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CHRONIC ARTHROPATHY ASSOCIATED WITH RUBELLA VACCINATION SPOTSWOOD L. SPRUANCE, ROBERT METCALF, CHARLES B. SMITH, MARIE M. GRIFFITHS, and JOHN R. WARD Eleven children suffered recurrent episodes of knee stiffness (“catcher’s crouch syndrome”) after receiving HPV-77DK12 rubella vaccine. One was evaluated by arthroscopy and the synovium was found to be hypertrophied posteriorly and to protrude in folds into the intercondylar notch and lateral joint space. Culture for rubella virus was unsuccessful. The authors’ observations provide evidence that “catcher’s crouch syndrome” is a synovial disease and that chronic joint disease can be a sequela of rubella immunization. Acute joint complaints occur in 25% of children with naturally acquired rubella, and a more frequent and severe form of arthritis occurs in adults (l,2). The possibility that acute rubella arthritis might progress to chronic arthritis has long been entertained by investigators, but to date only one report suggests such an association (3). Attempts to culture rubella virus from synovial tissue of patients with rheumatoid arthritis From the Divisions of Infectious Diseases and Arthritis, Department of Medicine. University of Utah College of Medicine, Salt Lake City. Utah. Supported by N I H grants AM-I3463 and RR-64. Spotswood L. Spruance, M .D.: Assistant Professor of Medicine: Robert Metcalf. M.D.: Assistant Clinical Professor of Orthopedic Surgery: Charles B. Smith, M.D.: Associate Professor of Medicine: Marie M . Grilfiths, Ph.D.: Research Instructor; John R. Ward, M.D.: Professor of Medicine. Address reprint requests to Spotswood L. Spruance, M.D., Department of Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84132. Submitted for publication June 14, 1976; accepted August 2, 1976. Arthritis and Rheumatism, Vol. 20, No. 2 (March 1977)
have been unsuccessful (4). However Ogra et a1 have demonstrated rubella virus antigen in synovial fluid from some children with juvenile rheumatoid arthritis (5). Studies of rubella antibody titers in patients with rheumatoid arthritis have generally shown no association (4,6-10). Administration of live, attenuated rubella vaccine has also been associated with joint complications, particularly the HPV-77DK12 vaccine strain ( 1 I ) . Two post-vaccination syndromes have been described: a neuritic “arm syndrome” characterized by pain and tingling in the fingers, and the “catcher’s crouch syndrome” characterized by inability to straighten one or both knees (12). These complications had their onset 1-14 weeks after vaccination and have mainly been transient in nature, although there are a few reports of joint problems persistent for several months (13-1 5). On April 11-12, 1970, 188,000 Utah children received H PV-77DK12 rubella vaccine by jet injector gun in a state-sponsored mass vaccination campaign. In an earlier report the authors described the joint complications observed in 3,052 children who were retrospectively surveyed by means of a questionnaire ( 1 I ) . Of the vaccinated children, 9.9% experienced joint complaints, compared with 0.3% of unvaccinated controls. Eight months after the initial survey, 225 (78%) of the children who initially had joint symptoms were contacted. Three children were still having recurrences. In addition, 8 other children with late recurrences were referred to the authors from the community. These 8 had also received the HPV-77DK12 vaccine but were
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not part of the original study. All of these children had the “catcher’s crouch syndrome” and have been described in detail in a previous report (13). In the present study these children were reexamined 5 years after vaccination; 3 children are still symptomatic, including 1 child who has been found to have objective evidence of joint disease by physical examination and arthroscopy.
MATERIALS AND METHODS Patient Follow-up. At intervals of 1 I , 48, and 66 months after vaccination, the 11 children with recurring joint complaints were reassessed by telephone interviews with their parents. When possible, individuals were seen and examined during a recurrent episode, and physical examinations were performed on the entire group at 66 months. Inability to fully extend one or both knees upon arising in the morning, with gradual improvement during the day, was considered to be characteristic of the “catcher’s crouch syndrome.” Culture of Synovial Tissue and Saline Knee Wash for Rubella Virus. Synovial tissue biopsied from Case 3 was used to establish synovial organ cultures as previously described (16). Explants were grown at 35°C and 37°C in Leibovitz medium (L-15) supplemented with 10% fetal bovine serum, glutamine (0.3 mg/mI), penicillin (100 U/ml), and gentamicin (40 bg/ml). A second portion of the biopsy specimen was minced and digested first with trypsin (0.2%, 37”C, 2 hours) and then with collagenase (0.02 mg%, 37”C, 1 hour). The cell suspensions obtained by these procedures were co-cultivated with human embryonic lung cells (W1-38) and a continuous line of monkey kidney cells (VERO). All co-cultivated cells were maintained with Eagle’s minimum essential medium and Hank’s salts ( M E M ) with the above-noted supplements, and were incubated at 35OC or 37°C in a humid atmosphere of 5% CO,, 95% air. Finally the undigested material was ground gently by hand in a glass tissue grinder with 10 ml of media and inoculated onto VERO, primary African green monkey kidney (AGMK), and continuous rabbit kidney (RK-13) cell cultures. N o synovial effusion was found at arthroscopy; therefore, before biopsy specimens were taken, the exposed area was rinsed with 50 ml sterile saline. Aliquots of the saline knee wash were inoculated directly onto A G M K , WI-38, VERO, and RK-13 cell monolayers. Interference Test for Rubella Virus. The primary synovial cell cultures derived from the explants, co-cultures, and cultures of the saline knee wash and ground biopsy material at passages 2, 3, 4, 5 , 7, 9, and 10 were assayed for rubella virus by the interference test (17). The test cells were co-cultivated with primary AGMK cells for 14 days, at which time the cultures were challenged with echovirus type 1 1 (500 TCID,,) and observed for CPE for 5 days. Controls included rubellainfected A G M K cells. Indirect Fluorescent Antibody Test for Rubella Virus Antigen. At alternate passages RK-13 cells that had been inoculated with ground biopsy material and the saline knee wash were examined for the presence of rubella antigen by the indirect fluorescent antibody technique (18). Human antirubella serum (Flow Labs) and fluorescein isothiocyanate
(FITC)-conjugated goat antihuman IgG (Melloy Labs) were used in the assay. Cytotoxicity Tests. Cellular immunity to rubella virus was tested by means of a 51Cr-release assay for lymphocytemediated cytotoxic activity toward rubella infected BHK-21 cells. The technique of Steele et a1 (19) was used, with the exception that the BHK-21 cells were chronically infected with the M-33 strain of rubella virus, and the labeled cells were allowed to form a monolayer on the surface of microtiter plate wells before lymphocytes were added. Lymphocytes from 2 healthy individuals with a history of rubella and serum antirubella antibody titers of > 1 : 8 by hemagglutination inhibition (HAI) were included in the test as positive controls. Inhibition of rubella-specific lysis by high titer human antirubella serum (25 pl per well) was used as a negative control. Cell-mediated cytotoxic activity of peripheral lymphocytes against 51Cr-labeled monolayers of synovium-derived fibroblastic cells was assayed as described in a previous report (20). Miscellaneous Studies. Tissue typing was done by the standard microlymphocytotoxic method (21) and tests for phytohemagglutinin (PHA) stimulation of peripheral lymphocytes were performed by uptake of SH-thymidine at 3 days. Rubella HA1 antibodies were determined by the Utah State Division of Health using a modification of the technique of Stewart ef al (22). Assay for IgM rubella HA1 antibodies was performed by fractionation of serum on a 5-ml 10-50% sucrose gradient centrifuged for 18 hours at 33,500 rpm in a Beckman SW-50.1 rotor. Fractions of 0.5 ml were assayed for rubella HA1 activity, and FITC-labeled human IgG was used as an internal marker.
