548-550
Clinicalrheumatology, 1992, 11, N ~ 4
Human Parvovirus B19 and Rheumatoid Arthritis H.G.
TAYLOR*,
A.A.
BORG,
P.T.
DAWES
Summary
Human parvovirus B19 infections have been linked with the development of a short-lived symmetrical polyarthritis and, rarely, a more persistent arthritis. We prospectively looked for serological evidence of recent B19 infection in 25 early synovitis patients presenting within 12 weeks of symptom onset and compared them with 21 controls seen over the same time period. None of the control patients had evidence of recent B19 infection while 3 of the early synovitis patients had raised IgM anti-B19 antibody levels. Two had a transient arthritis and 1 developed persistent seropositive rheumatoid arthritis.
Key Words
Rheumatoid Arthritis, Infection, Parvovirus, Early Synovitis.
INTRODUCTION A human parvovirus (B19) was discovered in 1975 while screening donated blood for hepatitis B virus (1). It was found to be a cause of aplastic crises in patients with chronic haemolytic anaemia (2,3) and later linked to its common disease manifestation, fifth disease (4). Since then several reports have linked recent B19 infection to the development of a symmetrical polyarthritis (5-11) although few of the patients reported could be described as having typical rheumatoid arthritis (RA). In the only study that included a control group 2 out of 39 R A patients who had sera tested within 5 months of symptom onset had IgM antibody to B19 compared to none in the control group (6). As the authors point out virus specific IgM is most reliably detected when specimens are obtained within 2 to 3 months of presumed infection (12) and could be missed in later specimens. We therefore prospectively studied patients with early synovitis presenting within 3 months of symptom onset to determine the frequency with which B19 infection is associated with an RA-like presentation and determine the outcome of these patients. PATIENTS AND METHODS Patients were actively recruited by requesting general practitioners to refer patients by telephone to an early synovitis clinic where they would be seen within 1 week. Over a 9-month period all patients with a definite polyarthritis seen within 12 weeks of symptom on*Department of Rheumatology, Leicester Royal Infirmary, Leicester; Staffordshire Rheumatology Centre, Haywood Hospital, Stokeon-Trent, United Kingdom.
set, in whom no clinical diagnosis apart from early RA could be made, were studied. All patients had a full history and physical examination as well as full blood count, biochemical screen, R A latex test, C-reactive protein (CRP) and X-rays as clinically indicated. Serum was obtained at the initial visit for measurement of parvovirus B19 antibody levels. Patients were followed up in the clinic for a minimum of 8 months. Serum was also obtained from a control group of established RA patients with a minimum disease duration of 2 years, seen in the clinic over the same time period. Anti-B19 IgM and IgG antibody levels were measured by radioimmunoassay (12). RESULTS The early synovitis group comprised 25 patients (13 male and 12 female) with, a mean age of 51 years (range = 21-78 years) and mean symptom duration of 8.4 weeks (range = 2-12 weeks). The 21 R A patients (8 male and 13 female) in the control group had a mean age of 54 years (range = 29-75 years) and mean disease duration of 7.1 years (range = 2-20 years). None of the control group had raised IgM anti-B19 levels although 9 out of 21 (43%) had IgG antibodies to B19. In the early synovitis group 7 patients had raised IgG but not IgM anti-B19 levels and 3 had raised IgM and IgG antibodies, indicating recent infection. Two of the 3 patients with serological evidence of recent B19 infection had a transient illness. A 42-yearold female developed a symmetrical polyarthritis affecting her hands and wrists after a flu-like illness associated with a rash on her trunk and arms. Serum taken 10 weeks after onset was positive for IgM and IgG antibodies to B19. A 21-year-old male developed wide-
Human parvovirus B19 and RA
spread arthralgia, myalgia and stiffness and had synovitis at the proximal interphalangeal (PIP) and metacarpo-phalangeal (MCP) joints but without any prodromal symptoms. He had both IgG and IgM antibodies to B19 12 weeks after symptom onset. They were both rheumatoid factor negative, did not fulfil the 1987 A R A criteria for rheumatoid arthritis (13) and were asymptomatic by 4 months. The third patient was a 37-year-old man who presented with a 10-week history of pain and stiffness in his metatarso-phalangeal (MTP) and PIP joints, progressing to involve wrists, ankles, knees and shoulders over several weeks. He had moderate early morning stiffness and examination showed marked synovitis at the PIP's and wrists bilaterally but no other abnormal findings. He had a lymphopaenia of 0.8 * 109/L, a raised CRP at 24 mg/L and positive RA latex test to a titre of 1:320. The rest of the full blood count and biochemical screen was normal. Serum at this time was positive for IgM and IgG antibodies to B19. Treatment with nonsteroidal anti-inflammatory drugs was only partially successful and 15 months after symptom onset he was still in significant pain with active synovitis at the MCP and MTP joints bilaterally. Hydroxychloroquine 400 mg/day was added to his treatment with resolution of the synovitis on review 4 months later. X-rays of his hands and feet 6 and 19 months after symptom onset showed juxta-articular osteoporosis around the affected joints but no erosions. The rheumatoid factor remained positive. DISCUSSION Although the association of B19 infection with an acute self-limiting arthritis affecting predominantly adult women is well accepted, its role as an initiating factor for RA has been questioned (14). Concerns have included the lack of controls in some studies and the paucity of cases with persistent arthritis (5,7). Comparison of our early synovitis patients with a group of established RA patients showed no serological evidence of recent B19 infection in the latter although 43% had IgG antibodies to B19. Although the numbers in our early synovitis study are small they are very similar to the larger Bristol cohort in which 12.5% of 153 early synovitis patients had evidence of recent B19 infection (7). In this study however, all B19 patients were female and the one rheumatoid factor positive patient complained of backache only.
