- Email: [email protected]
HLA-DRw4 AND RHEUMATOID ARTHRITIS
548
velopment of a cytomegalovirus (human herpesvirus 5) vaccine, although it has not been implicated in neoplasms. On the other hand, there is considerable evidence for a close association between hepatitis B virus and primary hepatocellular
HEADACHE AFTER LUMBAR PUNCTURE
carcinoma.7-1O It has therefore been
suggested" that before of the subunit 20 trials nm scale hepatitis B vaccines are large undertaken, particularly in young children in the developing countries (Maupas et al.12), it is essential to ensure that any benefit that accrues from immunisation is not outweighed by undesirable and potentially serious hazards. There is, therefore, a need to proceed cautiously with the design, purification, development, and preparation of safe and effective vaccines against human hepatitis B, such as the 20 nm surface antigen particle vaccines and the alternative hepatitis B polypeptide vaccines. 13-15 W.H.O. Collaborating Centre for Reference and Research on Viral Hepatitis, Department of Medical Microbiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT
ARIE J. ZUCKERMAN
D.D.A.V.P. AND HEADACHE AFTER LUMBAR PUNCTURE
SIR,-the frequency of headache after lumbar puncture has reported to be about 25%.’ In an attempt to prevent such headaches, prophylaxis with vasopressin has been tried2on the grounds that the antidiuretic action of vasopressin would retain fluid in the cerebrospinal-fluid system. However, the side-effects of vasopressin, including diarrhoea, abdominal
been
cramps, and
sweating, greatly limit its usefulness. In the synarginine-vasopressin analogue D.D.A.v.P. (1-desamino-8D-arginine-vasopressin), the antidiuretic action has been in-
thetic
creased and the vasopressor effect decreased with fewer side-effects. The structural alteration has also increased the half-life of the drug. D.D.A.v.P. has been tested as a prophylactic agent against lumbar-puncture headache in an open study3 with encouraging results. To evaluate this effect under controlled conditions, it is important to use healthy volunteers with no underlying disorders which might induce headache per se. We have done
study the effect OfD.D.A.V.P. with on compared placebo lumbar-puncture headache in sixteen physically and mentally healthy male volunteers (median age 28 years, range 20-48). Two samples of 12 ml C.S.F. were drawn by lumbar puncture between 8 and 9 A.M. with a 2-week interval between the two samples. This study was part of a larger project on c.s.F. endorphins. Immediately after the lumbar puncture, either D.D.A.v.P. 6 g or saline was injected i.m. in a double-blind cross-over design. The volunteers had to lie down for 3 h after the puncture, but thereafter physical activity was not restricted. Headache after lumbar puncture was self-rated after 1 and 3 h and then daily between 8 and 9 A.M. for 4 consecutive days on a "100 mm line", where 0 indicated no headache and 100 indicated severe, intractable headache. The distance in mm between the zero point and the mark made by the subject constitute the intensity of the headache.4 The a
double-blind
on
Szmuness, W. Prog. med. Virol. 1978, 24, 40. Zuckerman, A. J. Trans. R. Soc. trop. Med. Hyg. 1978, 71, 459. 9. Trichopoulos, D., Tabor, E. Gerety, R. J., Xirouchaki, E., Sparros, L., Munoz, N., Linsell, C. A. Lancet, 1978, ii, 1217. 10. Bassendine, M. F., Chadwick, R. G., Lyssiotis, T., Thomas, H. C., Sherlock, S., Cohen, B. J. Br. med. J. 1979, i, 166 11. Zuckerman, A. J. Nature, 1978, 272, 579. 12. Maupas, Ph., Goudeau, A., Coursaget, P., Drucker, J., Barin, F., Andre, M. in Viral Hepatitis (edited by G. N. Vyas, S. N., Cohen, and R. Schmid); p. 539. Philadelphia, 1978. 13. Hollinger, F. B., Dreesman, G. R., Sanchez, Y., Cabral, G. A., Melnick, 7. 8.
J. L. ibid. p.557. 14.
Peterson, D. L., Chien, D. Y., Vyas, G. N., Nitecki, D., Bond, H. E. ibid.
p. 569. 15. Skelly, J., Howard, C. R., Zuckerman, A. J.J. gen. 1. 2.
