J Neurosurg 47:561-566, 1977
The role of HLA B27 in the diagnosis and management of low-back pain and sciatica WILLIAM F. BINGHAM, M . D .
Department of Neurosurgery, Gundersen Clinic, Limited, and La Crosse Lutheran Hospital, La Crosse, Wisconsin Present diagnostic criteria for ankylosing spondylitis (AS) lean heavily on the xray examination, but there is much dispute as to its efficacy, especially in mild or early cases. Determinations of the HLA B27 histocompatibility antigen appear to define the population at risk far better than any other means. Of 31 patients who had the HLA B27 antigen, all had negative latex fixation tests and axial polyarthritic complaints (seronegative spondyloarthropathy or rheumatoid variant). Three had Reiter's syndrome and one had ulcerative colitis. Of the remaining 27 patients, nine had definite AS, 11 had probable AS, and seven had possible AS. Eleven of the 27 underwent at least one invasive spinal procedure (myelogram, laminectomy, fusion, facet denervation) before a diagnosis of AS was made. KEY WORDS 9 backache 9 histocompatibility antigen 9 histocompatibility testing 9 m y e l o g r a p h y 9 spinal fusion spondylitis 9 spondylitis, ankylosing
OR m a n y years ankylosing spondylitis (AS) was felt to be a rare, stereotyped, and debilitating disease. It is now appreciated that A S is relatively common, protean in symptomatology, and generally mild. 7,saSas Since the initial complaint is usually diffuse low-back pain with or without radiation into the buttocks and lower limbs, accurate and early diagnosis is especially important for the neurological and orthopedic surgeon. The diagnosis of AS is often missed, or at best delayed, despite a meticulous history, physical examination, and laboratory and radiological work-up. Sciatica is not an uncommon presenting complaint. Some individuals with A S even report an alternating phenomenon in which the pain shifts from side to side with weight bearing. Sciatic paresthesias are typically absent. When the onset is acute and episodic, lumbar disc dis-
F
J. Neurosurg. / Volume 47 / October, 1977
ease is frequently blamed. When s y m p t o m s are precipitated by trauma, the diagnosis is even m o r e obscured. 15 The "classic" physical findings are of little help. A critical analysis of chest expansion, TM for example, found considerable overlap between A S patients and the normal population. There m a y also be a disturbing c o n t r a d i c t i o n b e t w e e n s y m p tomatology and physical findings. One patient known to the author, but not included in the present study, has advanced A S with complete obliteration of both sacroiliac joints and an ankylosed lumbar spine. H e has been gainfully employed as a carpenter for m a n y years. His only complaint has been occasional, mild, diffuse backache. His underlying condition was discovered accidentally when he was injured at work and was subjected to diagnostic x-ray examination. Various l a b o r a t o r y tests, such as the erythrocyte sedimentation rate (ESR), lack specificity. Even the radiological 561
W. F. Bingham TABLE 1
HL.4 B27-positive patients
Diagnosis definite AS probable AS possible AS Reiter's syndrome enteropathic spondylitis total
Male 6 9 4 3 1 23
Female Total 3 9 2 11 3 7 0 3 0 1 8 31
examination has many sources of error (see below). In 1973, two teams researching in tissue transplantation independently reported that 88% to 96% of AS patients were found to have the H L A B27 (formerly W27) histocompatibility antigen compared to 4.8% of persons in a normal population. 8,2s Two subsequent prospective studies of normal, healthy B27-positive volunteers revealed an increased prevalence of the disease in a subclinical, low-grade, or atypical form. 7,s Both studies supported the notion that AS was far more prevalent than previously thought. In view of the diagnostic and therapeutic problems posed by early AS, especially when low-back pain and sciatica are the presenting complaints, a retrospective analysis of our B27 positive population was performed. Clinical Materials and Methods
The study includes the first 145 H L A B27 tests ordered at the Gundersen Clinic/La Crosse Lutheran Hospital complex during the period from April 18, 1975, to September 30, 1976. The first 18 determinations were made by the Tissue Typing Laboratory of the Department of Surgery at UCLA. Most testing was performed with the microdroplet lymphocyte cytotoxicity method; 17however, a few determinations were made with the newly developed platelet antigen inhibition technique? All subsequent testing was performed by the Immunobiology Research Center in Madison, Wisconsin, using only the former method. All charts were reviewed by the author. Multiple factors (presenting complaint, sex, occupation, and other historical items; physical examination, especially objective neurological, orthopedic, and rheumatological findings; laboratory and radiographic studies) were analyzed to determine 562
the efficacy of the test compared to traditional means of diagnosis. A diagnosis of definite AS was made when the patient fully satisfied Ogryzlo's modification 28 of the Rome criteria. A diagnosis of probable AS was made when the disease was strongly suspected but these criteria could not be met fully. In keeping with the epidemiological tenets of the American Rheumatism Association, 26 a diagnosis of possible AS was made when none of the diagnostic criteria could be met aside from a history of low-back pain with associated equivocal physical and radiological findings. Traditionally, the first two categories have been used for clinical investigation and statistical reporting. The third category necessarily includes subjects who may never develop AS. Summary of Cases
