Clinical and Experimental Rheumatology 2002; 20: 555-557. CASE REPORT 16-year remission of ABSTRACT vide a source of arthritogenic products. after This rep o rt describes a remission of Second, it is not necessary to hypothe- rheumatoid arthritis (RA) of 16 years si z e a path o genic bacterial strai n , whi c h unusually vigorous treat- d u rat i o n , ap p a re n t ly caused by the will mostly be transient, for one can ment of closed dental foci extraction of endodontically well-treat - i m agine that norm a l , n o n - p at h oge n i c ed, healthy looking teeth. The only clue and thus persisting commensals in A.C. Breebaart1, J.W.J. that the teeth were contributing to the these closed foci may deliver, by the Bijlsma2, W. van Eden3 disease pathogenesis in this case of RA constant pressure exerted on them, the was that the patient was able to repro - cross-reacting products we are looking 1Department of Ophthalmology, University ducibly induce severe attacks of arthri - for and which induce RA in susceptible of Amsterdam;2Department of Rheumatol- tis after prolonged, heavy pressure on individuals. The possibility of such a ogy and Clinical , University some of his teeth tre ated with ro o t mechanism is illustrated by the follow- Medical Center Utrecht; 3Department of canal fillings. After extraction, a small ing case report. The patient, a Veterinary Medicine, University of Utrecht, pus layer was found to cover the apices h i m s e l f, is also one of the authors The Netherlands. of the clinically healthy looking teeth. (ACB). Adrian C. Breebaart, MD, PhD, Professor The rheumatoid factor (RF) became Emeritus of Ophthalmology; Johannes n egat ive and the patient re m a i n e d Case report W.J. Bijlsma, MD, PhD, Professor of Rheumatology; Willem van Eden, MD, symptom free for the next 16 years. The The patient, a male Caucasian born in PhD, Professor of Immunology. p o s s i ble connections between micro - 1935, was diagnosed with RA at 34 Please address correspondence and organisms in closed dental foci under ye a rs of age. Po lya rt h ritis of both reprint requests to: Prof. Dr. A.C. constant pre s s u re and the ch ro n i c i t y hands (MCPs and PIPs) and wri s t s Breebaart, Offenbachlaan 76, and exacerbations of RA are discussed. were the leading signs, with a positive Heemstede 2102 ZP, The Netherlands. RF (Rose-test 1/128), that lasted from E-mail: [email protected] Introduction 1969 to 1971. Received on October 24, 2001; accepted Rheumatoid arthritis (RA) is a disease Though there was no evidence of RA in in revised form on March 1, 2002. of still unknown etiology. Current hy- his family, there was a familial history © Copyright CLINICAL AND potheses favor a possible autoimmune of joint pains with a striking relation EXPERIMENTAL RHEUMATOLOGY 2002. etiology by the action of bacteria or between teeth and joints. Both the pa- b a c t e rial products mimicking joint tient’s mother and her grandmother on Key words: Rheumatoid arthritis, components after bre a k d own of self- her mother’s side had a phenomenon of tooth, , focal infection, tolerance. Our ignorance of the loca- joint pains, which could be aggravated autoimmunity, microbiology. tion of such bacteria, if any, and their by pressing some teeth and wh i ch apparent persistence in these locations, could be ‘ c u re d ’ by ex t racting these as indicated by the chronicity of RA, is teeth. still a major drawback of this theory. Once the patient’s attention was drawn The fl o ra of oral cavity or dental to this curious relation, it appeared to plaques has been incri m i n at e d, bu t be a reproducible phenomenon also in without much success. Remembrances his case.Though his teeth were regular- of the ill-fated theory of focal infection ly checked by a dentist he could not still linger in our minds. boast a good set of teeth as 4 had re- To be sure, the case to be described quired treatment with root canal antibi- here also points to teeth as the location otics and jackets, partly because of an of the causative micro-organisms, but accident 10 years prior causing 2 bro- there are essential differences with the ken teeth and partly by loosening of . First, a form of some adjacent teeth. By exe rting a mechanical pressure exerted on bacte- large amount of pressure on these teeth