Virol.
(in the press).
Wolff, H. G. Headache and Other Pain. New York, 1963. Aziz, H., Pearce, J., Miller, E. Br. med. J. 1968, iv, 677. 3. Durward, W. F., Harrington, H. Lancet, 1976, ii, 1403. 4. Zealley, A. K., Aitken, R. C. B. Proc. R. Soc. Med. 1969, 62, 993.
results were categorised as no headache (0 mm), moderate headache (1-50 mm), or severe headache (> 50 mm). Of the sixteen volunteers (eight started with D.D.A.V.P. and eight with placebo injection), nine completed the study with two lumbar punctures. The remaining seven had severe headache after the first lumbar puncture and the second one was not done. Of these seven volunteers, five had had placebo and two had had D.D.A.V.P. after the puncture. 25 lumbar punctures were done, 11 with D.D.A.V.P. cover and 14 with placebo. The table shows the frequency and intensity of the headaches recorded. Severe headache was more frequent in the placebo group (43%) than in the D.D.A.v.P. group (18%). The D.D.A.V.P. group recorded no headache more often (64%) than did the placebo group (36%). However, the difference between the D.D.A.V.P. and placebo effects was not statisti-
cally significant (chi-squared test; p>0.05). The headache was most pronounced 2-3 days after the lumbar puncture, and in a few cases it lasted for 7 days. No sideeffects related to D.D.A.V.P. treatment were observed. Our series is small and the results should be interpreted with caution; however, this study does indicate that D.D.A.V.P. might reduce the frequency and/or the intensity of headache after lumbar puncture. Psychiatric Research Centre, University of Uppsala, 750 17 Uppsala 17, Sweden
ERIK WIDERLÖV LEIF LINDSTRÖM
HLA-DRw4 AND RHEUMATOID ARTHRITIS
SIR,- The HLA antigen DRw4 is unusually common in patients with rheumatoid arthritis (R.A.). Roitt et a1.5 reported on the association between DRw4 and seropositive R.A. and we have investigated the frequency of DRw4 antigen in patients with the seropositive compared with seronegative R.A. HLA-typing was carried out on 39 inpatients with classical in or definite6 R.A. 24 patients were seropositive (titre >32 Rose-Waaler reaction) and 15 patients were seronegative (titre < 16 in Rose-Waaler reaction and negative latex test for rheumatoid factor). HLA typing was done by microcytotoxicity technique with 87 highly selected sera defining 13, 21, 4, and 8 antigens of the A, B, C, and DR series, respectively.’ Only the results of typing for the DRw4 antigen are given in the table. The frequency of DRw4 in the seropositive group was 54% compared with 27% expected (r<001). Among the seronegative patients the frequency of the DRw4 antigen was less than normal, but the difference is not significant. However, the difference in DRw4 frequency between the seropositive and seronegative groups is significant (P=0.008, Fisher’s exact test). The lack of association with the HLA-DRw4 in seronegative patients compared with the seropositive group may indicate 1.McMichael, A. J., Sasazuki, T., McDevitt, H. O., Payne, R. O. Arthr. Rheum. 1977, 20, 1037. 2. Sachs, J. A., Brewerton, D. A. Br. med. Bull. 1978, 34, 275. 3. Stastny, P. New Engl. J. Med. 1978, 298, 869. 4. Svejgaard, A., Ryder, L. P. in HLA and Disease (edited by J. Dausset and A. Svejgaard); p. 46. Copenhagen, 1977. 5. Roitt, I. M., Corbett, M., Festenstein, H., Jaraquemada, D., Papasteriadis, C., Hay, F. C., Nineham, L. J. Lancet. 1978, i, 990. 6. Ropes, M. W., Bennet, G. A., Cobb, S., Jacox, R., Jessar, R. A. Ann. rheum Dis. 1959, 18, 49. 7. Albrechsten, D., Bratlie, A., Nousiainen, H., Solheim, B. G., Winther, N., Thorsby, E Immunogenetics, 1978, 6, 91.