RESULTS On follow-up of the children 11, 48, and 66 months after vaccination, ill-defined aches and pains were occasionally encountered. No numbness or tingling suggestive of the “arm syndrome” was described. The only outstanding and consistent symptomatology was episodic morning stiffness in the knees typical of the “catcher’s crouch syndrome.” The occurrence of the “catcher’s crouch syndrome” over a 66-month period in these I I children is shown in Table 1. When children were seen during an acute episode, the involved knee was flexed, and the child was generally comfortable. Passive extension of the knee could be accomplished by the examiner, although this Table 1. Persistence o/ the “Catcher’s Crouch Syndrome“
Duration of Follow-Up Number ofchildren Number Lost (months since vaccination) with Recurrent Episodes to Follow-Up 8 II 48 66
I 1 (100%) 8 (73%) 4 (44%) 3 (33%)
0 0
2 2
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p r o d u c e d pain in t h e b a c k of t h e knee. Slight synovial thickening, j o i n t tenderness, and/or j o i n t swelling w a s seen a t 8 m o n t h s i n 3 patients (13). After this t i m e t h e only physical a b n o r m a l i t y detected, other t h a n resist a n c e t o extension, w a s a j o i n t click t h a t developed in Case 3 (see below). A t t h e end of t h e 66 m o n t h s , 6 children had experienced a g r a d u a l decrease in t h e frequency of recurrence of t h e s y n d r o m e a n d had h a d no episodes for a t least 16 m o n t h s . Two children were lost to follow-up. T h e remaining 3 children w h o continued t o have recurrences are described in detail below.
CASE REPORTS Case 1 A 2-year-old white boy received the HPV-77DK12 rubella vaccine on April 12, 1970. Two weeks later both knees became swollen and stiff, and this condition persisted for 5 days. Over the next 6 months five more episodes, similar to the first, occurred with durations of 2-7 days. O n November 18, 1970, the patient was first seen by one of the authors on the fourth day of a flare-up in the left knee. Physical examination revealed a 15-20’ limitation of extension of the left knee because of the onset of pain. There was slight swelling of the left knee with loss of normal contours. According to the mother the swelling had been more pronounced at the beginning of the episode. The child had no other significant health problems. Blood studies revealed a normal erythrocyte sedimentation rate (ESR) and antistreptolysin 0 (ASO) titer, absence of rheumatoid factor ( R F ) and antinuclear antibody (ANA), and a rubella HA1 antibody titer of 1:8. Four siblings had been vaccinated at the same time, 2 of whom developed transient symptoms in their knees, and 1 of whom had the neuritic rubella “arm syndrome” in the right hand. When contacted 1 and 4 years after vaccination, the patient was continuing to have occasional episodes of knee symptoms. The patient was most recently evaluated on September 23, 1975, 5.5 years after vaccination. At that examination the problem was described as having existed continuously since vaccination, characterized by morning stiffness in the knees, usually in the left knee. The symptoms were noted on an average of 4 mornings a month, were worse in the winter, and were more likely to be present if the patient slept with his knees bent. Vigorous exercise was apparently not a precipitating factor. On physical examination the knees were unremarkable. N o clicks were demonstrable in either knee.
Case 2 An 8-year-old white boy was vaccinated with the HPV77DKI2 live, attenuated rubella vaccine on April 12, 1970. Six weeks later he became unable to straighten his legs because complete extension provoked pain in the back of his knees. The problem was worse in the morning and improved toward
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evening. Symptoms persisted for 6 weeks, after n.nich four other episodes occurred over the next year, a description of which has been previously reported (13). The child has had no other significant illnesses and no history of arthritis. He has 2 siblings who also received the HPV-77DK12 rubella vaccine at the same time, but neither had joint reactions. The patient was first seen and evaluated by the authors on October 15, 1970, 6 months after vaccination. He was asymptomatic at the time, and examination of the knees revealed no abnormalities. Serologic tests for R F and ANA were negative. An A S 0 titer and ESR were normal, and the rubella HA1 titer was 1:160. Motor nerve conduction in the right peroneal nerve was normal. When motor nerve testing was subsequently repeated during an episode of joint symptoms, conduction was 17% slower, although still well within normal limits (13). On September 22,1975,5.5 years after vaccination, the patient was reevaluated and reported that morning stiffness in one or both knees had occurred one to two times a month over the past year. The problem was worse in the winter and his knees were invariably stiff after skiing. Over the past year, he has noticed that his knees occasionally “squeak and pop.” O n physical examination, the knees were unremarkable. N o clicks were demonstrable. Roentgenograms of both knees were normal.