Thirty-one of the 145 patients screened had the H L A B27 antigen (Table 1). All had negative latex fixation tests and axial polyarthritic complaints (seronegative spondyloarthropathy or rheumatoid variant). Three of the positive patients had Reiter's syndrome; an additional patient with this disease did not have B27. This incidence of 75% corresponds roughly to the 63% to 96% positivity reported in the literature. 1,2,4,19,21 One B27-positive patient had ulcerative colitis; one B27negative patient had Crohn's disease. In 60% to 75% of patients with enteropathic spondylitis B27 is present. 2,4,2~ No patients were encountered with psoriatic spondylitis, Yersinia arthritis, or juvenile rheumatoid arthritis. All of these diseases are associated with significant B27 positivity? ,2,',1e,21,2. Several patients had uveitis, another entity with increased B27 positivity, 2,*,5 but this was always in association with definite AS or Reiter's syndrome. No patients with uveitis were encountered who did not have the B27 antigen. The remaining 27 B27-positive patients thus constituted a population of special interest, namely those persons without evidence of other obvious disease who presented with various combinations of pain in the low back, hips, and lower limbs. These patients are graphically depicted in Figure 1 according to the decades in which they were found to be B27 positive. Multiple data (sex, age at time of B27 diagnosis, occupation, trauma history, presenting complaints, highest ESR, history J. Neurosurg. / Volume 47 / October, 1977
Histocompatibility testing in ankylosing spondylitis Illustrative Cases
Case 9
0-9
10-19 20-29 30-39 40-49 50-59 60-69 70-79 AGE AT TIME OF B27 TESTING m
Definite ankylosing spondylitis
WL~'J Probable ankylosing spondylitis I'"1
Possible ankylosing spondylitis
FIG. 1. Graphic depiction of the HLA B27positive population (excluding three patients with Reiter's syndrome and one patient with ulcerative colitis) arranged according to the decades in which the patients were found to be B27-positive. of invasive spinal procedures, and diagnosis) for this population are tabulated in Table 2. Except for five patients with migratory joint pains, the presenting complaint was usually low-back pain with or without radiation into the hips or lower limbs. Classic sciatica was encountered in six cases. Most occupations were represented; in fact, it was surprising that some individuals continued to work in physically demanding occupations with minimal complaints. All 31 patients were white, usually of Nordic descent. Patients with definite AS tended to declare themselves at an early age without a history of trauma. The ESR was generally but inconsistently elevated. The initial radiographs were frequently diagnostic, and the diagnosis was sometimes made on the very first clinic visit. The group with probable AS presented in a variety of ways. Diagnosis and treatment were often prolonged and complicated. This was clearly the most troublesome subgroup from a diagnostic and therapeutic standpoint. Patients with possible AS tended to relate a history of trauma, develop symptoms in later life, and complain of mechanical low-back pain.
J. Neurosurg. / Volume 47 / October, 1977
This 26-year-old man sustained an anterior wedge compression fracture of the first lumbar vertebral body in an industrial accident in 1970. Over the ensuing 6 years, he had a total of seven plain films taken of the lumbar spine, pelvis, and abdomen for recurrent low-back pain and other medical problems. On the seventh examination, the fifth radiologist to view his films commented upon erosion and widening of the inferior portion of the right sacroiliac joint (Fig. 2 upper right). In retrospect, these changes were present on his initial films (Fig. 2 upper left). Tomograms of the sacroiliac joints showed unequivocal bilateral inflammatory changes (Fig. 2 lower left). His HLA B27 test was positive, and a diagnosis of definite AS was made on the basis of his clinical and radiographic findings.
Case 14 This 34-year-old man first developed lowback pain while working on a construction project in 1964. He underwent a lumbar myelogram and an anterior lumbosacral discectomy and fusion in 1967. Because of recurrent low-back pain he underwent a repeat myelogram in 1973, followed by an L3-4 and L4-5 laminectomy and bilateral L4-5 discectomy. Six months later he underwent a repeat laminectomy for "removal of scar tissue between L-4,5." One of the L-5 roots was inadvertently partially severed. A bilateral posterolateral L4-5 fusion was then performed. In 1976, the patient presented at the Gundersen Clinic with chief complaints of "leg aching, neck pain and stiffness, and back pain . . . usually the back pain is simply a nuisance." There were no objective neurological findings. Chest expansion was 4 cm; ESR was 1 mm/hr. The Minnesota Multiphasic Personality Inventory was diagnostic of depression. X-ray films of the lumbar spine showed a pseudoarthrosis at L4-5, with erosion of the midportion of the left sacroilac joint. The HLA B27 test was positive, and a diagnosis of probable AS was made. Discussion
Present diagnostic criteria lean heavily on the radiological examination.7,8,1~ This 563
W. F. Bingham TABLE 2
Comparative data for 27 HLA B27-positive patients* Case No. 1 2
Sex, Age (yrs)
Occupation Trauma History
Presenting Complaints
ESR
M, 19 student M, 19 grocery clerk F, 20 student M, 23 mechanic M, 23 laborer M, 24 farmer F, 24 bank clerk
no no
polyarthralgias polyarthralgias
no no yes no no
LBP, rt hip pain LBP LBP, rt sciatica LBP LBP, rt sciatica
8 9 10 11 12 13 14
F, M, F, M, M, M, M,
secretary laborer secretary machinist mason merchant laborer
no yes yes no yes no yes
LBP, bilat hip pain LBP LBP, It leg pain LBP LBP LBP, foot pain LBP
15 16 17
M, 36 executive M, 37 executive F, 40 teacher
no yes yes
LBP LBP, rt leg pain LBP, It sciatica
18
F, 40 ind artist
yes
LBP, It sciatica
19 20
F, 44 librarian M, 46 farmer
no yes
polyarthralgias LBP, rt sciatica
21 22
yes no
LBP, rt sciatica LBP
23 24
M, 46 farmer F, 48 factory worker F, 50 secretary M, 51 trucker
no yes
polyarthralgias LBP
25 26 27
M, 53 machinist M, 60 electrician M, 62 machinist
yes yes yes
LBP polyarthralgias LBP
3 4 5 6 7
26 26 30 33 33 34 34
8 7
Invasive Spinal Procedures ---
65 rt SI biopsy, fusion 4 -13 myelogram 13 -7 myelogram, rt L5-$1 discectomy 63 -9 -51 myelogram 11 -18 -67 -1 myelogram, ant L5-S1 discectomy/fusion; myelogram, post bilat L4-5 discectomy; post bilat L4-5 neurolysis, fusion 4 -2 myelogram 24 myelogram, It L5-S1 discectomy 19 myelogram, It L4-5 discectomy 7 -17 myelogram, rt L5-$1 discectomy 12 myelogram 6 -44 -12 myelogram, mult facet denervations 1 -22 -5 --
Diagnosis prob AS prob AS def AS prob AS prob AS defAS HNP; poss AS def AS defAS prob AS defAS defAS def AS pseudoarthrosis; prob AS
prob AS def AS HNP, poss AS HNP; poss AS prob AS prob AS prob AS poss AS def AS poss AS poss AS prob AS poss AS
*Three patients with Reiter's syndrome and one patient with ulcerative colitis not included. Abbreviations: AS = ankylosing spondylitis; ESR = erythrocyte sedimentation rate; HNP = herniated nucleus pulposus; LBP = low-back pain; SI = sacroiliac.