549 FREQUENCY
HLA-DRW4
OF
the results of Roitt and co-workers, we found no significant difference in the functional capacity between the DRw4 positive and the DRw4 negative patients (see table). The test for DRw4 antigen thus did not offer any prognostic discrimination to
among our patients. However, our series is
*Frequency in 116 healthy Norwegians.
seropositive and seronegative R.A. are different disease or that the pathogenesis in the two R.A. groups differs in some way. This is supported by the many clinical differences in the two forms of chronic polyarthritis, and by the possible immunological abnormality in the seropositive group. The increased frequency of the DRw4 in seropositive R.A. implies that this antigen, or a closely associated gene product, may play a role in the pathogenesis of seropositive R.A. Another possibility is that DRw4 or an associated immune-response gene product predisposes to the production of IgM rheumatoid factor,8.9 an autoantibody that seems to be correlated with a more severe that
entities,
form of the disease. Institute of Immunology and Rheumatology and Tissue Typing Laboratory,
J. H. DOBLOUG
Rikshospitalet, Oslo 1, Norway
E. THORSBY
SIR,-Roitt
et
al.
reported
a
Ø. FØRRE possible prognostic signifi-
in the serologically defined HLA-antigen DRw4 in patients with seropositive rheumatoid arthritis (R.A.). They found that patients with positive tests for both DRw4 and rheumatoid factor were more likely to have severe disease when tested within a year of onset. In an attempt to evaluate the prognostic significance of DRw4 at a later stage of the disease, we tested 39 patients with seropositive R.A. (Rose-Waaler litres 1/32) for the presence of DRw4 antigen, using methods and sera previously described.2 All the patients fulfilled the American Rheumatism cance
FUNCTIONAL CLASSIFICATION OF PATIENTS WITH SEROPOSITIVE R.A.
Association’s (A.R.A.) criteria3 of classical or definite R.A. As the table shows, the mean duration of disease in these patients was 10 years, and they all belonged to the group with the most severe disease activity warranting aggressive treatment according to the rating used by Roitt et al.’ We therefore used the A.R.A. classification of functional capacity4 in our clinical evaluation of the patients. 67% (26/39) of the patients were DRw4 positive, compared with 27% among 116 healthy controls (r<0001, chi-squared test). The increased frequency in R.A. accords well with the frequency of this antigen reported by Roitt et al.’ and confirmed during the 7th International Workshop.s However, in contrast 8
Engleman,
E.
G., Sponzilli, E. E., Batey, M. E., Ramcharan, S., McDevitt,
H O. Arthr. Rheum. 1978, 21, 690. 9 McDevitt, H. O., Delovitch, T. L., Press,
J. L., Murphy, D. B. Transpl. Rev.
1976, 30, 197. 1. Roitt,I. M., Corbett, M., Festenstein, H., Jaraquemada, D., Papasteriadis, C., Hay, F. C., Nineham, L. J. Lancet, 1978, i, 990. 2 Albrechtsen, D., Bratlie, A., Nousiainen, H., Solheim, B. G., Winther, N.,
Thorsby, E. Immunogenetics, 1978, 6, 91. 3. Ropes, M. W. Bull. rheum. Dis. 1958, 9, 175. 4
5
Stembrocker, O., Traeger, C: H., Batterman, R. C. J. Am. med. Ass. 1949, 140, 659. Batchelor, J. R., Morris, P. J. in Histocompatibility Testing 1977; p. 218.
Copenhagen, 1978.
a small one, and further studies are needed. Another observation was a predominance of DRw4 in female patients, which was also found in the workshop studies.5 No difference in the sex distribution of DRw4 is apparent in the normal population.