Case 3 On April 12, 1970, a 6-year-old girl received the HPV77DK12 live, attenuated rubella vaccine in the course of a statewide rubella immunization program. Approximately 3 weeks after vaccination, she experienced pain in the back of the right knee when running, jumping, twisting, or trying to fully extend her right leg. The problem was worse in the morning upon arising and improved gradually during the day. The parents noticed a small bulging behind the right knee. On approximately May 16, she began to have similar symptoms in her left knee. Before this time she had had no significant health problems. Two siblings had been similarly vaccinated, without complications. O n May 19, 1970, she was hospitalized with a presumptive diagnosis of bilateral “Baker’s cysts.” O n physical examination a “firm, fixed, slightly indentable” mass I .5 cm in diameter was described on the posterior-medial aspect of her right knee, and a similar but smaller mass was believed to be present on the left. The masses were nontender, but pain behind the knees could be elicited by extension of the legs. The remainder of the physical examination was within normal limits. X-rays of the knees taken at that time have been reviewed and show slight soft tissue fullness posterior to the right knee joint, as compared with the left. O n May 27 an orthopedic consultant believed there was no longer any evidence of popliteal swelling. Rheumatic fever was considered, but an ESR and A S 0 titer were normal. The patient was then discharged with a diagnosis of postrubella vaccination arthritis. Shortly thereafter, knee symptoms resolved, the total duration of the initial episode having been approximately 4 weeks. Over the next 5 months the patient was well, except for occasional transient knee pains associated with vigorous exercise. On November 27, 1970,7.5 months after vaccination, the
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patient awoke and was unable to straighten her right leg. The right knee stiffness persisted and 3 days later she was examined by one of the authors. There was a 10" limitation of extension of the right knee joint secondary to pain, but no synovial thickening, tenderness, or evidence of effusion. ESR and an A S 0 titer were normal, a rubella virus HA1 antibody titer was 1:80, and tests for R F and A N A were negative. Several days later the stiffness subsided. Eleven months after vaccination the patient had a similar episode. Physical examination again revealed a 10-15" limitation of extension of the right knee secondary to pain (13). The next follow-up was made 4 years after vaccination, at which time the mother stated that the patient's knees continued to bother her. The patient sometimes had pain with vigorous exercise, and episodes of stiffness of a few days duration occurred every 6-8 weeks. Although usually the right knee was involved, the left knee or both knees were sometimes affected. Six months later, on November 7 , 1974, the patient was seen by one of the authors because of a 3-week episode of stiffness in her right knee, which was interfering with her athletic activity at school. The symptoms were worse in the morning and tended to recur if the patient was in a sitting position for a period of time. Physical examination revealed that the right knee was half-bent as she stood or attempted to walk. O n passive extension there was a 25" limitation secondary to pain. There was increased fullness in the lateral aspect of the right posterior knee joint, and the superior margin of the right patella was indistinctly felt. Rubella HA1 antibody titer was 1:U. In March 1975 the patient first began t o notice a clicking in her right knee. A damaged meniscus was considered likely, and on May 12, 1975, she was admitted to the University of Utah Medical Center for arthroscopy of the right knee joint. The patient had not had any acute episodes of joint stiffness for several weeks prior to admission. Examination on admission revealed a healthy appearing, cheerful 12-year-old girl. Vital signs were within normal limits. A click was demonstrable on extension of the right knee with either medial or lateral torsion. Resistance to extension was encountered at 10". Quantitative immunoglobulins, C, and C,, ANA, R F , and LE preparation were all normal. Rubella virus HA1 antibody titer had continued to decrease and was 1 :32. N o IgM rubella HA1 antibody was detectable. The patient's tissue type was determined and found to be AlO, A10, B6, B18. The immune response to rubella virus of the patient's peripheral lymphocytes was tested by means of a 61Cr-release assay for cell-mediated cytotoxic activity toward rubella-infected BHK-21 cells. The specific immune release (SIR) of lymphocytes was 10.0 f 3.6%. Although this value was slightly lower than the mean SIR exhibited by lymphocytes from two rubella antibody positive normal individuals (13.3% and 14.3%). the difference was not significant. Lymphocyte response to PHA stimulation was normal. The patient's lymphocytes were also tested for cytotoxic activity against one rheumatoid and two nonrheumatoid synovial cell lines. N o increased cytotoxicity for any of the three lines was observed. The patient was placed under general anesthesia and the right knee joint examined with a Wolfe 6.5-mm arthroscope. N o synovial fluid could be removed. The joint space was rinsed with normal saline, which was saved for viral culture. The articular surface of the patella was normal. The
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articular surfaces of the femoral condyles and tibia1 plateau also appeared normal. The medial and lateral menisci were normal and could be well visualized. The intercondylar notch area showed significant hypertrophy of the synovium. The synovium looked thickened and protruded in folds (Figure I ) . With the knee flexed, the synovium could be seen to impinge on the lateral joint space. As the knee was extended, a palpable click occurred at the point where there was approximately 20" of extension remaining. At this moment it could be observed through the arthroscope that the synovium slipped free from the joint space. This slippage could be consistently correlated. Biopsies were taken from the hypertrophied synovium in the intercondylar notch and also from more normal-appearing synovium in the suprapatellar region. The biopsy forceps were used to remove as much synovium as possible from the intercondylar notch; however additional folds of synovium appeared from the posterior popliteal fossa as traction was applied, and it was not possible to eliminate the click with the amount of synovium that could be removed through the art hroscope. Representative portions of the biopsy were sectioned and examined histologically. The synovium in the normalappearing suprapatellar region was unremarkable. The synovium from the intercondylar notch showed some areas of proliferation of the synovial lining cells, but no inflammatory cells could be seen (Figure 2). Biopsy tissue from the intercondylar notch and suprapatellar pouch was pooled and used for attempts at virus isolation. N o cytopathic effects were observed in any of the cultures, interference tests failed to reveal the presence of rubella virus, and indirect fluorescent antibody tests for rubella antigen were also negative. Postoperatively, the patient has continued to have problems. Six weeks after surgery she had an episode of stiffness in the left knee. On examination there was a 20" resistance to passive extension of the left knee, which could gradually be straightened but with discomfort. No tenderness or synovial thickening could be detected. Clicks were now demonstrable in both the left and right knees. Four months after surgery the patient was seen again in routine follow-up. The right knee was easily extended 170°, whereupon resistance was encountered. The knee could then be forced to full extension with a sudden "give" or apparent mechanical release. Although the patient was not having an acute episode, she walked with a limp without fully extending her right knee. Small amounts of aspirin were being used daily to control pain and stiffness. Arthrotomy and synovectomy might become necessary to control the patient's symptoms, but these procedures are being deferred until she is older.
DISCUSSION The possibility that chronic arthritis might be a sequela o f rubella vaccination has been the subject of considerable interest t o investigators ever since a high frequency of post-vaccination j o i n t complications was observed following t h e mass rubella vaccination compaigns in 1970. T h i s r e p o r t provides the first documentat i o n t h a t chronic j o i n t disease c a n , t h o u g h rarely, follow
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Fig 1. View ihrough the arthroscope and diagrammatic illusiration showing fold of synovium in ihe intercondylar notch oj Case 3.
Fig 2. Lighi microscopy of synovial tissue from the iniercondylar notch of Case 3. Hematoxylin and eosin
(X
300).