549
Our third patient had a persistent rheumatoid factor positive polyarthritis satisfying the 1987 A R A criteria for RA and requiring a second line agent. Although most patients who develop arthritis following a B19 infection have a transient arthritis, 2 patients reported by Cohen et al (6) developed persistent, sero-positive R A which became erosive. In other studies 3 out of 19 and 3 out Of 12 patients with B19 associated arthritis fulfilled the A R A criteria for RA and only 2 patients were seropositive (7,9). In experimental B19 infection previously unexposed adults have a biphasic illness (15). A non-specific febrile illness develops approximately 1 week after infection, which coincides with the period of viraemia. This subsides to be followed by the development of rash, arthralgia and sometimes arthritis towards the end of the third week. This sequence of events would be compatible with an immune complex-mediated disease and there is some evidence for raised levels of circulating immune complexes in symptomatic patients (7). B19 DNA has been demonstrated in the synovial tissue of a patient with B19 associated arthritis (16) but this does not differentiate between viral invasion and immunologically - mediated deposition of viral DNA. Klouda et al found that possession of HLA-DR4 predisposed patients infected with B19 to develop a persistent arthritis (17) but this has not been substantiated by others (18) and a thorough epidemiological study found no association between arthritis and H L A - D R types (11). B19 infection in adults commonly causes arthralgia or a short-lived arthritis and this may be immune complex mediated. A few patients will have a persistent disease indistinguishable from R A and some of these are seropositive. Whether a patient's H L A status is important in determining the outcome remains unclear. Our own experience and review of the literature suggests that even those patients with persistent arthritis have a relatively mild disease. The finding of IgM anti-B19 antibodies in the first few months of an RA-like polyarthritis may therefore allow clinicians to give the patient a more reassuring prognosis. Acknowledgements: Our thanks to J. Shirley and R.
McEwan for measurement of the human parvovirus antibody levels.
550
H.G. Taylor, A.A. Borg, P.T. Dawes
REFERENCES 1.
Cossart, Y.E., Cant, B., Field, A.M., Widdows, D. Parvoviruslike particles in human sera. Lancet 1975, i, 72-73. 2. Serjeant, G.R., Mason, K., Topley, J.M., Serjeant, B.E., Pattison, J.R., Jones, S.E., Mohamed, R. Outbreak of aplastic crises in sickle-cell anaemia associated with parvovirus-like agent. Lancet 1981, 2, 595-597. 3. Rao, K.R.P., Patel, A.R., Anderson, M.J., Hodgson, J., Jones, S.E., Pattison, J.R. Infection with parvovirus-like virus and aplastic crisis in chronic hemolytic anaemia. Ann Intern Med 1983, 98, 930-932. 4. Anderson, M.J., Lewis, E., Kidd, I.M., Hall, S.M., Cohen, B.J. An outbreak of erythema infectiosum associated with human parvovirus infection. J Hyg (Camb) 1984, 93, 85-93. 5. Reid, D.M., Reid, T.M.S., Brown, T., Rennie, J.A.N., Eastmond, C.J. Human parvovirus-associated arthritis : a clinical and laboratory description. Lancet 1985, i, 422-425. 6. Cohen, B.J., Buckley, M.M., Clewly, J.P., Jones, V.E., Puttick, A.H., Jacoby, R.K. Human parvovirus infection in early rheumatoid and inflammatory arthritis. Ann Rheum Dis 1986, 45, 832-838. 7. White, D.G., Mortimer, P.P., Blake, D.R., Woolf, A.D., Cohen, B.J., Bacon, P.A. Human parvovirus arthropathy. Lancet 1985, i, 419-421. 8. Luzzi, G.A., Kurtz, J.B., Chapel, H. Human parvovirus arthropthy and rheumatoid factor (letter). Lancet 1985, i, 1218. 9. Naides, S.J., Scharosch, L.L., Foto, F., Howard, E.J. Rheumatological manifestations of human parvovirus B19 infection in adults. Initial two-year experience. Arthritis Rheum 1990, 33, 1297-1309. 10. Rowe, I.F., Deans, A.C., Midgley, J., Anderson, M.J., Keat, A.C. Parvovirus infection in hospital practice. Br J Rheumatol 1987, 26, 13-16.