ria lodged in a closed focus is seen as a (best generated by eating hard food like p re re q u i s i t e. Bacteria lining the ora l peanuts, raw carrots and the like) the cavity, within dental plaques or in the patient could in each instance induce an do not live in a closed niche and ex a c e r b ation of his art h ritis (pain, do not endure mechanical pre s s u re. swelling, warmth and decreased range H oweve r, m i c ro - o rganisms in ro o t of motion of the involved joints) which canals tre ated with fillings or at the started about 1 to 2 hours after pressing apices of teeth with extensive recon- the tooth and lasted for several hours. structions do live in a closed surround- This relation was so constantly repro- ing and endure continuous pre s s u re d u c i ble that a dentist was asked to from grinding teeth which could pro- extract the tooth that was once broken,

555 CASE REPORT 16-year remission of rheumatoid arthritis / A.C. Breebaart et al. had been rep a i red with a cap , a n d It is notewo rt hy that the patient had causative micro-organisms (2) and the which had been treated with received 3 inoculations with BCG-vac- sites where they persist for some time in the root canal. The dentist objected cine at 17 years of age, as was then cus- are known. Here, too, it is assumed that on the grounds that the tooth was well tomary for beginning medical students either bacteria or bacterial pro d u c t s treated and did not show, clinically or who had negative Mantoux reactions. A re a ch the joints, mimic body tissue radiologically, any sign of disease. mildly positive Mantoux reaction ulti- components, and in susceptible hosts However, at the patient’s insistence the mately occurred. stimulate immune cells to react with tooth was extracted. It was found to a u t o a n t i gens. A l s o , a u t o i m mune ani- have a thin layer of pus covering the Discussion mal models, especially adjuvant arthri- apex. The affected joints suffered an The striking aspect of the disease in t i s , point to similar mechanisms of ex a c e r b ation of infl a m m ation in the this patient, and the reason for writing c ro s s - re a c t ivity of bacterial pro d u c t s following days Ð a phenomenon also this case report, was a three-fold rela- with disease critical self- of the ex p e rienced by the pat i e n t ’s mother tion between teeth and joint symptoms. joints (3). Although the re l at i o n s h i p and great grandmother Ð after which Fi rs t , m e chanical pre s s u re caused an between immunity to heat shock pro- period the arthritis subsided for several exacerbation of the arthritis. This flare- teins (hsp) and arthritis is still under months. The disease once again be- up came about 2 to 3 hours after the study, the model of mycobacteria-in- came active, and again exacerbations of mechanical pressure, lasted for some duced adjuvant arthritis has shown that the baseline arthritis could be induced hours and then subsided.This was a a peculiar mimicry between the hsp60 by pressure on loose teeth. This led to c o n s t a n t ly rep ro d u c i ble phenomenon. molecule of mycobacteria and cartilage the successive extraction of another 3 To our knowledge, such a direct corre- proteoglycan-associated molecules can teeth, with the same result. During this l ation in time between mech a n i c a l lead to induction of arthritis. On the period 1969 - 1971 ‘traditional’ treat- stress on the teeth and exacerbations of other hand, immunity to conserv- ment consisted of salicylates. RA symptoms has not been described. ed non-mimicry epitopes of hsp now From 1971 onward the patient remain- The second re l ationship consisted of has been shown to be related to the pro- ed completely free of symptoms, the similar exacerbations, but lasting a few duction of regulatory T cells having the RF had become negative, and for 16 days, after extraction of the involved capacity to control arthritic inflamma- years no signs or symptoms of joint teeth. The third relationship was remis- tion. While the hsp molecule in isola- problems were present. sion for some months after each extrac- tion tends to promote this form of regu- In 1988 a re c u rrence occurred; the tion, and the complete remission for 16 l at i o n , when it is presented to the hands and wrists were only