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rubella immunization. I n addition to one surgically proven case, 2 other of the children examined continued to have intermittent symptoms 5.5 years after vaccination, although at this point there is no objective evidence of joint disease. Thompson’s 3-year follow-up of 39 children with post-vaccination arthritis revealed that most children appeared to have resolved the problem, although 2 continued to have attacks in the 9 months prior to the last follow-up (14). A 2.5-year follow-up of 32 children by Shaffner similarly identified 2 children who were continuing to have recurrences (15). Whether the 6 remaining children in these three studies, all of whom have the “catcher’s crouch syndrome,” will resolve their problem or progress to overt joint disease must await a later fo Ilow- up. None of the present patients with “catcher’s crouch” developed any significant serologic or clinical evidence suggestive of rheumatoid arthritis or systemic lupus erythematosus. Two of the 1 1 children had reactive tests for RF (1:20) 7.5 months after vaccination, but the results of these tests were negative when repeated 2.5 months later (13). The authors have followed 2 other children, not part of the present study, who developed classic juvenile rheumatoid arthritis after receiving rubella vaccine in Utah’s mass vaccination campaign in 1970 (23). Because 188,000 children were vaccinated during the campaign, this association is viewed as coincidental. I n addition, rubella HA1 antibody tests in these 2 children were not unusually high, in contrast to the case of rheumatoid arthritis following rubella that was reported by Martenis (3). Controversy surrounds the question of whether the “catcher’s crouch” post-rubella vaccination syndrome is a neuritis or an arthritis. Shaffner has reviewed the argument in favor of a neuritic etiology, which includes the usual absence of objective evidence of joint inflammation, and the finding of abnormal nerve conduction velocities both in his study and that of Gilmartin ( 1 2,1524). The present authors feel that the evidence favors joint disease as the cause. Among our 1 1 patients, examination of 3 children during an acute episode revealed some evidence of joint inflammation: synovial thickening in one patient, joint tenderness and synovial thickening in another child, and joint swelling in a third. I n contrast to the description of the syndrome by Shaffner, none of these cases had knee joint pain at rest (as might be expected with neuritis), but only with forced extension. I n the third case there is a suggestion that there was posterior synovial hypertrophy 5 weeks after vaccination (“Baker’s cyst,” soft tissue fullness on x-
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ray) and 4 years after vaccination (fullness in the lateral popliteal fossa), in addition to posterior synovial hypertrophy seen at arthroscopy. This abnormal synovium may be sufficient to produce the symptoms of the “catcher’s crouch syndrome.” As the knee joint is extended, the posterior capsule tightens against the back of the knee joint. This mechanism could compress the hypertrophied synovium and cause pain and a limitation of motion. The episodic nature of the syndrome could be due to changes in the position of the redundant synovium or to transient inflammation. The mechanism by which rubella virus might produce synovial hypertrophy is unclear. Rubella virus has been isolated from the joint in both natural and post-vaccination rubella arthritis (25,26). However in these cases the children had more classic inflammatory arthritis with effusion and not the “catcher’s crouch syndrome.” Data from the third case weighs against persistent viral infection in “catcher’s crouch”: the gradually declining rubella HA1 antibody titers, the absence of IgM antibody, the absence of inflammatory cells in the biopsied synovium, and the inability to culture the virus. Possibly the virus is present only transiently in the joint several weeks after vaccination, and persistence of viral antigen or infection of chondrocytes plays a role (27.28). One of the authors has made arthroscopic observations that folds of hypertrophied synovium develop as an apparent reactive phenomenon in the post-traumatic or post-operative joint (29). Other puzzling problems include a) the apparent localization of the synovial hypertrophy to the intercondylar notch and posterior joint space; and b) the apparent absence of the “catcher’s crouch syndrome” as a complication of natural rubella. Local synovial reaction is an unprecedented form of viral joint disease, and suggests that the mechanism involved must similarly be unique and different from the inflammatory reaction of either direct viral joint invasion or viral immune-complex arthritis. Concerning the second question, it seems unlikely that “catcher’s crouch” has been overlooked as a complication of natural rubella. It is more likely to be a permutation of the virus inadvertently induced during the process of vaccine attenuation. It is fortunate that “catcher’s crouch” is uncommon and generally transient. The HPV-77DK12 strain of rubella vaccine is no longer produced, and “catcher’s crouch” has been seen only rarely with the currently available strains of rubella vaccine (15). Future live, attenuated virus vaccines should be subjected to longterm assessment to ensure that chronic reactions are not a complication.
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REFERENCES I . Judelsohn RG, Wyll SA: Rubella in Bermuda: termination of an epidemic by mass vaccination. J A M A 223:401406. 1973 2. Johnson RE, Hall AP: Rubella arthritis: report of cases studied by latex tests. N Engl J Med 258:743-745, 1958 3. Martenis TW, Bland J H , Phillips CA: Rheumatoid arthritis after rubella. Arthritis Rheum 11:683-685, 1968 4. Wilkes R M , Simsarian JP, Hopps HE, et al: Virologic studies on rheumatoid arthritis. Arthritis Rheum 16:446454, 1973 5. Ogra PL, Ogra SS, Chiba Y, et al: Rubella-virus infection in juvenile rheumatoid arthritis. Lancet 1:1157-1161, 1975 6. Smiley JD. Casey JL: Decreased C F antibodies in sera and decreased lymphocyte transformation to herpes simplex in patients with rheumatoid arthritis (RA). Arthritis Rheum 12:698, 1969 7. Kacaki J N , Balduzzi PC, Vaughan JH: A study of rubella haemagglutination inhibition antibodies in rheumatoid arthritis. Clin Exp lmmunol 6385-889, 1970 8. Christian CL, Phillips PE: Viruses and autoimmunity. Am J Med 54:661-620, 1973 9. Deinard AS, Bilka PJ, Venters H D , et al: Rubella-antibody titers in rheumatoid arthritis. Lancet 1:526-528, I974 10. Stanford F: Rubella-antibody titers in rheumatoid arthritis. Lancet 1:1000, 1974 1 I . Spruance SL, Smith CB: Joint complications associated with derivatives of HPV-77 rubella virus vaccine. Am J Dis Child 122:105-11 I , 1971 12. Kilroy AW, Schaffner W, Fleet WF, et al: Two syndromes following rubella immunization: clinical observations and epidemiological studies. JAMA 2 14:2287-2292, 1970 13. Spruance SL, Klock LE, Bailey A, et al: Recurrent joint symptoms in children vaccinated with HPV-77DK12 rubella vaccine. J Pediatr 8 0 4 1 3 4 1 7 , 1972 14. Thompson GR. Weiss JJ, Eloise MI, et al: Intermittent arthritis following rubella vaccination. Am J Dis Child 125526-530. 1973 15. Schaffner W, Fleet W F , Kilroy AW, et al: Polyneuropathy
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following rubella immunization: a follow-up study and review of the problem. Am J Dis Child 127:684-688, 1974 Spruance SL, Smith CB, Krall J, et al: Growth of Newcastle disease virus and rubella virus in rheumatoid and nonrheumatoid synovial cell cultures. Infect l m m u n 6: 326-329, I972 Parkman PD, Buescher EL, Artenstein MS, et al: Studies of rubella. I . Properties of the virus. J Immunol 93595-607, 1964 Lennette EH, Woodie JD, Schmidt NJ. A modified indirect immunofluorescent staining technique for the demonstration of rubella antibodies in human sera. J Lab Clin Med 69:689-695, 1967 Steele RW, Hansen SA, Vincent MV, et al: A T r microassay technique for cell-mediated immunity t o viruses. J lmmunol 110:1502-1510, 1973 Griffiths MM, Smith CB, Ward JR. et al: Cytotoxic activity of rheumatoid and normal lymphocytes against allogeneic and autologous synovial cells in uifro. J Clin Invest 58:6 13-622, 1976 Mittal K K , Mickey MR, Singal DP, et al: Serotyping for homotransplantation. XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6:9 13-927, 1968 Stewart G L , Parkman PD, Hopps HE, et al: Rubella virus hemagglutination inhibition test. N Engl J Med 276:554557, 1967 Ward JR: Unpublished data Gilmartin RC Jr, Jabbour JT, Duenas DA: Rubella vaccine myeloradiculoneuritis. J Pediatr 80406-4 12, 1972 Hildebrandt H M , Maassab HF: Rubella synovitis in a one-year-old patient. N Engl J Med 274:1428-1430, 1966 Ogra PL. Herd JK: Arthritis associated with induced rubella infection. J lmmunol 107:810-813, 1971 Hollister JR, Mannik M: Antigen retention in joint tissues in antigen-induced synovitis. Clin Exp Immunol l6:6 15627, 1974 Smith JL, Early EM, London WT, et al: Persistent rubella virus production in embryonic rabbit chondrocyte cell cultures. Proc SOCExp Biol Med 143:1037-1041, 1973 Metcalf R: Unpublished data