11. Woolf, A.D., Campion, G.V., Chishick, A. et al. Clinical manifestations of human parvovirus B19 in adults. Arch Intern Med 1989, 149, 1153-1156. 12. Cohen, B.J., Mortimer, P.P., Pereira, M.S. Diagnostic assays with monoclonal antibodies for the human serum parvovirus-like virus (SPLV). J Hyg(Lond) 1983, 91, 113-131. 13. Arnett, F.C., Edworthy, S.M., Bloch, D.A. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31,315-323. 14. Anonymous. Arthritis and parvovirus infection (Editorial). Lancet 1985, i, 436-438. 15. Anderson, M.J., Higgins, P.G., Davis, L.R. et al. Experimental parvoviral infection in humans. J Infect Dis 1985, 152, 257-265. 16. Dijkmans, B.A.C., van Elsacker-Niele, A.M.W., Salismans, M.M.M., van Albada-Kuipers, G.A., de Vries, E., Weiland, H.T. Human parvovirus B19 DNA in synovial fluid. Arthritis Rheum 1988, 31, 279-281. 17. Klouda, P.T., Corbin, S.A., Bradley, B.A., Cohen, B.J., Woolf, A.D. HLA and acute arthritis following parvovirus infection. Tissue Antigens 1986, 28, 318-319. 18. Dykmans, B.A.C., Breedveld, F.C., de Vries, R.R.P. HLA antigens in human parvovirus arthropathy (letter). J Rheumatol 1986, 13, 1192-1193.
Received: 15 May 1992; Revision-accepted: 3 August 1992 Correspondence to: Dr. H.G. TAYLOR, Department of Rheumatology, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom.
Clinicalrheumatology, 1992, 11, N ~ 4
Human Parvovirus B19 and Rheumatoid Arthritis H.G.
TAYLOR*,
A.A.
BORG,
P.T.
DAWES
Summary
Human parvovirus B19 infections have been linked with the development of a short-lived symmetrical polyarthritis and, rarely, a more persistent arthritis. We prospectively looked for serological evidence of recent B19 infection in 25 early synovitis patients presenting within 12 weeks of symptom onset and compared them with 21 controls seen over the same time period. None of the control patients had evidence of recent B19 infection while 3 of the early synovitis patients had raised IgM anti-B19 antibody levels. Two had a transient arthritis and 1 developed persistent seropositive rheumatoid arthritis.
Key Words
Rheumatoid Arthritis, Infection, Parvovirus, Early Synovitis.
INTRODUCTION A human parvovirus (B19) was discovered in 1975 while screening donated blood for hepatitis B virus (1). It was found to be a cause of aplastic crises in patients with chronic haemolytic anaemia (2,3) and later linked to its common disease manifestation, fifth disease (4). Since then several reports have linked recent B19 infection to the development of a symmetrical polyarthritis (5-11) although few of the patients reported could be described as having typical rheumatoid arthritis (RA). In the only study that included a control group 2 out of 39 R A patients who had sera tested within 5 months of symptom onset had IgM antibody to B19 compared to none in the control group (6). As the authors point out virus specific IgM is most reliably detected when specimens are obtained within 2 to 3 months of presumed infection (12) and could be missed in later specimens. We therefore prospectively studied patients with early synovitis presenting within 3 months of symptom onset to determine the frequency with which B19 infection is associated with an RA-like presentation and determine the outcome of these patients. PATIENTS AND METHODS Patients were actively recruited by requesting general practitioners to refer patients by telephone to an early synovitis clinic where they would be seen within 1 week. Over a 9-month period all patients with a definite polyarthritis seen within 12 weeks of symptom on*Department of Rheumatology, Leicester Royal Infirmary, Leicester; Staffordshire Rheumatology Centre, Haywood Hospital, Stokeon-Trent, United Kingdom.