is u n f o r t u n a t e since t h e sacroiliac j o i n t s a r e p r o b a b l y t h e m o s t difficult ones to i n t e r p r e t r a d i o l o g i c a l l y , p a r t i c u l a r l y in adolescent a n d m i l d cases. 1~ T h e r e is no single view which s h o w s all p a r t s o f t h e j o i n t to a d v a n t a g e . 1~ T h e r e is no c o m m o n l y a c c e p t e d system e f int e r p r e t a t i o n o f g r a d i n g . 1~ A tendency m a y also exist on t h e p a r t o f r a d i o l o g i s t s to u n d e r d i a g n o s e A S b e c a u s e o f its p r e s u m e d rarity. 7 W h e n t h e r a d i o l o g i c a l criteria for the diagnosis of ankylosing spondylitis are a p p l i e d in a c r i t i c a l fashion, m u l t i p l e ab564
normalities are noted that were previously missed. C a l i n and F r i e s 7 f o u n d no n o r m a l s a c r o i l i a c j o i n t s in t h e i r r e t r o s p e c t i v e study o f pelvic x - r a y films in 19 " h e a l t h y " persons who were B27-positive. This c o n t r a s t e d significantly with o n l y nine o f 36 c o n t r o l s with r a d i o g r a p h i c a b n o r m a l i t i e s . C o h e n , et al., a also f o u n d a s t a t i s t i c a l l y significant increase in s a c r o i l i a c a b n o r m a l i t i e s in their study o f 24 B 2 7 - p o s i t i v e p a t i e n t s a n d their m a t c h e d c o n t r o l s . O f t h e 23 patients w h o a l l o w e d pelvic x - r a y f i l m s to be t a k e n , only
J. Neurosurg. / Volume 47 / October, 1977
Histocompatibility testing in ankylosing spondylitis
Fl~. 2. Case 9. Upper Left: Anteroposterior film of lumbosacral spine taken in 1970. An anterior wedge compression fracture of L-1 is not evident on this view, but erosion and widening of the inferior portion of the right sacroiliac joint are clearly seen (arrow). The left sacroiliac joint is normal. Upper Right." A similar view taken in 1976. There had been minimal interim changes in either joint, but those on the right were first commented upon at this time. Lower Left: Anteroposterior tomographic cut through both sacroiliac joints taken in 1976 showing unequivocal bilateral inflammatory changes (arrows). nine were free of any cortical breaks, erosions, and sclerosis involving the sacroiliac joints. There were statistically significant differences between the B27 group and their matched controls for bilateral cortical breaks and unilateral and bilateral erosions. Asymmetrical involvement, sometimes only unilateral a b n o r m a l i t y , was commonly encountered. The most disturbing association of the present study was the high incidence of invasive spinal procedures (myelogram, laminectomy, fusion, facet denervation). Eleven of the 27 patients underwent at least one invasive spinal procedure. Three of the 11 had classic sciatica and symptoms suggesting pain of mechanical origin. Their physical and myelographic findings were consistent with lumbar disc herniations. At laminectomy, two patients had extruded discs, and the third had a modest midline disc protrusion. The former two have done well postoperatively. The third remains symptomatic, but she has improved considerably over her preoperative status. Therapeutic plans for two patients (Cases 9 and 12) were altered radically when they were found to be J. Neurosurg. / Volume 4 7 / October, 1977
B27-positive. More critical clinical and x-ray assessment resulted in a diagnosi~ oi" definite AS in both. No myelogram or surgery was performed, although these were the principal reasons for admission. Unlike m a n y of the other screening tests, such as lumbosacral spine films, ESR, white blood count, and rheumatoid factor, the H L A B27 test result will not vary. Like a person's ABO blood group the antigen is genetically determined? a2 It is either present or absent, and a single reliable determination suffices. Grahame, et al., la found the H L A B27 test to be of little value as a screening technique in the orthopedic clinic. In their survey, the prevalence of B27-positive patients did not differ greatly from that of AS in the parent population. In the author's experience the test has been more useful for inpatients, particularly those for whom invasive diagnostic and/or therapeutic spinal procedures are considered. Case 14 serves as an excellent example. The literature describes many similar diagnostic and therapeutic dilemmas? a~ To be sure, the patient may harbor both ankylosing spondylitis and a lumbar disc rupture, and he may require appropriate therapy 565