CHRONIC ARTHROPATHY ASSOCIATED WITH RUBELLA VACCINATION SPOTSWOOD L. SPRUANCE, ROBERT METCALF, CHARLES B. SMITH, MARIE M. GRIFFITHS, and JOHN R. WARD Eleven children suffered recurrent episodes of knee stiffness (“catcher’s crouch syndrome”) after receiving HPV-77DK12 rubella vaccine. One was evaluated by arthroscopy and the synovium was found to be hypertrophied posteriorly and to protrude in folds into the intercondylar notch and lateral joint space. Culture for rubella virus was unsuccessful. The authors’ observations provide evidence that “catcher’s crouch syndrome” is a synovial disease and that chronic joint disease can be a sequela of rubella immunization. Acute joint complaints occur in 25% of children with naturally acquired rubella, and a more frequent and severe form of arthritis occurs in adults (l,2). The possibility that acute rubella arthritis might progress to chronic arthritis has long been entertained by investigators, but to date only one report suggests such an association (3). Attempts to culture rubella virus from synovial tissue of patients with rheumatoid arthritis From the Divisions of Infectious Diseases and Arthritis, Department of Medicine. University of Utah College of Medicine, Salt Lake City. Utah. Supported by N I H grants AM-I3463 and RR-64. Spotswood L. Spruance, M .D.: Assistant Professor of Medicine: Robert Metcalf. M.D.: Assistant Clinical Professor of Orthopedic Surgery: Charles B. Smith, M.D.: Associate Professor of Medicine: Marie M . Grilfiths, Ph.D.: Research Instructor; John R. Ward, M.D.: Professor of Medicine. Address reprint requests to Spotswood L. Spruance, M.D., Department of Medicine, University of Utah College of Medicine, Salt Lake City, Utah 84132. Submitted for publication June 14, 1976; accepted August 2, 1976. Arthritis and Rheumatism, Vol. 20, No. 2 (March 1977)
have been unsuccessful (4). However Ogra et a1 have demonstrated rubella virus antigen in synovial fluid from some children with juvenile rheumatoid arthritis (5). Studies of rubella antibody titers in patients with rheumatoid arthritis have generally shown no association (4,6-10). Administration of live, attenuated rubella vaccine has also been associated with joint complications, particularly the HPV-77DK12 vaccine strain ( 1 I ) . Two post-vaccination syndromes have been described: a neuritic “arm syndrome” characterized by pain and tingling in the fingers, and the “catcher’s crouch syndrome” characterized by inability to straighten one or both knees (12). These complications had their onset 1-14 weeks after vaccination and have mainly been transient in nature, although there are a few reports of joint problems persistent for several months (13-1 5). On April 11-12, 1970, 188,000 Utah children received H PV-77DK12 rubella vaccine by jet injector gun in a state-sponsored mass vaccination campaign. In an earlier report the authors described the joint complications observed in 3,052 children who were retrospectively surveyed by means of a questionnaire ( 1 I ) . Of the vaccinated children, 9.9% experienced joint complaints, compared with 0.3% of unvaccinated controls. Eight months after the initial survey, 225 (78%) of the children who initially had joint symptoms were contacted. Three children were still having recurrences. In addition, 8 other children with late recurrences were referred to the authors from the community. These 8 had also received the HPV-77DK12 vaccine but were
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not part of the original study. All of these children had the “catcher’s crouch syndrome” and have been described in detail in a previous report (13). In the present study these children were reexamined 5 years after vaccination; 3 children are still symptomatic, including 1 child who has been found to have objective evidence of joint disease by physical examination and arthroscopy.
MATERIALS AND METHODS Patient Follow-up. At intervals of 1 I , 48, and 66 months after vaccination, the 11 children with recurring joint complaints were reassessed by telephone interviews with their parents. When possible, individuals were seen and examined during a recurrent episode, and physical examinations were performed on the entire group at 66 months. Inability to fully extend one or both knees upon arising in the morning, with gradual improvement during the day, was considered to be characteristic of the “catcher’s crouch syndrome.” Culture of Synovial Tissue and Saline Knee Wash for Rubella Virus. Synovial tissue biopsied from Case 3 was used to establish synovial organ cultures as previously described (16). Explants were grown at 35°C and 37°C in Leibovitz medium (L-15) supplemented with 10% fetal bovine serum, glutamine (0.3 mg/mI), penicillin (100 U/ml), and gentamicin (40 bg/ml). A second portion of the biopsy specimen was minced and digested first with trypsin (0.2%, 37”C, 2 hours) and then with collagenase (0.02 mg%, 37”C, 1 hour). The cell suspensions obtained by these procedures were co-cultivated with human embryonic lung cells (W1-38) and a continuous line of monkey kidney cells (VERO). All co-cultivated cells were maintained with Eagle’s minimum essential medium and Hank’s salts ( M E M ) with the above-noted supplements, and were incubated at 35OC or 37°C in a humid atmosphere of 5% CO,, 95% air. Finally the undigested material was ground gently by hand in a glass tissue grinder with 10 ml of media and inoculated onto VERO, primary African green monkey kidney (AGMK), and continuous rabbit kidney (RK-13) cell cultures. N o synovial effusion was found at arthroscopy; therefore, before biopsy specimens were taken, the exposed area was rinsed with 50 ml sterile saline. Aliquots of the saline knee wash were inoculated directly onto A G M K , WI-38, VERO, and RK-13 cell monolayers. Interference Test for Rubella Virus. The primary synovial cell cultures derived from the explants, co-cultures, and cultures of the saline knee wash and ground biopsy material at passages 2, 3, 4, 5 , 7, 9, and 10 were assayed for rubella virus by the interference test (17). The test cells were co-cultivated with primary AGMK cells for 14 days, at which time the cultures were challenged with echovirus type 1 1 (500 TCID,,) and observed for CPE for 5 days. Controls included rubellainfected A G M K cells. Indirect Fluorescent Antibody Test for Rubella Virus Antigen. At alternate passages RK-13 cells that had been inoculated with ground biopsy material and the saline knee wash were examined for the presence of rubella antigen by the indirect fluorescent antibody technique (18). Human antirubella serum (Flow Labs) and fluorescein isothiocyanate
(FITC)-conjugated goat antihuman IgG (Melloy Labs) were used in the assay. Cytotoxicity Tests. Cellular immunity to rubella virus was tested by means of a 51Cr-release assay for lymphocytemediated cytotoxic activity toward rubella infected BHK-21 cells. The technique of Steele et a1 (19) was used, with the exception that the BHK-21 cells were chronically infected with the M-33 strain of rubella virus, and the labeled cells were allowed to form a monolayer on the surface of microtiter plate wells before lymphocytes were added. Lymphocytes from 2 healthy individuals with a history of rubella and serum antirubella antibody titers of > 1 : 8 by hemagglutination inhibition (HAI) were included in the test as positive controls. Inhibition of rubella-specific lysis by high titer human antirubella serum (25 pl per well) was used as a negative control. Cell-mediated cytotoxic activity of peripheral lymphocytes against 51Cr-labeled monolayers of synovium-derived fibroblastic cells was assayed as described in a previous report (20). Miscellaneous Studies. Tissue typing was done by the standard microlymphocytotoxic method (21) and tests for phytohemagglutinin (PHA) stimulation of peripheral lymphocytes were performed by uptake of SH-thymidine at 3 days. Rubella HA1 antibodies were determined by the Utah State Division of Health using a modification of the technique of Stewart ef al (22). Assay for IgM rubella HA1 antibodies was performed by fractionation of serum on a 5-ml 10-50% sucrose gradient centrifuged for 18 hours at 33,500 rpm in a Beckman SW-50.1 rotor. Fractions of 0.5 ml were assayed for rubella HA1 activity, and FITC-labeled human IgG was used as an internal marker.
