at risk of committing analogous errors.

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LATE 19TH CENTURY CONCEPTS OF RHEUMATISM AND BACTERIOLOGY

Several vague hypotheses were advanced in the last quarter of the 19th century to explain “rheumatism.” An abnormality of the spinal cord of unknown cause predominated. The strongest evidence claimed for this was the symmetry of symptoms and the development of contractures.1 Another, advocated particularly by the influential surgeon, Jonathan Hutchinson (1828–1913, London), was “diathesis.” This meant a predisposition that facilitated various extrinsic and intrinsic influences to initiate symptoms. Two of Hutchinson’s 6 principal diatheses were the catarrhal and the rheumatic, but “rheumatism after all is only the catarrhal diathesis affecting the joints.”2 A third concept considered rheumatism to be one disease that, influenced by age, gender, exposure, and so on, was manifested principally as acute rheumatic fever at one end of the spectrum and chronic RA at the other. Here an infectious agent was substituted for diathesis.3

Belief a bacteriologic etiology of human diseases was gathering acceptance. For example, from a lecture in 1901:

“We now have satisfactory scientific evidence of the bacteriologic origin of many previously obscure diseases…. There is, however, much virgin soil yet to be tilled…. While the clinical evidence of the infectious nature of some other diseases is beyond dispute, their bacteriologic origin is still undetermined. Thus, we await the demonstration of the bacterial nature of such diseases as smallpox, syphilis, soft chancre, measles, mumps, scarlet fever, typhus fever, yellow fever, rabies, pertussis, rheumatism, arthritis deformans, and so on. The origin of certain of these diseases has already been ascribed to certain bacteria, but the evidence is yet inconclusive. There can, however, be no reasonable doubt that ere long the specific causative bacteria will be isolated…”4

Hopes for effective therapy therefore became antimicrobic. According to Nathan S. Davis (1817–1904), the founding dean of Northwestern University School of Medicine, “One great therapeutic discovery has been made at the end of the 19th century—the discovery of antitoxins, the natural antidotes to the poisons of infectious agents….” Until the existence of parasites and of poisons generated by them was proven, an antitoxin was of course unidentifiable. Even though it should be found that few natural antitoxins can be isolated for use as remedies, those already discovered confirmed physicians in the hope that specifics will be found some day.5 Schüller’s research orientation should be considered in the light of this optimism.

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BIOGRAPHY OF SCHÜLLER

Karl Heinrich Maximillian (Max) Schüller (1843–1907) was born in the German state of Thuringia and in 1869 completed his medical education there at the University of Jena with submission of a thesis on perineal hernia. Following a brief tenure as a surgical resident in Hanover, he joined the Prussian army medical corps during the Franco-Prussian war (1870–71). Then, after practicing in Saxony for a year or two, he became an assistant to Carl Hueter (1838–1882), the professor of surgery in Greifswald, a small university town on the Baltic Sea.6,7 Hueter was a well-known surgeon who had published 2 editions of a textbook on joint diseases.8 Upon completion of his surgical training in 1875, Schüller, under Hueter’s supervision, wrote a second thesis, entitled “Experimental contributions to the study of septic infections,”9 thereby demonstrating an interest in bacteriology at the very beginning of this science. Schüller recalled that in about 1878 when he was “…clinical assistant and collaborator of Professor Carl Hueter…. I was led to make numerous clinical, pathological, anatomical, and bacteriological investigations of these [joint] diseases and to experiment on animals in order to study the causes, the origin of the different forms of arthritic inflammation.”10(p232) He was promoted to professor of surgery in 1880. The practice of a general surgeon included the then limited scope of orthopedics. While Schüller’s investigative interest in joints focused on pathology and microbiology rather than innovations in surgical technique, in his practice he undoubtedly performed joint fusions and resections. His numerous publications include a wide variety of surgical topics. In 1881,11 Schüller performed the first successful operation for undescended testis, and in 1889 he performed the first appendectomy in Germany.12 In 1883, he moved to Berlin as chief surgeon at the Polyclinic of the Association of Domestic Hygiene, part of a charitable organization for women and children that had been founded in 1878. He held this position for the rest of his life. Schüller died, 64 years of age, of gastric carcinoma.