W. F. Bingham for each condition (Cases 7, 17, and 18). The patient may be one of the 4% to 8% of the normal population who is B27-positive, and effective surgical treatment may even be postponed or declined because of a false-positive result. Similarly, the clinician should not exclude a diagnosis of A S because the test is falsely negative. Results should be interpreted cautiously with the intent of modifying the diagnostic work-up and therapeutic plans if there is reason to believe the patient has AS in one of its protean forms. Acknowledgments
The author is indebted to Drs. George Liang and Kermit Newcomer for their many helpful comments; Mrs. Susan Stetter for secretarial assistance; Mr. Joseph Tiedt and Mr. Larry LaSeure for photographic help; and Miss Kathy Troyanek for artwork. References
1. Aho K, Ahvonen P, Lassus A, et al: HL-A 27 in reactive arthritis. A study of Yersinia arthritis and Reiter's disease. Arthritis Rheum 17:521-526, 1974 2. Arnett FC Jr: The implications of HL-A W27. Ann Intern Med 84:94-95, 1976 (Editorial) 3. Billings R J, Terasaki PI: A platelet antigen inhibition test for B27. (In preparation) 4. Brewerton DA: HLA-B27 and the inheritance of susceptibility to rheumatic disease. Arthritis Rheum 19:656-668, 1976 5. Brewerton DA, Caffrey M, Nicholls A, et al: Acute anterior uveitis and HL-A 27. Lancet 2:994-996, 1973 6. Brewerton DA, Hart FD, Nicholls A, et al: Ankylosing spondylitis and HL-A 27. Lancet 1:904-907, 1973 7. Calin A, Fries JF: Striking prevalence of ankylosing spondylitis in "healthy" W27 positive males and females. N Engl J Med 293:835-839, 1975 8. Cohen LM, Mittal KK, Schmid FR, et al: Increased risk for spondylitis stigmata in apparently healthy HL-A W27 men. Ann Intern Med 84:1-7, 1976 9. Finneson BE: Low Back Pain. Philadelphia: JB Lippincott, 1973, 376 pp 10. Forrester DM, Nesson JW: The Radiology of Joint Disease. Philadelphia: WB Saunders, 1973, pp 421-446 11. Gofton JP: Report from the subcommittee on diagnostic criteria for ankylosing spondylitis, in Bennett PH, Wood PHN (eds): Population Studies of the Rheumatic Diseases. Amsterdam: Excerpta Medica, 1966, pp 314-316 12. Golding FC: The radiology of the rheumatic diseases, in Copeman WSC (ed): Textbook of 566
the Rheumatic Diseases, ed 4. Edinburgh: E
and S Livingstone, 1969, pp 734-774 13. Grahame R, Calin A, Tudor M, et al: Cited in Reference 7 14. Macrae IF, Haslock DI, Wright V: Grading of films for sacro-iliitis in population studies. Ann Rheum Dis 30:58-66, 1971 15. Mason RM: Ankylosing spondylitis, in Copeman WSC (ed): Textbook of the Rheumatic Diseases, ed 4. Edinburgh: E and S Livingstone, 1969, pp 344-365 16. Metzger AL, Morris RI, Bluestone R, et al: HL-A W27 in psoriatic arthropathy. Arthritis Rheum 18:111-115, 1975 17. Mittal KK, Mickey MR, Singal DP, et al: Serotyping for homotransplantation. XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6:913-927, 1968 18. Moll JMH, Wright V: An objective clinical study of chest expansion. Ann Rheum Dis 31:1-8, 1972 19. Morris R, Metzger AL, Bluestone R, et al: HL-A W27 - a clue to the diagnosis and pathogenesis of Reiter's syndrome. N Engl J Med 290:554-556, 1974 20. Morris RI, Metzger AL, Bluestone R, et al: HL-A W27 - a useful discriminator in the arthropathies of inflammatory bowel disease. N Engl J Med 290:1117-1119, 1974 21. McCluskey OE, Lordon RE, Arnett FC Jr: HL-A 27 in Reiter's syndrome and psoriatic arthritis: a genetic factor in disease susceptibility and expression. J Rheum 1:263-268, 1974 22. McKusick VA: Human Genetics, ed 2. Englewood Cliffs, N J: Prentice-Hall, 1969 23. Ogryzlo MA: Ankylosing spondylitis, in Hollander JL, McCarty DJ (eds): Arthritis and Allied Conditions, ed 8. Philadelphia: Lea and Febiger, 1972, pp 699-723 24. Rachelefsky GS, Terasaki PI, Katz R, et al: Increased prevalence of W27 in juvenile rheumatoid arthritis. N Engl J Med 290: 892-893, 1974 25. Schlosstein L, Terasaki PI, Bluestone R, et al: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704-706, 1973 26. Wolfe AM: The epidemiology of rheumatoid arthritis: a review. Part II. Incidence and diagnostic criteria. Bull Rheum Dis 19:524-526, 1968 This paper was presented in part at the Annual Meeting of the Wisconsin Neurosurgical Society, Lake Geneva, Wisconsin, on October 2, 1976. Address reprint requests to: William F. Bingham, M.D., Department of Neurosurgery, Gundersen Clinic, Ltd., La Crosse, Wisconsin 54601.