RESULTS On follow-up of the children 11, 48, and 66 months after vaccination, ill-defined aches and pains were occasionally encountered. No numbness or tingling suggestive of the “arm syndrome” was described. The only outstanding and consistent symptomatology was episodic morning stiffness in the knees typical of the “catcher’s crouch syndrome.” The occurrence of the “catcher’s crouch syndrome” over a 66-month period in these I I children is shown in Table 1. When children were seen during an acute episode, the involved knee was flexed, and the child was generally comfortable. Passive extension of the knee could be accomplished by the examiner, although this Table 1. Persistence o/ the “Catcher’s Crouch Syndrome“
Duration of Follow-Up Number ofchildren Number Lost (months since vaccination) with Recurrent Episodes to Follow-Up 8 II 48 66
I 1 (100%) 8 (73%) 4 (44%) 3 (33%)
0 0
2 2
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p r o d u c e d pain in t h e b a c k of t h e knee. Slight synovial thickening, j o i n t tenderness, and/or j o i n t swelling w a s seen a t 8 m o n t h s i n 3 patients (13). After this t i m e t h e only physical a b n o r m a l i t y detected, other t h a n resist a n c e t o extension, w a s a j o i n t click t h a t developed in Case 3 (see below). A t t h e end of t h e 66 m o n t h s , 6 children had experienced a g r a d u a l decrease in t h e frequency of recurrence of t h e s y n d r o m e a n d had h a d no episodes for a t least 16 m o n t h s . Two children were lost to follow-up. T h e remaining 3 children w h o continued t o have recurrences are described in detail below.
CASE REPORTS Case 1 A 2-year-old white boy received the HPV-77DK12 rubella vaccine on April 12, 1970. Two weeks later both knees became swollen and stiff, and this condition persisted for 5 days. Over the next 6 months five more episodes, similar to the first, occurred with durations of 2-7 days. O n November 18, 1970, the patient was first seen by one of the authors on the fourth day of a flare-up in the left knee. Physical examination revealed a 15-20’ limitation of extension of the left knee because of the onset of pain. There was slight swelling of the left knee with loss of normal contours. According to the mother the swelling had been more pronounced at the beginning of the episode. The child had no other significant health problems. Blood studies revealed a normal erythrocyte sedimentation rate (ESR) and antistreptolysin 0 (ASO) titer, absence of rheumatoid factor ( R F ) and antinuclear antibody (ANA), and a rubella HA1 antibody titer of 1:8. Four siblings had been vaccinated at the same time, 2 of whom developed transient symptoms in their knees, and 1 of whom had the neuritic rubella “arm syndrome” in the right hand. When contacted 1 and 4 years after vaccination, the patient was continuing to have occasional episodes of knee symptoms. The patient was most recently evaluated on September 23, 1975, 5.5 years after vaccination. At that examination the problem was described as having existed continuously since vaccination, characterized by morning stiffness in the knees, usually in the left knee. The symptoms were noted on an average of 4 mornings a month, were worse in the winter, and were more likely to be present if the patient slept with his knees bent. Vigorous exercise was apparently not a precipitating factor. On physical examination the knees were unremarkable. N o clicks were demonstrable in either knee.
Case 2 An 8-year-old white boy was vaccinated with the HPV77DKI2 live, attenuated rubella vaccine on April 12, 1970. Six weeks later he became unable to straighten his legs because complete extension provoked pain in the back of his knees. The problem was worse in the morning and improved toward
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evening. Symptoms persisted for 6 weeks, after n.nich four other episodes occurred over the next year, a description of which has been previously reported (13). The child has had no other significant illnesses and no history of arthritis. He has 2 siblings who also received the HPV-77DK12 rubella vaccine at the same time, but neither had joint reactions. The patient was first seen and evaluated by the authors on October 15, 1970, 6 months after vaccination. He was asymptomatic at the time, and examination of the knees revealed no abnormalities. Serologic tests for R F and ANA were negative. An A S 0 titer and ESR were normal, and the rubella HA1 titer was 1:160. Motor nerve conduction in the right peroneal nerve was normal. When motor nerve testing was subsequently repeated during an episode of joint symptoms, conduction was 17% slower, although still well within normal limits (13). On September 22,1975,5.5 years after vaccination, the patient was reevaluated and reported that morning stiffness in one or both knees had occurred one to two times a month over the past year. The problem was worse in the winter and his knees were invariably stiff after skiing. Over the past year, he has noticed that his knees occasionally “squeak and pop.” O n physical examination, the knees were unremarkable. N o clicks were demonstrable. Roentgenograms of both knees were normal.