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BACTERIOLOGY OF JOINTS

Evidence that a nontraumatic joint inflammation could be caused by bacterial invasion was just being discovered when Schüller became interested in this subject. Conflicting interpretations of bacteriologic research into the pathogenesis of gonorrheal arthritis were to become critical by analogy in the interpretation of the variable results in the bacteriology of rheumatoid joints. Albert L. Neisser (1859–1914) had discovered the gonococcus in 1879,13 and it was first demonstrated in synovial fluid microscopically in 1883,14 2 years before a method for culturing it was devised.15 The early efforts to grow gonococci from joint effusions frequently were unsuccessful, even when bacteria were visible under the microscope. Hence, whether this bacterium by itself was the etiologic agent of the local infection was in dispute. The first report of culturally proven gonococcal arthritis without typical urethritis was not reported until 1894.16 In 1895, the British epidemiologist, Arthur Newsholme (1857–1943), in the fourth of his Milroy Lectures, exemplified the prevalent diagnostic and etiologic uncertainty:

“The chronic characteristic of some forms of rheumatism may be used as an argument against its infectious character. It is not certain that chronic and acute rheumatism are the same diseases…. In blennorhagic arthritis, admittedly due to infection, the synovial fluid is sterile, and no germs are found in the blood; we must not, therefore, be surprised at the lack of success in the examination of the blood and synovial fluid for germs in rheumatic fever.”17

At the 1884 meeting of the German Surgical Society, Schüller presented a lecture “on bacteria in metastatic joint infections.” Synovial fluid and/or synovium from 28 cases of 6 different infections were studied bacteriologically and pathologically. Two specimens were obtained at surgery and the others at autopsies no longer than 24 hours postmortem. In a knee infected with glanders (Pseudomonas mallei): “Within the synovium there are relatively small round cocci and individual small bacilli. The cocci as well as bacilli lie partially between cells in the most superficial layer, partially in deeper layers.”18(p169) Schüller noted:

“Several types of microbes are almost always found together in joints, usually including those that were found in the original site of infection. I do not believe that the inference is justified that these bacteria have invaded the joints after death.”16

He considered that after cessation of blood flow the only source of bacteria would be extrinsic, but not through intact skin.

In 1896, Franz Chvostek, Jr (1864–1944), subsequently professor of medicine in Vienna, published a substantial review in which he pointed out the unreliability of postmortem cultures and the likelihood that the finding of morphologically different bacteria in a specimen indicates that at least one is a contaminant.19 Schüller in his later observations still doubted this.

Most relevant to RA of his early publications is “pathology and treatment of arthritis” in 1887. In this, he tried to explain quite nonspecifically the causes of joint inflammation.

“The inflammatory substances far more frequently [than due to external trauma] enter the joint with the bloodstream. We may assume this to be certain in the so-called metastatic arthritides, in most pyogenic processes of closed joints, in rheumatic fever, in the various chronic rheumatic joint inflammations, in the senile, in arthritis deformans, in gout, in the syphilitic, in the tuberculous, simple acute and chronic arthritides, as well as in association with the forms of individual inflammatory pathogens…. In other cases, however, inflammatory agents are not maintained in the blood, but only occasionally or under certain circumstances leave one or several disease foci to enter the blood and therein are transmitted into the joint. In this way, some tuberculous arthritides certainly develop, some metastatic (eg, the gonorrhoic), some chronic rheumatic, and others.”20

At the 1892 convention of the German Surgical Society, Schüller presented a paper that primarily was a histopathologic study of the synovium in RA, but included the first mention of bacilli in this disease.