mildly af- years after the last of the 4 treated and immune system in the context of other fected this time but the shoulders, an- loose teeth had been extracted. proinflammatory bacterial antigens, an kles and feet were now severely afflict- This three-fold relation can most easily aggre s s ive art h ritis inducing immu n e ed. From time to time the neck, tempor- be explained by assuming a connection response develops (4). omandibular joints, elbows and knees b e t ween the release of art h ri t oge n i c We tried to explain the full-bl ow n were involved as well. Radiologically bacterial products from closed dental recurrence 16 years later in the light of both the hands and feet showed erosive foci and RA symptoms. All 4 extracted this theory. By the beginning of 1988 changes of the MCPs and MTPs, the teeth had a pus layer present at their the patient had only a few remaining left wrist showed ankylosis of the apex at the time of extraction. It is like- teeth, all others having been extracted radio-ulnar joints and in the course of ly that mechanical pressure could have in the course of time as they succes- the fo l l owing ye a rs the cart i l age of p ressed either bacteria or bacteri a l sively loosened. As these last remain- both shoulder joints disappeared.The products into the bloodstream. The la- ing teeth also gradually became loose laboratory values were consistent with tent period of 2 to 3 hours accounts for and even tended to grow askew onto the diagnosis of RA: a positive RF the time necessary for these products to each other, and as some RA symptoms (latex test), raised ESR and high levels reach the joints and exert cross-reactiv- were beginning to develop again, ex- of CRP.Tests for Borrelia burgdorferii ity.That the well-known occurrence of traction was planned and it was hoped and Epstein-Barr were negative. bacteremia following tooth extraction that we now would be able to analyze Of the predisposing HLA-components can lead to an exacerbation lasting sev- the subdental bacterial flora and estab- DR1+ expression was present. Extra- e ral days befo re the re m oval of the lish a possible connection between bac- articular symptoms of RA were never causative flora takes effect may easily terial products of cultures from these o b s e rve d. Tre atment consisted of be imagined. Unfortunately, no further pockets and some of the patient’s blood NSAIDs; no disease modifying agents i nve s t i gat i o n s , in particular culture s , and joint components. Dental flora was were used.Twice (in 1990) an intra- were done on this material. obtained by anaerobic culture of the a rticular deposit of prednisone wa s The theory of micro-organisms acting apices of the last four extracted teeth. injected into the right shoulder; since at a distant site on joints to produce An enhanced proliferative response of Feb ru a ry 1999 prednisolone (15 mg a rt h ritis is, of cours e, a we l l - k n ow n the patient’s peripheral blood cells to per day) keeps the patient in a relative- t h e o ry for explaining sero n egat ive heat shock proteins and to his dental ly stable condition. reactive arthritis (1). Here, the putative flora was found (Fig. 1).

556 16-year remission of rheumatoid arthritis / A.C. Breebaart et al. CASE REPORT

developed countries where endodontic treatment is mostly absent. Unfortunately, proving the hypothesis will not be easy. A comparison of eden- tulous and non-edentulous populations should show a significant difference in down-regulated, burnt-out cases of RA, but such a cohort would be difficult to assemble. Alternatively, a careful case- controlled study of patients with a sim- ilar constellation of clinical fi n d i n g s (i.e., pressure on seemingly well-treat- ed teeth leading to exacerbations of RA with remissions after clean-up of the dental foci) could be studied.Though the proof may be difficult to obtain, the gain if such a connection betwe e n seemingly healthy teeth and RA could Fig. 1. Enhanced proliferative response of the patient’s peripheral blood cells to hsp and to his dental flora. Methods have been described previously (5). Dental flora was obtained by anaerobic culture of be established would, of course, be of the apices of the extracted last four teeth. Peripheral blood cells were separated from fresh