Case 3 On April 12, 1970, a 6-year-old girl received the HPV77DK12 live, attenuated rubella vaccine in the course of a statewide rubella immunization program. Approximately 3 weeks after vaccination, she experienced pain in the back of the right knee when running, jumping, twisting, or trying to fully extend her right leg. The problem was worse in the morning upon arising and improved gradually during the day. The parents noticed a small bulging behind the right knee. On approximately May 16, she began to have similar symptoms in her left knee. Before this time she had had no significant health problems. Two siblings had been similarly vaccinated, without complications. O n May 19, 1970, she was hospitalized with a presumptive diagnosis of bilateral “Baker’s cysts.” O n physical examination a “firm, fixed, slightly indentable” mass I .5 cm in diameter was described on the posterior-medial aspect of her right knee, and a similar but smaller mass was believed to be present on the left. The masses were nontender, but pain behind the knees could be elicited by extension of the legs. The remainder of the physical examination was within normal limits. X-rays of the knees taken at that time have been reviewed and show slight soft tissue fullness posterior to the right knee joint, as compared with the left. O n May 27 an orthopedic consultant believed there was no longer any evidence of popliteal swelling. Rheumatic fever was considered, but an ESR and A S 0 titer were normal. The patient was then discharged with a diagnosis of postrubella vaccination arthritis. Shortly thereafter, knee symptoms resolved, the total duration of the initial episode having been approximately 4 weeks. Over the next 5 months the patient was well, except for occasional transient knee pains associated with vigorous exercise. On November 27, 1970,7.5 months after vaccination, the
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patient awoke and was unable to straighten her right leg. The right knee stiffness persisted and 3 days later she was examined by one of the authors. There was a 10" limitation of extension of the right knee joint secondary to pain, but no synovial thickening, tenderness, or evidence of effusion. ESR and an A S 0 titer were normal, a rubella virus HA1 antibody titer was 1:80, and tests for R F and A N A were negative. Several days later the stiffness subsided. Eleven months after vaccination the patient had a similar episode. Physical examination again revealed a 10-15" limitation of extension of the right knee secondary to pain (13). The next follow-up was made 4 years after vaccination, at which time the mother stated that the patient's knees continued to bother her. The patient sometimes had pain with vigorous exercise, and episodes of stiffness of a few days duration occurred every 6-8 weeks. Although usually the right knee was involved, the left knee or both knees were sometimes affected. Six months later, on November 7 , 1974, the patient was seen by one of the authors because of a 3-week episode of stiffness in her right knee, which was interfering with her athletic activity at school. The symptoms were worse in the morning and tended to recur if the patient was in a sitting position for a period of time. Physical examination revealed that the right knee was half-bent as she stood or attempted to walk. O n passive extension there was a 25" limitation secondary to pain. There was increased fullness in the lateral aspect of the right posterior knee joint, and the superior margin of the right patella was indistinctly felt. Rubella HA1 antibody titer was 1:U. In March 1975 the patient first began t o notice a clicking in her right knee. A damaged meniscus was considered likely, and on May 12, 1975, she was admitted to the University of Utah Medical Center for arthroscopy of the right knee joint. The patient had not had any acute episodes of joint stiffness for several weeks prior to admission. Examination on admission revealed a healthy appearing, cheerful 12-year-old girl. Vital signs were within normal limits. A click was demonstrable on extension of the right knee with either medial or lateral torsion. Resistance to extension was encountered at 10". Quantitative immunoglobulins, C, and C,, ANA, R F , and LE preparation were all normal. Rubella virus HA1 antibody titer had continued to decrease and was 1 :32. N o IgM rubella HA1 antibody was detectable. The patient's tissue type was determined and found to be AlO, A10, B6, B18. The immune response to rubella virus of the patient's peripheral lymphocytes was tested by means of a 61Cr-release assay for cell-mediated cytotoxic activity toward rubella-infected BHK-21 cells. The specific immune release (SIR) of lymphocytes was 10.0 f 3.6%. Although this value was slightly lower than the mean SIR exhibited by lymphocytes from two rubella antibody positive normal individuals (13.3% and 14.3%). the difference was not significant. Lymphocyte response to PHA stimulation was normal. The patient's lymphocytes were also tested for cytotoxic activity against one rheumatoid and two nonrheumatoid synovial cell lines. N o increased cytotoxicity for any of the three lines was observed. The patient was placed under general anesthesia and the right knee joint examined with a Wolfe 6.5-mm arthroscope. N o synovial fluid could be removed. The joint space was rinsed with normal saline, which was saved for viral culture. The articular surface of the patella was normal. The
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articular surfaces of the femoral condyles and tibia1 plateau also appeared normal. The medial and lateral menisci were normal and could be well visualized. The intercondylar notch area showed significant hypertrophy of the synovium. The synovium looked thickened and protruded in folds (Figure I ) . With the knee flexed, the synovium could be seen to impinge on the lateral joint space. As the knee was extended, a palpable click occurred at the point where there was approximately 20" of extension remaining. At this moment it could be observed through the arthroscope that the synovium slipped free from the joint space. This slippage could be consistently correlated. Biopsies were taken from the hypertrophied synovium in the intercondylar notch and also from more normal-appearing synovium in the suprapatellar region. The biopsy forceps were used to remove as much synovium as possible from the intercondylar notch; however additional folds of synovium appeared from the posterior popliteal fossa as traction was applied, and it was not possible to eliminate the click with the amount of synovium that could be removed through the art hroscope. Representative portions of the biopsy were sectioned and examined histologically. The synovium in the normalappearing suprapatellar region was unremarkable. The synovium from the intercondylar notch showed some areas of proliferation of the synovial lining cells, but no inflammatory cells could be seen (Figure 2). Biopsy tissue from the intercondylar notch and suprapatellar pouch was pooled and used for attempts at virus isolation. N o cytopathic effects were observed in any of the cultures, interference tests failed to reveal the presence of rubella virus, and indirect fluorescent antibody tests for rubella antigen were also negative. Postoperatively, the patient has continued to have problems. Six weeks after surgery she had an episode of stiffness in the left knee. On examination there was a 20" resistance to passive extension of the left knee, which could gradually be straightened but with discomfort. No tenderness or synovial thickening could be detected. Clicks were now demonstrable in both the left and right knees. Four months after surgery the patient was seen again in routine follow-up. The right knee was easily extended 170°, whereupon resistance was encountered. The knee could then be forced to full extension with a sudden "give" or apparent mechanical release. Although the patient was not having an acute episode, she walked with a limp without fully extending her right knee. Small amounts of aspirin were being used daily to control pain and stiffness. Arthrotomy and synovectomy might become necessary to control the patient's symptoms, but these procedures are being deferred until she is older.
DISCUSSION The possibility that chronic arthritis might be a sequela o f rubella vaccination has been the subject of considerable interest t o investigators ever since a high frequency of post-vaccination j o i n t complications was observed following t h e mass rubella vaccination compaigns in 1970. T h i s r e p o r t provides the first documentat i o n t h a t chronic j o i n t disease c a n , t h o u g h rarely, follow
CHRONIC ARTHROPATHY
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Fig 1. View ihrough the arthroscope and diagrammatic illusiration showing fold of synovium in ihe intercondylar notch oj Case 3.
Fig 2. Lighi microscopy of synovial tissue from the iniercondylar notch of Case 3. Hematoxylin and eosin
(X
300).