“On freshly prepared slides, one could see within the synovium, between its uppermost layers as well as in the deep inflammatory foci and occasionally adjacent to blood vessels single round cocci, but predominantly short rod-like structures, apparently bacilli, with 2 shiny polar granules (spores?), or small groups of such structures that could be stained with various aniline dyes. I am at present engaged in the examination of cultures and inoculations [of specimens taken] from closed joints of such patients.”21(p169–170)

His initial interpretation of this observation was conservative. “I can say no more about the etiology of the chronic rheumatic arthritides beyond that I either infer that they are caused by similar local infectious agents as in acute rheumatism [rheumatic fever], their influence only being slower or weaker but more frequent, or that perhaps the cocci/bacilli found in the joints may be related, because I have aspirated fluid from a closed joint with appropriate precautions and have seen identical short bacilli develop in bouillon-gelatin. Nevertheless, a further amplification of these inferences so far would be useless.”21(p176)

He “at once initiated animal experiments.” Injection of a culture into pigeon joints was unsuccessful. Rabbits proved to be better suited. Injection of 0.1 mL. caused swelling for a few weeks, but 0.5 mL caused persistent arthritis, transiently with systemic symptoms, after which only swelling persisted. After 2 months, the same short bacilli could be cultured, and injection of these cultures into a joint of other rabbits gave the same result. At autopsy, there was mild synovitis with bacteria in the synovium of the injected joint, but other joints and viscera were normal. “The synovial fluid, as in RA, was nonpurulent…. The fact that the arthritis was achieved with the bacilli that I recently discovered and cultivated from human joints strengthens my conviction even more and converts my earlier inference to certainty that the proliferative rheumatic arthritis in man results from the bacilli I have discovered.”22 Thus, a partial confirmation of “Koch’s postulates” was achieved.23(p175,177) Their verification by injecting the culture into a volunteer was not undertaken.

In 1897, some additional, mainly clinical, information was given. By then Schüller had cultured 23 joint aspirates and fluid from 16 arthrotomies. All but 6 showed growth. However, bacteria were infrequently observed in synovial fluid.

“When I aspirated 2 joints from a patient, whether at once or at different times, the culture sometimes revealed only bacilli, the other time also cocci that sometimes also appeared to be diplococci. In sections one frequently sees bacilli and cocci together. I cannot assume that these cocci cause the disease. They entirely resemble pyogenic cocci…. I have previously seen them in various acute systemic arthritides, such as scarlatina, diphtheria, etc. In previous experiments I have injected pyogenic cocci into joints and never obtained hypertrophic synovitis, such as occurs with the bacilli.”24(p133)

This multiplicity of bacterial forms apparently still failed to raise the question of contamination.

Schüller differentiated the microscopic appearance of synovium in osteoarthritis from that in RA and stated that his bacilli could not be found in the former.

“I believe that this is an independent infectious disease that is elicited by the invasion, probably through mucous membranes, that mainly localizes in joints. This is supported not only by the histologic and bacteriologic findings and animal experiments, but how the disease develops. It is a villous arthritis, independent of the rheumatic fever that may occur in children. It occurs in the prime of life and in all economic circumstances. I have observed accompanying illnesses of the bronchi or kidneys in several of these patients, with the same bacilli in foamy bronchial secretions and in nephritic urine.”24(p135)

Several culture methods were described. A resected piece of synovium from a knee with proliferative synovitis “was immediately enclosed in small watch glasses held together with mucilage and rubber bands and placed in the abdomen of a rabbit. After suturing of the wound, the glasses remain in the abdomen for 10 to 14 days without being disturbed. When removed through another laparotomy, the glasses were still well sealed. In the coagulum that surrounded the villi, there now were numerous colonies of the dumbbell-shaped bacilli. Pure cultures of these could be obtained by inoculation on agar supplemented by various [unspecified] nutrients in plates and tubes.” Subsequently, use of an incubator, rather than animals, also was successful. Another technique was to centrifuge a sufficiently large effusion. Dumbbell-shaped bacilli could be found free and intracellularly in the sediment. This could then be placed similarly on nutrient media.25