J. Neurosurg. / Volume 4 7 / October, 1977
The role of HLA B27 in the diagnosis and management of low-back pain and sciatica WILLIAM F. BINGHAM, M . D .
Department of Neurosurgery, Gundersen Clinic, Limited, and La Crosse Lutheran Hospital, La Crosse, Wisconsin Present diagnostic criteria for ankylosing spondylitis (AS) lean heavily on the xray examination, but there is much dispute as to its efficacy, especially in mild or early cases. Determinations of the HLA B27 histocompatibility antigen appear to define the population at risk far better than any other means. Of 31 patients who had the HLA B27 antigen, all had negative latex fixation tests and axial polyarthritic complaints (seronegative spondyloarthropathy or rheumatoid variant). Three had Reiter's syndrome and one had ulcerative colitis. Of the remaining 27 patients, nine had definite AS, 11 had probable AS, and seven had possible AS. Eleven of the 27 underwent at least one invasive spinal procedure (myelogram, laminectomy, fusion, facet denervation) before a diagnosis of AS was made. KEY WORDS 9 backache 9 histocompatibility antigen 9 histocompatibility testing 9 m y e l o g r a p h y 9 spinal fusion spondylitis 9 spondylitis, ankylosing
OR m a n y years ankylosing spondylitis (AS) was felt to be a rare, stereotyped, and debilitating disease. It is now appreciated that A S is relatively common, protean in symptomatology, and generally mild. 7,saSas Since the initial complaint is usually diffuse low-back pain with or without radiation into the buttocks and lower limbs, accurate and early diagnosis is especially important for the neurological and orthopedic surgeon. The diagnosis of AS is often missed, or at best delayed, despite a meticulous history, physical examination, and laboratory and radiological work-up. Sciatica is not an uncommon presenting complaint. Some individuals with A S even report an alternating phenomenon in which the pain shifts from side to side with weight bearing. Sciatic paresthesias are typically absent. When the onset is acute and episodic, lumbar disc dis-
F
J. Neurosurg. / Volume 47 / October, 1977
ease is frequently blamed. When s y m p t o m s are precipitated by trauma, the diagnosis is even m o r e obscured. 15 The "classic" physical findings are of little help. A critical analysis of chest expansion, TM for example, found considerable overlap between A S patients and the normal population. There m a y also be a disturbing c o n t r a d i c t i o n b e t w e e n s y m p tomatology and physical findings. One patient known to the author, but not included in the present study, has advanced A S with complete obliteration of both sacroiliac joints and an ankylosed lumbar spine. H e has been gainfully employed as a carpenter for m a n y years. His only complaint has been occasional, mild, diffuse backache. His underlying condition was discovered accidentally when he was injured at work and was subjected to diagnostic x-ray examination. Various l a b o r a t o r y tests, such as the erythrocyte sedimentation rate (ESR), lack specificity. Even the radiological 561
W. F. Bingham TABLE 1
HL.4 B27-positive patients
Diagnosis definite AS probable AS possible AS Reiter's syndrome enteropathic spondylitis total
Male 6 9 4 3 1 23
Female Total 3 9 2 11 3 7 0 3 0 1 8 31
examination has many sources of error (see below). In 1973, two teams researching in tissue transplantation independently reported that 88% to 96% of AS patients were found to have the H L A B27 (formerly W27) histocompatibility antigen compared to 4.8% of persons in a normal population. 8,2s Two subsequent prospective studies of normal, healthy B27-positive volunteers revealed an increased prevalence of the disease in a subclinical, low-grade, or atypical form. 7,s Both studies supported the notion that AS was far more prevalent than previously thought. In view of the diagnostic and therapeutic problems posed by early AS, especially when low-back pain and sciatica are the presenting complaints, a retrospective analysis of our B27 positive population was performed. Clinical Materials and Methods
The study includes the first 145 H L A B27 tests ordered at the Gundersen Clinic/La Crosse Lutheran Hospital complex during the period from April 18, 1975, to September 30, 1976. The first 18 determinations were made by the Tissue Typing Laboratory of the Department of Surgery at UCLA. Most testing was performed with the microdroplet lymphocyte cytotoxicity method; 17however, a few determinations were made with the newly developed platelet antigen inhibition technique? All subsequent testing was performed by the Immunobiology Research Center in Madison, Wisconsin, using only the former method. All charts were reviewed by the author. Multiple factors (presenting complaint, sex, occupation, and other historical items; physical examination, especially objective neurological, orthopedic, and rheumatological findings; laboratory and radiographic studies) were analyzed to determine 562
the efficacy of the test compared to traditional means of diagnosis. A diagnosis of definite AS was made when the patient fully satisfied Ogryzlo's modification 28 of the Rome criteria. A diagnosis of probable AS was made when the disease was strongly suspected but these criteria could not be met fully. In keeping with the epidemiological tenets of the American Rheumatism Association, 26 a diagnosis of possible AS was made when none of the diagnostic criteria could be met aside from a history of low-back pain with associated equivocal physical and radiological findings. Traditionally, the first two categories have been used for clinical investigation and statistical reporting. The third category necessarily includes subjects who may never develop AS. Summary of Cases