Department of Rheumatology, Institute of Clinical Medicine,
G. HUSBY
University of Tromsø,
M. ØSTENSEN
J. T. GRAN
and Tissue Typing Laboratory, Rikshospitalet, Oslo, Norway
A. JOHANNESSEN E. THORSBY
INFECTION WITH E. B. VIRUS AND RHEUMATOID ARTHRITIS
SIR,-Dr Elson and colleagues (Jan. 13, p. 105) discuss
our
study of antibodies in rheumatoid arthritis (R.A.) sera which reacted with a nuclear antigen in Epstein-Barr virus (E.B.v.) infected cells. Elson et al. found that 5 of 30 patients (17%) with classical or definite R.A. did not have antibodies to viral capsid antigen. This observation was interpreted as showing absence of infection with E.B.v. in these patients. Elson and colleagues stated that we had "raised the possibility of an aetiological relationship between E.B. virus infection and R.A.", and cited their observations as an argument against this. Elson and colleagues have overinterpreted our results. We clearly stated in the last paragraph of our paper’ that "these studies do not tell us if there is an aaiological relationship between E.B.v. infection and R.A. If a relationship is present, specific host and other factors must play important roles since E.B.v. has been implicated in such diverse diseases as Burkitt’s lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis". The apparent dissociation between antibody to E.B. viral antigens and antibody to R.A.-associated nuclear antigen (R.A.N.A.) was observed in our studies,! where we showed that several patients with Burkitt’s lymphoma had antibodies to E.B.N.A. but not to R.A.N.A. In addition, one of our patients with R.A. whose serum was used extensively in these studies had antibodies to R.A.N.A. but not to E.B.N.A. Recent studies by Slaughter and colleagues2 showed that peripheral-blood lymphocytes of patients with R.A. when intentionally infected with E.B.v. produced large amounts of rheumatoid factor. Lymphocytes from normal individuals were also capable of producing a rheumatoid-factor-like substance, which had lower affinity for aggregated gammaglobulin and was produced in much lower concentration. Host factors involved in R.A. include the higher frequency ofHLA-Dw4. The relationship of E.B.v. to R.A. is not clear but if it is thought that a persistent infectious agent should be one of the factors causing R.A., the role of Epstein-Barr virus might merit further study. One should also not lose sight of the possibility that there may be more than one wtiological factor causing the disease. Division of Rheumatic Diseases, University ofColorado Medical Center, Denver, Colorado 80262, U.S.A.
ENG M. TAN
Scripps Clinic & Research Foundation, La Jolla, California
FRED C.
University of Louisiana
School of Medicine,
New Orleans
JENSEN
MARGARET A. ALSPAUGH
Frederick Cancer Research Center,
Frederick, Maryland
HARVEY RABIN
1.
Alspaugh, M A., Jensen, F. C., Rabin, H., Tan, E. M. J. exp. Med. 1978, 147, 1018. 2. Slaughter, L, Carson, D., Jensen, F. C., Holbrook, T. L., Vaughan, J. H. ibid.
1978, 148, 1429.
3. Stastny, P. J. clin. Invest. 1976, 57, 1148. 4. McMichael, A. J., Sasazuki, T., McDevitt, H. O., Rheum. 1977, 20, 1037.
Payne,
R. O. Arthritis
velopment of a cytomegalovirus (human herpesvirus 5) vaccine, although it has not been implicated in neoplasms. On the other hand, there is considerable evidence for a close association between hepatitis B virus and primary hepatocellular
HEADACHE AFTER LUMBAR PUNCTURE
carcinoma.7-1O It has therefore been
suggested" that before of the subunit 20 trials nm scale hepatitis B vaccines are large undertaken, particularly in young children in the developing countries (Maupas et al.12), it is essential to ensure that any benefit that accrues from immunisation is not outweighed by undesirable and potentially serious hazards. There is, therefore, a need to proceed cautiously with the design, purification, development, and preparation of safe and effective vaccines against human hepatitis B, such as the 20 nm surface antigen particle vaccines and the alternative hepatitis B polypeptide vaccines. 13-15 W.H.O. Collaborating Centre for Reference and Research on Viral Hepatitis, Department of Medical Microbiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT
ARIE J. ZUCKERMAN
D.D.A.V.P. AND HEADACHE AFTER LUMBAR PUNCTURE