In the 1890s, the question of whether RA and osteoarthritis are clinically discrete or manifestations of the same rheumatic entity remained in dispute. In 1899, Axel Johannessen, a Norwegian clinician, cited a discussion of this question at the 1897 internal medicine congress in Berlin: “Professor Schüller objected to the unitary concept. He maintained and expanded the views that he previously (in 1893) expressed about a particular form of chronic articular rheumatism that develops into hyperplasia of synovial cells with consequent swelling and proliferation of synovial villi and eventual swelling and deforming of joints.”26

Schüller did not speculate why the pyogenic cocci in the patients’ synovium are not associated with purulent synovial fluid, as was recognized in diseases such as streptococcal arthritis. However, he did speculate a specific pathogenic role for them.

“There is another type [of arthritis] in which the villi, instead of massively proliferating, soon begin to shrink. The joint capsule shrinks, and this finally results in ankylosis. I have called this type ankylopoetica in distinction from the massively proliferative type that I designate hyperplastica….27 This is pathologically as well as clinically an entirely different process from the one we understand as arthritis deformans [osteoarthritis]. In this shrinking or ankylosing type, I have not seen the cartilage changes of arthritis deformans, nor many of my “dumbbell-shaped” bacilli in the scanty villi and shrunken fibrotic synovium, but cocci constantly. I have surmised that the cocci may perhaps directly induce the shrinkage of the inflamed synovium.”28

The presence of any “dumbbell-shaped” bacilli in this type of process and their absence in arthritis deformans were considered evidence that the shrinkage type is related to RA rather than to osteoarthritis.

The first quasi-confirmation of the bacterial cause of RA was published in 1896, 3 years after Schüller’s first report of his discovery, by Gilbert A. Bannatyne (1867–1960, MD Edinburgh 1891) and Arthur S. Wohlmann (1867–1944), physicians at the Royal Mineral Water (rheumatism) Hospital in Bath, England and Frank R. Blaxall (1867–1930), a London bacteriologist. All eventually had distinguished careers, respectively in medicine, balneology, and microbiology. Bannatyne stated that in 1893, when their research was begun, “the idea of an organism as a causative factor in any one of the ‘rheumatic’ diseases seemed somewhat wild and improbable.”29(p1120) While Schüller appears to have been stimulated to conduct his research by serendipitous observations in a histopathologic study of synovial tissue, the English investigators were first prompted by “the close analogy of RA to tuberculosis.” Contrary to the surgeon, Schüller, Bannatyne, and Wohlmann considered themselves to have both a practical and an ethical problem in obtaining specimens for examination. It was rare for a case of RA to come to autopsy, and “the number of cases of synovial [joint] distention honestly likely to be benefited by tapping was extremely limited.” Their clinical description is adequate to be convinced that all of their cases really had RA. “Often, although the joint [usually a knee] seemed distended with fluid, none could be obtained in the aspirator bottle, but in such cases, there would generally be found a drop of fluid or a plug of synovial membrane in the point of the needle.”29(p1125)

Nowhere else in the early publications on joint infections is the method used for aspirating synovial fluid mentioned. Bannatyne undoubtedly used a vacuum bottle either because he lacked access to sufficiently large, effective syringes or was uncertain that they could be sterilized. Although the first joint aspiration with an experimental syringe was already reported in 1869,30 syringes were intended for injection, and designs that could exert reliable suction and use a needle rather than a trocar or incision only became expensively available just before the end of the century. Burroughs-Wellcome (London) uniquely sold 20-mL syringes in 1895. F. W. Lüer (1868–1943) invented the quasi-modern all-glass syringe in 1896, beginning with a 2-mL model.31

Bannatyne obtained a morphologically consistent microbe in all but 1 of 25 aspirates. Eighteen samples of synovial fluid were sent to Blaxall for detailed bacteriologic examination, of which he recognized 2 to be contaminated. Neither the volume of fluid or the interval between obtaining of the specimens and their examination was stated. Blaxall also revealed that he was sent 5 specimens of blood. He obtained the same organism from synovial fluid and blood samples from the 3 most severely arthritic patients. Blaxall described his culture methods and the difficulty in staining this microbe. Preliminary animal experiments were unsuccessful. He concluded, “It is obvious that the organism described by Schüller differs markedly from the one under discussion. In fact, the only points of resemblance are the polar staining and the easy discoloration”29(p1122)