Thirty-one of the 145 patients screened had the H L A B27 antigen (Table 1). All had negative latex fixation tests and axial polyarthritic complaints (seronegative spondyloarthropathy or rheumatoid variant). Three of the positive patients had Reiter's syndrome; an additional patient with this disease did not have B27. This incidence of 75% corresponds roughly to the 63% to 96% positivity reported in the literature. 1,2,4,19,21 One B27-positive patient had ulcerative colitis; one B27negative patient had Crohn's disease. In 60% to 75% of patients with enteropathic spondylitis B27 is present. 2,4,2~ No patients were encountered with psoriatic spondylitis, Yersinia arthritis, or juvenile rheumatoid arthritis. All of these diseases are associated with significant B27 positivity? ,2,',1e,21,2. Several patients had uveitis, another entity with increased B27 positivity, 2,*,5 but this was always in association with definite AS or Reiter's syndrome. No patients with uveitis were encountered who did not have the B27 antigen. The remaining 27 B27-positive patients thus constituted a population of special interest, namely those persons without evidence of other obvious disease who presented with various combinations of pain in the low back, hips, and lower limbs. These patients are graphically depicted in Figure 1 according to the decades in which they were found to be B27 positive. Multiple data (sex, age at time of B27 diagnosis, occupation, trauma history, presenting complaints, highest ESR, history J. Neurosurg. / Volume 47 / October, 1977
Histocompatibility testing in ankylosing spondylitis Illustrative Cases
Case 9
0-9
10-19 20-29 30-39 40-49 50-59 60-69 70-79 AGE AT TIME OF B27 TESTING m
Definite ankylosing spondylitis
WL~'J Probable ankylosing spondylitis I'"1
Possible ankylosing spondylitis
FIG. 1. Graphic depiction of the HLA B27positive population (excluding three patients with Reiter's syndrome and one patient with ulcerative colitis) arranged according to the decades in which the patients were found to be B27-positive. of invasive spinal procedures, and diagnosis) for this population are tabulated in Table 2. Except for five patients with migratory joint pains, the presenting complaint was usually low-back pain with or without radiation into the hips or lower limbs. Classic sciatica was encountered in six cases. Most occupations were represented; in fact, it was surprising that some individuals continued to work in physically demanding occupations with minimal complaints. All 31 patients were white, usually of Nordic descent. Patients with definite AS tended to declare themselves at an early age without a history of trauma. The ESR was generally but inconsistently elevated. The initial radiographs were frequently diagnostic, and the diagnosis was sometimes made on the very first clinic visit. The group with probable AS presented in a variety of ways. Diagnosis and treatment were often prolonged and complicated. This was clearly the most troublesome subgroup from a diagnostic and therapeutic standpoint. Patients with possible AS tended to relate a history of trauma, develop symptoms in later life, and complain of mechanical low-back pain.
J. Neurosurg. / Volume 47 / October, 1977
This 26-year-old man sustained an anterior wedge compression fracture of the first lumbar vertebral body in an industrial accident in 1970. Over the ensuing 6 years, he had a total of seven plain films taken of the lumbar spine, pelvis, and abdomen for recurrent low-back pain and other medical problems. On the seventh examination, the fifth radiologist to view his films commented upon erosion and widening of the inferior portion of the right sacroiliac joint (Fig. 2 upper right). In retrospect, these changes were present on his initial films (Fig. 2 upper left). Tomograms of the sacroiliac joints showed unequivocal bilateral inflammatory changes (Fig. 2 lower left). His HLA B27 test was positive, and a diagnosis of definite AS was made on the basis of his clinical and radiographic findings.
Case 14 This 34-year-old man first developed lowback pain while working on a construction project in 1964. He underwent a lumbar myelogram and an anterior lumbosacral discectomy and fusion in 1967. Because of recurrent low-back pain he underwent a repeat myelogram in 1973, followed by an L3-4 and L4-5 laminectomy and bilateral L4-5 discectomy. Six months later he underwent a repeat laminectomy for "removal of scar tissue between L-4,5." One of the L-5 roots was inadvertently partially severed. A bilateral posterolateral L4-5 fusion was then performed. In 1976, the patient presented at the Gundersen Clinic with chief complaints of "leg aching, neck pain and stiffness, and back pain . . . usually the back pain is simply a nuisance." There were no objective neurological findings. Chest expansion was 4 cm; ESR was 1 mm/hr. The Minnesota Multiphasic Personality Inventory was diagnostic of depression. X-ray films of the lumbar spine showed a pseudoarthrosis at L4-5, with erosion of the midportion of the left sacroilac joint. The HLA B27 test was positive, and a diagnosis of probable AS was made. Discussion
Present diagnostic criteria lean heavily on the radiological examination.7,8,1~ This 563
W. F. Bingham TABLE 2
Comparative data for 27 HLA B27-positive patients* Case No. 1 2
Sex, Age (yrs)
Occupation Trauma History
Presenting Complaints
ESR
M, 19 student M, 19 grocery clerk F, 20 student M, 23 mechanic M, 23 laborer M, 24 farmer F, 24 bank clerk
no no
polyarthralgias polyarthralgias
no no yes no no
LBP, rt hip pain LBP LBP, rt sciatica LBP LBP, rt sciatica
8 9 10 11 12 13 14
F, M, F, M, M, M, M,
secretary laborer secretary machinist mason merchant laborer
no yes yes no yes no yes
LBP, bilat hip pain LBP LBP, It leg pain LBP LBP LBP, foot pain LBP
15 16 17
M, 36 executive M, 37 executive F, 40 teacher
no yes yes
LBP LBP, rt leg pain LBP, It sciatica
18
F, 40 ind artist
yes
LBP, It sciatica
19 20
F, 44 librarian M, 46 farmer
no yes
polyarthralgias LBP, rt sciatica
21 22
yes no
LBP, rt sciatica LBP
23 24
M, 46 farmer F, 48 factory worker F, 50 secretary M, 51 trucker
no yes
polyarthralgias LBP
25 26 27
M, 53 machinist M, 60 electrician M, 62 machinist
yes yes yes
LBP polyarthralgias LBP
3 4 5 6 7
26 26 30 33 33 34 34
8 7
Invasive Spinal Procedures ---
65 rt SI biopsy, fusion 4 -13 myelogram 13 -7 myelogram, rt L5-$1 discectomy 63 -9 -51 myelogram 11 -18 -67 -1 myelogram, ant L5-S1 discectomy/fusion; myelogram, post bilat L4-5 discectomy; post bilat L4-5 neurolysis, fusion 4 -2 myelogram 24 myelogram, It L5-S1 discectomy 19 myelogram, It L4-5 discectomy 7 -17 myelogram, rt L5-$1 discectomy 12 myelogram 6 -44 -12 myelogram, mult facet denervations 1 -22 -5 --
Diagnosis prob AS prob AS def AS prob AS prob AS defAS HNP; poss AS def AS defAS prob AS defAS defAS def AS pseudoarthrosis; prob AS
prob AS def AS HNP, poss AS HNP; poss AS prob AS prob AS prob AS poss AS def AS poss AS poss AS prob AS poss AS
*Three patients with Reiter's syndrome and one patient with ulcerative colitis not included. Abbreviations: AS = ankylosing spondylitis; ESR = erythrocyte sedimentation rate; HNP = herniated nucleus pulposus; LBP = low-back pain; SI = sacroiliac.