heparinized great value. blood of the patient on Ficoll-Hypaque gradients (Nyegaard, Oslo, Norway). Proliferative responses were measured by 16 h [3H]thymidine incorporation in cells (2 x 105 per well) cultured for 4 days. The Acknowledgment counts per minute (cpm) for [ 3H]thymidine incorporation were measured in triplicate test cultures and The authors would like to thank Dr. D. divided by the mean of triplicate cultures without . Results are expressed on a ratio of mean cpm Muller and Prof. Dr. M.D. de Smet for with antigen per cpm control without antigen: Stimulation Index (SI). X-axis:concentrations of antigen inducing maximum SI. Mt = Mycobacterium tuberculosis.Y-axis:the their contribution to the investigation maximum SI induced by any of the concentrations of antigen is presented in the results. SI > 3 is posi- and the preparation of the manuscript. tive. Controls: concanavalin A: SI > 900 w/o antigen presenting cells (APC) and SI > 570 with APC. References 1. KEAT A: Reactive arthritis. Adv Exp Med Biol It is, of course, well-known that in the responses. As only transient pathogens 1999; 455: 201-6. first four decades of the twentieth cen- a re the alleged culprits in re a c t ive 2. BEBEAR CM,SCHAEVERBEKE T, BEBEAR CH: tury the theory of focal infection (6-8) a rt h ri t i s , the disease is self limited, Characteristics of arthritogenic bacteria. Rev had unfortunately led, as Newman (8) although the art h ri t rogenic pro c e s s Rhum 1999; 66 (1, Suppl.): 57S-59S. 3. E D E N W VA N, HOLOSHITZ J, N E VO Z, has put it, to an “orgy of extractions” lasts longer than the transient infection. FRENKEL A, KLAJMAN A, COHENIR: Arthri- when supposedly causat ive foci of Our hypothesis goes one step further: tis induced by a T- clone that re- pathogenic bacteria like tonsils, sinus- n o n - t ra n s i e n t , n o n - p at h ogenic micro - sponds to M. tuberculosis and to cartilage pro- teoglycans. Proc Natl Acad Sci USA 1985; 82: es, gall bladders and so on, were re- organisms persisting in closed dental 5117-20. moved in the hope of curing systemic fo c i , e s p e c i a l ly and para d ox i c a l ly in 4. E D E N W VA N, Z E E R VAN DER, PAU L AG A , diseases Ð amongst others, arthritis. As ap p a re n t ly we l l - t re ated but thereby PRAKKEN BJ, WENDLING U, ANDERTON SM, the vast literature trying to prove this sealed-off root canals or tooth pockets, WAUBEN MHM: Do heat-shock proteins con- trol the balance of T cell r egulation in inflam- hypothesis was pre d o m i n a n t ly anec- continuously release under the pressure matory diseases ? Immunol Today 1998; 19: dotical, with few if any rigorous clini- of gri n d i n g, p roducts that enter the 303-7. cal or experimental investigations, and blood stream and cause, t h rough a 5. HOLOSHITZ J, D RUCKER I, YARETZKY A , numerous patients were operated upon mechanism similar to molecular mim- EDEN W VAN et al.: T of rheuma- toid arthritis patients show augmented reactiv- without ove r whelming evidence of icry, a cross-reactive immune response ity to a fraction of mycobacteria cross-reactive improvement, the theory was gradually in susceptible individuals, thus leading with cartilage. Lancet 1986; ii: 305-9. abandoned. It should be noted that the to joint infl a m m ation and ch ro n i c 6. THODEN VAN VELZEN SK, ABRAHAM-INPIJN mainstay of the theory of focal infec- seropositive arthritis. A point in favor L,MOORER WR: Plaque and systemic disease: a reappraisal of the focal infection concept. J tion was the dissemination and colo- of this theory might be the observation Clin Periodontol 1984; 11: 209-20. nization of bacteria. New insights into made by some rheumatologists (9) that 7. HUGHES RA:Focal infection revisited. Br J s e ro n egat ive re a c t ive art h ritis funda- RA seems to be a recent disease of civ- Rheumatol 1994; 33: 370-7. m e n t a l ly altered this paradigm. Only ilization, and was much rarer in earlier 8. N E W M A N H N: Focal infection. J Dent Res 1996; 75: 1912-9. b a c t e rial products supposedly re a ch times when dental reconstructions did 9. A D E BA J O AO: R h e u m at o l ogy in the third distant organs and elicit inflammatory not exist and remains ra re in under- world. Ann Rheum Dis 1990; 49: 813-6.

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