SIR,-the frequency of headache after lumbar puncture has reported to be about 25%.’ In an attempt to prevent such headaches, prophylaxis with vasopressin has been tried2on the grounds that the antidiuretic action of vasopressin would retain fluid in the cerebrospinal-fluid system. However, the side-effects of vasopressin, including diarrhoea, abdominal
been
cramps, and
sweating, greatly limit its usefulness. In the synarginine-vasopressin analogue D.D.A.v.P. (1-desamino-8D-arginine-vasopressin), the antidiuretic action has been in-
thetic
creased and the vasopressor effect decreased with fewer side-effects. The structural alteration has also increased the half-life of the drug. D.D.A.v.P. has been tested as a prophylactic agent against lumbar-puncture headache in an open study3 with encouraging results. To evaluate this effect under controlled conditions, it is important to use healthy volunteers with no underlying disorders which might induce headache per se. We have done
study the effect OfD.D.A.V.P. with on compared placebo lumbar-puncture headache in sixteen physically and mentally healthy male volunteers (median age 28 years, range 20-48). Two samples of 12 ml C.S.F. were drawn by lumbar puncture between 8 and 9 A.M. with a 2-week interval between the two samples. This study was part of a larger project on c.s.F. endorphins. Immediately after the lumbar puncture, either D.D.A.v.P. 6 g or saline was injected i.m. in a double-blind cross-over design. The volunteers had to lie down for 3 h after the puncture, but thereafter physical activity was not restricted. Headache after lumbar puncture was self-rated after 1 and 3 h and then daily between 8 and 9 A.M. for 4 consecutive days on a "100 mm line", where 0 indicated no headache and 100 indicated severe, intractable headache. The distance in mm between the zero point and the mark made by the subject constitute the intensity of the headache.4 The a
double-blind
on
Szmuness, W. Prog. med. Virol. 1978, 24, 40. Zuckerman, A. J. Trans. R. Soc. trop. Med. Hyg. 1978, 71, 459. 9. Trichopoulos, D., Tabor, E. Gerety, R. J., Xirouchaki, E., Sparros, L., Munoz, N., Linsell, C. A. Lancet, 1978, ii, 1217. 10. Bassendine, M. F., Chadwick, R. G., Lyssiotis, T., Thomas, H. C., Sherlock, S., Cohen, B. J. Br. med. J. 1979, i, 166 11. Zuckerman, A. J. Nature, 1978, 272, 579. 12. Maupas, Ph., Goudeau, A., Coursaget, P., Drucker, J., Barin, F., Andre, M. in Viral Hepatitis (edited by G. N. Vyas, S. N., Cohen, and R. Schmid); p. 539. Philadelphia, 1978. 13. Hollinger, F. B., Dreesman, G. R., Sanchez, Y., Cabral, G. A., Melnick, 7. 8.
J. L. ibid. p.557. 14.
Peterson, D. L., Chien, D. Y., Vyas, G. N., Nitecki, D., Bond, H. E. ibid.
p. 569. 15. Skelly, J., Howard, C. R., Zuckerman, A. J.J. gen. 1. 2.
Virol.
(in the press).
Wolff, H. G. Headache and Other Pain. New York, 1963. Aziz, H., Pearce, J., Miller, E. Br. med. J. 1968, iv, 677. 3. Durward, W. F., Harrington, H. Lancet, 1976, ii, 1403. 4. Zealley, A. K., Aitken, R. C. B. Proc. R. Soc. Med. 1969, 62, 993.
results were categorised as no headache (0 mm), moderate headache (1-50 mm), or severe headache (> 50 mm). Of the sixteen volunteers (eight started with D.D.A.V.P. and eight with placebo injection), nine completed the study with two lumbar punctures. The remaining seven had severe headache after the first lumbar puncture and the second one was not done. Of these seven volunteers, five had had placebo and two had had D.D.A.V.P. after the puncture. 25 lumbar punctures were done, 11 with D.D.A.V.P. cover and 14 with placebo. The table shows the frequency and intensity of the headaches recorded. Severe headache was more frequent in the placebo group (43%) than in the D.D.A.v.P. group (18%). The D.D.A.V.P. group recorded no headache more often (64%) than did the placebo group (36%). However, the difference between the D.D.A.V.P. and placebo effects was not statisti-
cally significant (chi-squared test; p>0.05). The headache was most pronounced 2-3 days after the lumbar puncture, and in a few cases it lasted for 7 days. No sideeffects related to D.D.A.V.P. treatment were observed. Our series is small and the results should be interpreted with caution; however, this study does indicate that D.D.A.V.P. might reduce the frequency and/or the intensity of headache after lumbar puncture. Psychiatric Research Centre, University of Uppsala, 750 17 Uppsala 17, Sweden
ERIK WIDERLÖV LEIF LINDSTRÖM
HLA-DRw4 AND RHEUMATOID ARTHRITIS