is u n f o r t u n a t e since t h e sacroiliac j o i n t s a r e p r o b a b l y t h e m o s t difficult ones to i n t e r p r e t r a d i o l o g i c a l l y , p a r t i c u l a r l y in adolescent a n d m i l d cases. 1~ T h e r e is no single view which s h o w s all p a r t s o f t h e j o i n t to a d v a n t a g e . 1~ T h e r e is no c o m m o n l y a c c e p t e d system e f int e r p r e t a t i o n o f g r a d i n g . 1~ A tendency m a y also exist on t h e p a r t o f r a d i o l o g i s t s to u n d e r d i a g n o s e A S b e c a u s e o f its p r e s u m e d rarity. 7 W h e n t h e r a d i o l o g i c a l criteria for the diagnosis of ankylosing spondylitis are a p p l i e d in a c r i t i c a l fashion, m u l t i p l e ab564
normalities are noted that were previously missed. C a l i n and F r i e s 7 f o u n d no n o r m a l s a c r o i l i a c j o i n t s in t h e i r r e t r o s p e c t i v e study o f pelvic x - r a y films in 19 " h e a l t h y " persons who were B27-positive. This c o n t r a s t e d significantly with o n l y nine o f 36 c o n t r o l s with r a d i o g r a p h i c a b n o r m a l i t i e s . C o h e n , et al., a also f o u n d a s t a t i s t i c a l l y significant increase in s a c r o i l i a c a b n o r m a l i t i e s in their study o f 24 B 2 7 - p o s i t i v e p a t i e n t s a n d their m a t c h e d c o n t r o l s . O f t h e 23 patients w h o a l l o w e d pelvic x - r a y f i l m s to be t a k e n , only
J. Neurosurg. / Volume 47 / October, 1977
Histocompatibility testing in ankylosing spondylitis
Fl~. 2. Case 9. Upper Left: Anteroposterior film of lumbosacral spine taken in 1970. An anterior wedge compression fracture of L-1 is not evident on this view, but erosion and widening of the inferior portion of the right sacroiliac joint are clearly seen (arrow). The left sacroiliac joint is normal. Upper Right." A similar view taken in 1976. There had been minimal interim changes in either joint, but those on the right were first commented upon at this time. Lower Left: Anteroposterior tomographic cut through both sacroiliac joints taken in 1976 showing unequivocal bilateral inflammatory changes (arrows). nine were free of any cortical breaks, erosions, and sclerosis involving the sacroiliac joints. There were statistically significant differences between the B27 group and their matched controls for bilateral cortical breaks and unilateral and bilateral erosions. Asymmetrical involvement, sometimes only unilateral a b n o r m a l i t y , was commonly encountered. The most disturbing association of the present study was the high incidence of invasive spinal procedures (myelogram, laminectomy, fusion, facet denervation). Eleven of the 27 patients underwent at least one invasive spinal procedure. Three of the 11 had classic sciatica and symptoms suggesting pain of mechanical origin. Their physical and myelographic findings were consistent with lumbar disc herniations. At laminectomy, two patients had extruded discs, and the third had a modest midline disc protrusion. The former two have done well postoperatively. The third remains symptomatic, but she has improved considerably over her preoperative status. Therapeutic plans for two patients (Cases 9 and 12) were altered radically when they were found to be J. Neurosurg. / Volume 4 7 / October, 1977
B27-positive. More critical clinical and x-ray assessment resulted in a diagnosi~ oi" definite AS in both. No myelogram or surgery was performed, although these were the principal reasons for admission. Unlike m a n y of the other screening tests, such as lumbosacral spine films, ESR, white blood count, and rheumatoid factor, the H L A B27 test result will not vary. Like a person's ABO blood group the antigen is genetically determined? a2 It is either present or absent, and a single reliable determination suffices. Grahame, et al., la found the H L A B27 test to be of little value as a screening technique in the orthopedic clinic. In their survey, the prevalence of B27-positive patients did not differ greatly from that of AS in the parent population. In the author's experience the test has been more useful for inpatients, particularly those for whom invasive diagnostic and/or therapeutic spinal procedures are considered. Case 14 serves as an excellent example. The literature describes many similar diagnostic and therapeutic dilemmas? a~ To be sure, the patient may harbor both ankylosing spondylitis and a lumbar disc rupture, and he may require appropriate therapy 565