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rubella immunization. I n addition to one surgically proven case, 2 other of the children examined continued to have intermittent symptoms 5.5 years after vaccination, although at this point there is no objective evidence of joint disease. Thompson’s 3-year follow-up of 39 children with post-vaccination arthritis revealed that most children appeared to have resolved the problem, although 2 continued to have attacks in the 9 months prior to the last follow-up (14). A 2.5-year follow-up of 32 children by Shaffner similarly identified 2 children who were continuing to have recurrences (15). Whether the 6 remaining children in these three studies, all of whom have the “catcher’s crouch syndrome,” will resolve their problem or progress to overt joint disease must await a later fo Ilow- up. None of the present patients with “catcher’s crouch” developed any significant serologic or clinical evidence suggestive of rheumatoid arthritis or systemic lupus erythematosus. Two of the 1 1 children had reactive tests for RF (1:20) 7.5 months after vaccination, but the results of these tests were negative when repeated 2.5 months later (13). The authors have followed 2 other children, not part of the present study, who developed classic juvenile rheumatoid arthritis after receiving rubella vaccine in Utah’s mass vaccination campaign in 1970 (23). Because 188,000 children were vaccinated during the campaign, this association is viewed as coincidental. I n addition, rubella HA1 antibody tests in these 2 children were not unusually high, in contrast to the case of rheumatoid arthritis following rubella that was reported by Martenis (3). Controversy surrounds the question of whether the “catcher’s crouch” post-rubella vaccination syndrome is a neuritis or an arthritis. Shaffner has reviewed the argument in favor of a neuritic etiology, which includes the usual absence of objective evidence of joint inflammation, and the finding of abnormal nerve conduction velocities both in his study and that of Gilmartin ( 1 2,1524). The present authors feel that the evidence favors joint disease as the cause. Among our 1 1 patients, examination of 3 children during an acute episode revealed some evidence of joint inflammation: synovial thickening in one patient, joint tenderness and synovial thickening in another child, and joint swelling in a third. I n contrast to the description of the syndrome by Shaffner, none of these cases had knee joint pain at rest (as might be expected with neuritis), but only with forced extension. I n the third case there is a suggestion that there was posterior synovial hypertrophy 5 weeks after vaccination (“Baker’s cyst,” soft tissue fullness on x-
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ray) and 4 years after vaccination (fullness in the lateral popliteal fossa), in addition to posterior synovial hypertrophy seen at arthroscopy. This abnormal synovium may be sufficient to produce the symptoms of the “catcher’s crouch syndrome.” As the knee joint is extended, the posterior capsule tightens against the back of the knee joint. This mechanism could compress the hypertrophied synovium and cause pain and a limitation of motion. The episodic nature of the syndrome could be due to changes in the position of the redundant synovium or to transient inflammation. The mechanism by which rubella virus might produce synovial hypertrophy is unclear. Rubella virus has been isolated from the joint in both natural and post-vaccination rubella arthritis (25,26). However in these cases the children had more classic inflammatory arthritis with effusion and not the “catcher’s crouch syndrome.” Data from the third case weighs against persistent viral infection in “catcher’s crouch”: the gradually declining rubella HA1 antibody titers, the absence of IgM antibody, the absence of inflammatory cells in the biopsied synovium, and the inability to culture the virus. Possibly the virus is present only transiently in the joint several weeks after vaccination, and persistence of viral antigen or infection of chondrocytes plays a role (27.28). One of the authors has made arthroscopic observations that folds of hypertrophied synovium develop as an apparent reactive phenomenon in the post-traumatic or post-operative joint (29). Other puzzling problems include a) the apparent localization of the synovial hypertrophy to the intercondylar notch and posterior joint space; and b) the apparent absence of the “catcher’s crouch syndrome” as a complication of natural rubella. Local synovial reaction is an unprecedented form of viral joint disease, and suggests that the mechanism involved must similarly be unique and different from the inflammatory reaction of either direct viral joint invasion or viral immune-complex arthritis. Concerning the second question, it seems unlikely that “catcher’s crouch” has been overlooked as a complication of natural rubella. It is more likely to be a permutation of the virus inadvertently induced during the process of vaccine attenuation. It is fortunate that “catcher’s crouch” is uncommon and generally transient. The HPV-77DK12 strain of rubella vaccine is no longer produced, and “catcher’s crouch” has been seen only rarely with the currently available strains of rubella vaccine (15). Future live, attenuated virus vaccines should be subjected to longterm assessment to ensure that chronic reactions are not a complication.
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REFERENCES I . Judelsohn RG, Wyll SA: Rubella in Bermuda: termination of an epidemic by mass vaccination. J A M A 223:401406. 1973 2. Johnson RE, Hall AP: Rubella arthritis: report of cases studied by latex tests. N Engl J Med 258:743-745, 1958 3. Martenis TW, Bland J H , Phillips CA: Rheumatoid arthritis after rubella. Arthritis Rheum 11:683-685, 1968 4. Wilkes R M , Simsarian JP, Hopps HE, et al: Virologic studies on rheumatoid arthritis. Arthritis Rheum 16:446454, 1973 5. Ogra PL, Ogra SS, Chiba Y, et al: Rubella-virus infection in juvenile rheumatoid arthritis. Lancet 1:1157-1161, 1975 6. Smiley JD. Casey JL: Decreased C F antibodies in sera and decreased lymphocyte transformation to herpes simplex in patients with rheumatoid arthritis (RA). Arthritis Rheum 12:698, 1969 7. Kacaki J N , Balduzzi PC, Vaughan JH: A study of rubella haemagglutination inhibition antibodies in rheumatoid arthritis. Clin Exp lmmunol 6385-889, 1970 8. Christian CL, Phillips PE: Viruses and autoimmunity. Am J Med 54:661-620, 1973 9. Deinard AS, Bilka PJ, Venters H D , et al: Rubella-antibody titers in rheumatoid arthritis. Lancet 1:526-528, I974 10. Stanford F: Rubella-antibody titers in rheumatoid arthritis. Lancet 1:1000, 1974 1 I . Spruance SL, Smith CB: Joint complications associated with derivatives of HPV-77 rubella virus vaccine. Am J Dis Child 122:105-11 I , 1971 12. Kilroy AW, Schaffner W, Fleet WF, et al: Two syndromes following rubella immunization: clinical observations and epidemiological studies. JAMA 2 14:2287-2292, 1970 13. Spruance SL, Klock LE, Bailey A, et al: Recurrent joint symptoms in children vaccinated with HPV-77DK12 rubella vaccine. J Pediatr 8 0 4 1 3 4 1 7 , 1972 14. Thompson GR. Weiss JJ, Eloise MI, et al: Intermittent arthritis following rubella vaccination. Am J Dis Child 125526-530. 1973 15. Schaffner W, Fleet W F , Kilroy AW, et al: Polyneuropathy
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