Bannatyne and Wohlmann concluded:

“We have a disease due to the presence of microorganisms found in the joint fluids and tissue, and which must until disproved be regarded as specific. Just as in fibrinoid phthisis the fibrous tissue is a protective effort of nature to limit the growth of the bacillus, so in the fibrous and osteosclerotic ankylosis of joints in RA, we have a similar defensive action.”

They appear not to have pursued these investigations further.

Alfred Pribram (1841–1912), professor of medicine at the German University in Prague, recorded in his 1902 monograph on rheumatoid and osteoarthritis that he failed to obtain bacteria from rheumatoid joints.

“Schüller’s findings, as well as those of Bannatyne, Blaxall, and Wohlmann, in their clarity leave nothing to be wished for. We would ascribe the fundamental cause of RA to either of them if one would concede the discovery to the other. Unfortunately, the experiments that we have conducted on joint contents from several chronic cases of RA, both with Schüller’s simpler as well as Bannatyne’s more complicated method, have given negative results, so that the question, as near as it appears to its solution, remains unresolved at the moment.”32

Schüller attributed Pribram’s failure to confirm his bacteriologic findings to having cultured only synovial fluid and not biopsies of synovial tissue.32

Hans Spitzy, an Austrian orthopedist, in 1899 cited Schüller for his division of arthritis into 3 categories and reported the case of a 6-year-old girl, who was in the third year of Still disease (juvenile chronic arthritis). Synovial fluid that he cultured from her remained sterile.33

In 1901, Charles F. Painter (1869–1947), a Boston surgeon, using Bannatyne’s technique, cultured synovial fluid from 8 cases he considered to have RA and obtained no growth.34 Soon thereafter, Thomas McCrae (1870–1935), then William Osler’s associate at Johns Hopkins Hospital, Baltimore, wrote:

“Could we determine a definite organism to be associated with [RA] the matter [of etiology] is settled. In this series, we have never succeeded in obtaining any results from cultures, in spite of the greatest care in following the method given (for example by Blaxall). If we hold the view that many organisms (such as those of influenza [sic], gonorrhea, etc) are etiologic factors, there are many suggestive facts to support this. There seems no doubt of the association of attacks or exacerbations with various infections such as influenza. This may mean only lowered resistance…”35

Russell L. Cecil (1881–1965, New York) commented in 1931: “The perfect analogue of RA is gonococcal arthritis, a well-recognized infection characterized by a primary focus in the genitourinary tract with metastatic infections in the joints. It occasionally progresses into a condition clinically indistinguishable from advanced RA.”36 Lack of confidence in the correctness of negative synovial fluid cultures in RA can be attributed to the experience in culturing synovial fluid from cases of gonococcal arthritis. In 1937, after 50 years of improving culture methods, growth of gonococci from synovial fluid was obtained in only 26% of 78 cases of this disease.37

Some authors ignored rather that criticized the bacteriologic portion of Schüller’s study of synovial pathology. Karl Schuchardt (1856–1901, Stettin), in a section on synovial pathology in his rheumatologic textbook, published in 1899, recorded only: “Several years ago Schüller mentioned that in many cases of so-called ‘chronic rheumatic arthritis’ markedly enlarged and fatty synovial villi are present and that all possible transitions from early fatty villous proliferation to fully developed lipoma arborescens occur.”38