W. F. Bingham for each condition (Cases 7, 17, and 18). The patient may be one of the 4% to 8% of the normal population who is B27-positive, and effective surgical treatment may even be postponed or declined because of a false-positive result. Similarly, the clinician should not exclude a diagnosis of A S because the test is falsely negative. Results should be interpreted cautiously with the intent of modifying the diagnostic work-up and therapeutic plans if there is reason to believe the patient has AS in one of its protean forms. Acknowledgments
The author is indebted to Drs. George Liang and Kermit Newcomer for their many helpful comments; Mrs. Susan Stetter for secretarial assistance; Mr. Joseph Tiedt and Mr. Larry LaSeure for photographic help; and Miss Kathy Troyanek for artwork. References
1. Aho K, Ahvonen P, Lassus A, et al: HL-A 27 in reactive arthritis. A study of Yersinia arthritis and Reiter's disease. Arthritis Rheum 17:521-526, 1974 2. Arnett FC Jr: The implications of HL-A W27. Ann Intern Med 84:94-95, 1976 (Editorial) 3. Billings R J, Terasaki PI: A platelet antigen inhibition test for B27. (In preparation) 4. Brewerton DA: HLA-B27 and the inheritance of susceptibility to rheumatic disease. Arthritis Rheum 19:656-668, 1976 5. Brewerton DA, Caffrey M, Nicholls A, et al: Acute anterior uveitis and HL-A 27. Lancet 2:994-996, 1973 6. Brewerton DA, Hart FD, Nicholls A, et al: Ankylosing spondylitis and HL-A 27. Lancet 1:904-907, 1973 7. Calin A, Fries JF: Striking prevalence of ankylosing spondylitis in "healthy" W27 positive males and females. N Engl J Med 293:835-839, 1975 8. Cohen LM, Mittal KK, Schmid FR, et al: Increased risk for spondylitis stigmata in apparently healthy HL-A W27 men. Ann Intern Med 84:1-7, 1976 9. Finneson BE: Low Back Pain. Philadelphia: JB Lippincott, 1973, 376 pp 10. Forrester DM, Nesson JW: The Radiology of Joint Disease. Philadelphia: WB Saunders, 1973, pp 421-446 11. Gofton JP: Report from the subcommittee on diagnostic criteria for ankylosing spondylitis, in Bennett PH, Wood PHN (eds): Population Studies of the Rheumatic Diseases. Amsterdam: Excerpta Medica, 1966, pp 314-316 12. Golding FC: The radiology of the rheumatic diseases, in Copeman WSC (ed): Textbook of 566
the Rheumatic Diseases, ed 4. Edinburgh: E
and S Livingstone, 1969, pp 734-774 13. Grahame R, Calin A, Tudor M, et al: Cited in Reference 7 14. Macrae IF, Haslock DI, Wright V: Grading of films for sacro-iliitis in population studies. Ann Rheum Dis 30:58-66, 1971 15. Mason RM: Ankylosing spondylitis, in Copeman WSC (ed): Textbook of the Rheumatic Diseases, ed 4. Edinburgh: E and S Livingstone, 1969, pp 344-365 16. Metzger AL, Morris RI, Bluestone R, et al: HL-A W27 in psoriatic arthropathy. Arthritis Rheum 18:111-115, 1975 17. Mittal KK, Mickey MR, Singal DP, et al: Serotyping for homotransplantation. XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6:913-927, 1968 18. Moll JMH, Wright V: An objective clinical study of chest expansion. Ann Rheum Dis 31:1-8, 1972 19. Morris R, Metzger AL, Bluestone R, et al: HL-A W27 - a clue to the diagnosis and pathogenesis of Reiter's syndrome. N Engl J Med 290:554-556, 1974 20. Morris RI, Metzger AL, Bluestone R, et al: HL-A W27 - a useful discriminator in the arthropathies of inflammatory bowel disease. N Engl J Med 290:1117-1119, 1974 21. McCluskey OE, Lordon RE, Arnett FC Jr: HL-A 27 in Reiter's syndrome and psoriatic arthritis: a genetic factor in disease susceptibility and expression. J Rheum 1:263-268, 1974 22. McKusick VA: Human Genetics, ed 2. Englewood Cliffs, N J: Prentice-Hall, 1969 23. Ogryzlo MA: Ankylosing spondylitis, in Hollander JL, McCarty DJ (eds): Arthritis and Allied Conditions, ed 8. Philadelphia: Lea and Febiger, 1972, pp 699-723 24. Rachelefsky GS, Terasaki PI, Katz R, et al: Increased prevalence of W27 in juvenile rheumatoid arthritis. N Engl J Med 290: 892-893, 1974 25. Schlosstein L, Terasaki PI, Bluestone R, et al: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704-706, 1973 26. Wolfe AM: The epidemiology of rheumatoid arthritis: a review. Part II. Incidence and diagnostic criteria. Bull Rheum Dis 19:524-526, 1968 This paper was presented in part at the Annual Meeting of the Wisconsin Neurosurgical Society, Lake Geneva, Wisconsin, on October 2, 1976. Address reprint requests to: William F. Bingham, M.D., Department of Neurosurgery, Gundersen Clinic, Ltd., La Crosse, Wisconsin 54601.
J. Neurosurg. / Volume 4 7 / October, 1977