SIR,- The HLA antigen DRw4 is unusually common in patients with rheumatoid arthritis (R.A.). Roitt et a1.5 reported on the association between DRw4 and seropositive R.A. and we have investigated the frequency of DRw4 antigen in patients with the seropositive compared with seronegative R.A. HLA-typing was carried out on 39 inpatients with classical in or definite6 R.A. 24 patients were seropositive (titre >32 Rose-Waaler reaction) and 15 patients were seronegative (titre < 16 in Rose-Waaler reaction and negative latex test for rheumatoid factor). HLA typing was done by microcytotoxicity technique with 87 highly selected sera defining 13, 21, 4, and 8 antigens of the A, B, C, and DR series, respectively.’ Only the results of typing for the DRw4 antigen are given in the table. The frequency of DRw4 in the seropositive group was 54% compared with 27% expected (r<001). Among the seronegative patients the frequency of the DRw4 antigen was less than normal, but the difference is not significant. However, the difference in DRw4 frequency between the seropositive and seronegative groups is significant (P=0.008, Fisher’s exact test). The lack of association with the HLA-DRw4 in seronegative patients compared with the seropositive group may indicate 1.McMichael, A. J., Sasazuki, T., McDevitt, H. O., Payne, R. O. Arthr. Rheum. 1977, 20, 1037. 2. Sachs, J. A., Brewerton, D. A. Br. med. Bull. 1978, 34, 275. 3. Stastny, P. New Engl. J. Med. 1978, 298, 869. 4. Svejgaard, A., Ryder, L. P. in HLA and Disease (edited by J. Dausset and A. Svejgaard); p. 46. Copenhagen, 1977. 5. Roitt, I. M., Corbett, M., Festenstein, H., Jaraquemada, D., Papasteriadis, C., Hay, F. C., Nineham, L. J. Lancet. 1978, i, 990. 6. Ropes, M. W., Bennet, G. A., Cobb, S., Jacox, R., Jessar, R. A. Ann. rheum Dis. 1959, 18, 49. 7. Albrechsten, D., Bratlie, A., Nousiainen, H., Solheim, B. G., Winther, N., Thorsby, E Immunogenetics, 1978, 6, 91.
549 FREQUENCY
HLA-DRW4
OF
the results of Roitt and co-workers, we found no significant difference in the functional capacity between the DRw4 positive and the DRw4 negative patients (see table). The test for DRw4 antigen thus did not offer any prognostic discrimination to
among our patients. However, our series is
*Frequency in 116 healthy Norwegians.
seropositive and seronegative R.A. are different disease or that the pathogenesis in the two R.A. groups differs in some way. This is supported by the many clinical differences in the two forms of chronic polyarthritis, and by the possible immunological abnormality in the seropositive group. The increased frequency of the DRw4 in seropositive R.A. implies that this antigen, or a closely associated gene product, may play a role in the pathogenesis of seropositive R.A. Another possibility is that DRw4 or an associated immune-response gene product predisposes to the production of IgM rheumatoid factor,8.9 an autoantibody that seems to be correlated with a more severe that
entities,
form of the disease. Institute of Immunology and Rheumatology and Tissue Typing Laboratory,
J. H. DOBLOUG
Rikshospitalet, Oslo 1, Norway
E. THORSBY
SIR,-Roitt
et
al.
reported
a
Ø. FØRRE possible prognostic signifi-
in the serologically defined HLA-antigen DRw4 in patients with seropositive rheumatoid arthritis (R.A.). They found that patients with positive tests for both DRw4 and rheumatoid factor were more likely to have severe disease when tested within a year of onset. In an attempt to evaluate the prognostic significance of DRw4 at a later stage of the disease, we tested 39 patients with seropositive R.A. (Rose-Waaler litres 1/32) for the presence of DRw4 antigen, using methods and sera previously described.2 All the patients fulfilled the American Rheumatism cance
FUNCTIONAL CLASSIFICATION OF PATIENTS WITH SEROPOSITIVE R.A.
Association’s (A.R.A.) criteria3 of classical or definite R.A. As the table shows, the mean duration of disease in these patients was 10 years, and they all belonged to the group with the most severe disease activity warranting aggressive treatment according to the rating used by Roitt et al.’ We therefore used the A.R.A. classification of functional capacity4 in our clinical evaluation of the patients. 67% (26/39) of the patients were DRw4 positive, compared with 27% among 116 healthy controls (r<0001, chi-squared test). The increased frequency in R.A. accords well with the frequency of this antigen reported by Roitt et al.’ and confirmed during the 7th International Workshop.s However, in contrast 8
Engleman,
E.