In 1905, Roades Fayerweather (Baltimore) published an investigation he had carried out while he was an orthopedic resident in Boston. He expressed surprise that “…we should have failed to recognize the significance of Schüller’s and of Bannatyne’s work and that we have contributed so little to the investigation of this large and important group of [arthritic] cases.” He adopted Schüller’s classification of arthritides and his name for RA, “polyarthritis chronica villosa.” Fayerweather described 5 patients whose synovial fluid cultures showed no growth, one of whom probably had RA, and 4 with positive cultures, each of whom would appear to have had a different disease: ankylosing spondylitis, traumatic monoarthritis of a knee, RA, and acute rheumatic fever. Contrary to Schüller and Blaxall, Fayerweather performed some metabolic tests on the bacteria he recovered, as well as pathogenicity tests in rabbits that indicated that the strains recovered from the 4 patients were not identical. He concluded:

The findings in these cases differ from those of Schüller, who found in his own cases the same organism constantly. Bannatyne likewise, in the same type of cases, constantly found a single organism, but it was not Schüller’s. It is impossible to explain the constancy of Schüller’s results or of Bannatyne’s. It is clear that they worked with the same type of cases as my own.39

Fayerweather had obtained some of the specimens of synovium and synovial fluid from arthrotomies done by Painter. One of these strains that Schüller from the description agreed to be identical with his organism was used to make a therapeutic vaccine. However, after about a year, Painter concluded: “When it comes to treatment, I think it is fair to say that there has been no considerable degree of improvement in any case [of RA].”40 This was an important negative observation, because so much faith was then being placed in the curative potential of vaccines for specific diseases.

Schüller’s last paper on the “dumbbell-shaped bacilli” essentially was a rebuke to Fayerweather. He agreed that of the 4 cases the bacteriologic findings of the 2 with ankylosing spondylitis and RA appeared to coincide with his. However, the conclusion that “Bacteriologically, there is no evidence to show that there is any essential difference between acute articular rheumatism and infectious polyarthritis chronica villosa” was drawn from far too few cases. He had demonstrated dumbbell-shaped bacilli in 150, of whom 30 specimens had been obtained surgically. He again expressed great confidence in his aseptic technique and rejected no findings as contaminants.41

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SCHÜLLER’S SHADOW

Llewellyn Jones, a former colleague of Bannatyne, in 1909 reviewed the literature on the bacteriology of RA. He began: “It is to Max Schüller that we are indebted for the suggestion of a microbial origin for certain cases of RA,” and summarized his publications. However,

“Unfortunately for the conclusiveness of the microbic theory so strongly advocated by these observers (Schüller, Bannatyne, Fayerweather), the bacteriologic findings lack adequate confirmation, as do similarly those of all other workers in the same field. Reviewing the organisms themselves collectively, one is struck by the variety they display, and presuming the disease to be infectious in origin, the only inference to be drawn is that not one but many different organisms may produce the disease…. It is, however, more difficult to account for the flatly contradictory results obtained by different observers, even when working along the same lines of technique…”42

Schüller then rapidly faded from rheumatologic discussions. Edwin Jordan (1866–1936) in his 1930 review: “The Microbiology of Rheumatic Fever and Arthritis” states “Probably the earliest of these [findings of bacilli in arthritis] was Schüller’s bacillus.” He then summarizes Schüller’s description of the microbe and his rabbit experiments, followed by citation of the articles by Bannatyne (listed as Blaxall) and Fayerweather.43 Martin Dawson (1889–1945) et al (1932) cite Schüller and Bannatyne at the head of a chronologic list of 18 publications entitled “Results of Bacteriologic Study Recorded in the Literature.”44 David Hamerman (1975) lists Bannatyne in his review,45 whereas R. A. Hughes (1994) lists both Schüller and Bannatyne in his.46 Eric Bywaters (1910–2003) in “Historical Aspects of the Aetiology of Rheumatoid Arthritis” (1988) states: “People began to explore the possibility that direct bacterial infection was the prime cause of RA, starting perhaps with Max Schüller in 1892 and followed quickly by a host of others.”47 Although there no longer is any focus on causative bacterial joint invasion in RA, interest in possible roles of microorganisms or products thereof as triggering mechanisms continues.

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Keywords:

Schüller; rheumatoid arthritis; gonococcal arthritis; microbiology

© 2014 by Lippincott Williams & Wilkins, Inc.

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