G., Sponzilli, E. E., Batey, M. E., Ramcharan, S., McDevitt,
H O. Arthr. Rheum. 1978, 21, 690. 9 McDevitt, H. O., Delovitch, T. L., Press,
J. L., Murphy, D. B. Transpl. Rev.
1976, 30, 197. 1. Roitt,I. M., Corbett, M., Festenstein, H., Jaraquemada, D., Papasteriadis, C., Hay, F. C., Nineham, L. J. Lancet, 1978, i, 990. 2 Albrechtsen, D., Bratlie, A., Nousiainen, H., Solheim, B. G., Winther, N.,
Thorsby, E. Immunogenetics, 1978, 6, 91. 3. Ropes, M. W. Bull. rheum. Dis. 1958, 9, 175. 4
5
Stembrocker, O., Traeger, C: H., Batterman, R. C. J. Am. med. Ass. 1949, 140, 659. Batchelor, J. R., Morris, P. J. in Histocompatibility Testing 1977; p. 218.
Copenhagen, 1978.
a small one, and further studies are needed. Another observation was a predominance of DRw4 in female patients, which was also found in the workshop studies.5 No difference in the sex distribution of DRw4 is apparent in the normal population.
Department of Rheumatology, Institute of Clinical Medicine,
G. HUSBY
University of Tromsø,
M. ØSTENSEN
J. T. GRAN
and Tissue Typing Laboratory, Rikshospitalet, Oslo, Norway
A. JOHANNESSEN E. THORSBY
INFECTION WITH E. B. VIRUS AND RHEUMATOID ARTHRITIS
SIR,-Dr Elson and colleagues (Jan. 13, p. 105) discuss
our
study of antibodies in rheumatoid arthritis (R.A.) sera which reacted with a nuclear antigen in Epstein-Barr virus (E.B.v.) infected cells. Elson et al. found that 5 of 30 patients (17%) with classical or definite R.A. did not have antibodies to viral capsid antigen. This observation was interpreted as showing absence of infection with E.B.v. in these patients. Elson and colleagues stated that we had "raised the possibility of an aetiological relationship between E.B. virus infection and R.A.", and cited their observations as an argument against this. Elson and colleagues have overinterpreted our results. We clearly stated in the last paragraph of our paper’ that "these studies do not tell us if there is an aaiological relationship between E.B.v. infection and R.A. If a relationship is present, specific host and other factors must play important roles since E.B.v. has been implicated in such diverse diseases as Burkitt’s lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis". The apparent dissociation between antibody to E.B. viral antigens and antibody to R.A.-associated nuclear antigen (R.A.N.A.) was observed in our studies,! where we showed that several patients with Burkitt’s lymphoma had antibodies to E.B.N.A. but not to R.A.N.A. In addition, one of our patients with R.A. whose serum was used extensively in these studies had antibodies to R.A.N.A. but not to E.B.N.A. Recent studies by Slaughter and colleagues2 showed that peripheral-blood lymphocytes of patients with R.A. when intentionally infected with E.B.v. produced large amounts of rheumatoid factor. Lymphocytes from normal individuals were also capable of producing a rheumatoid-factor-like substance, which had lower affinity for aggregated gammaglobulin and was produced in much lower concentration. Host factors involved in R.A. include the higher frequency ofHLA-Dw4. The relationship of E.B.v. to R.A. is not clear but if it is thought that a persistent infectious agent should be one of the factors causing R.A., the role of Epstein-Barr virus might merit further study. One should also not lose sight of the possibility that there may be more than one wtiological factor causing the disease. Division of Rheumatic Diseases, University ofColorado Medical Center, Denver, Colorado 80262, U.S.A.
ENG M. TAN
Scripps Clinic & Research Foundation, La Jolla, California
FRED C.
University of Louisiana
School of Medicine,
New Orleans
JENSEN
MARGARET A. ALSPAUGH
Frederick Cancer Research Center,
Frederick, Maryland
HARVEY RABIN
1.
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