set, in whom no clinical diagnosis apart from early RA could be made, were studied. All patients had a full history and physical examination as well as full blood count, biochemical screen, R A latex test, C-reactive protein (CRP) and X-rays as clinically indicated. Serum was obtained at the initial visit for measurement of parvovirus B19 antibody levels. Patients were followed up in the clinic for a minimum of 8 months. Serum was also obtained from a control group of established RA patients with a minimum disease duration of 2 years, seen in the clinic over the same time period. Anti-B19 IgM and IgG antibody levels were measured by radioimmunoassay (12). RESULTS The early synovitis group comprised 25 patients (13 male and 12 female) with, a mean age of 51 years (range = 21-78 years) and mean symptom duration of 8.4 weeks (range = 2-12 weeks). The 21 R A patients (8 male and 13 female) in the control group had a mean age of 54 years (range = 29-75 years) and mean disease duration of 7.1 years (range = 2-20 years). None of the control group had raised IgM anti-B19 levels although 9 out of 21 (43%) had IgG antibodies to B19. In the early synovitis group 7 patients had raised IgG but not IgM anti-B19 levels and 3 had raised IgM and IgG antibodies, indicating recent infection. Two of the 3 patients with serological evidence of recent B19 infection had a transient illness. A 42-yearold female developed a symmetrical polyarthritis affecting her hands and wrists after a flu-like illness associated with a rash on her trunk and arms. Serum taken 10 weeks after onset was positive for IgM and IgG antibodies to B19. A 21-year-old male developed wide-
Human parvovirus B19 and RA
spread arthralgia, myalgia and stiffness and had synovitis at the proximal interphalangeal (PIP) and metacarpo-phalangeal (MCP) joints but without any prodromal symptoms. He had both IgG and IgM antibodies to B19 12 weeks after symptom onset. They were both rheumatoid factor negative, did not fulfil the 1987 A R A criteria for rheumatoid arthritis (13) and were asymptomatic by 4 months. The third patient was a 37-year-old man who presented with a 10-week history of pain and stiffness in his metatarso-phalangeal (MTP) and PIP joints, progressing to involve wrists, ankles, knees and shoulders over several weeks. He had moderate early morning stiffness and examination showed marked synovitis at the PIP's and wrists bilaterally but no other abnormal findings. He had a lymphopaenia of 0.8 * 109/L, a raised CRP at 24 mg/L and positive RA latex test to a titre of 1:320. The rest of the full blood count and biochemical screen was normal. Serum at this time was positive for IgM and IgG antibodies to B19. Treatment with nonsteroidal anti-inflammatory drugs was only partially successful and 15 months after symptom onset he was still in significant pain with active synovitis at the MCP and MTP joints bilaterally. Hydroxychloroquine 400 mg/day was added to his treatment with resolution of the synovitis on review 4 months later. X-rays of his hands and feet 6 and 19 months after symptom onset showed juxta-articular osteoporosis around the affected joints but no erosions. The rheumatoid factor remained positive. DISCUSSION Although the association of B19 infection with an acute self-limiting arthritis affecting predominantly adult women is well accepted, its role as an initiating factor for RA has been questioned (14). Concerns have included the lack of controls in some studies and the paucity of cases with persistent arthritis (5,7). Comparison of our early synovitis patients with a group of established RA patients showed no serological evidence of recent B19 infection in the latter although 43% had IgG antibodies to B19. Although the numbers in our early synovitis study are small they are very similar to the larger Bristol cohort in which 12.5% of 153 early synovitis patients had evidence of recent B19 infection (7). In this study however, all B19 patients were female and the one rheumatoid factor positive patient complained of backache only.
549
Our third patient had a persistent rheumatoid factor positive polyarthritis satisfying the 1987 A R A criteria for RA and requiring a second line agent. Although most patients who develop arthritis following a B19 infection have a transient arthritis, 2 patients reported by Cohen et al (6) developed persistent, sero-positive R A which became erosive. In other studies 3 out of 19 and 3 out Of 12 patients with B19 associated arthritis fulfilled the A R A criteria for RA and only 2 patients were seropositive (7,9). In experimental B19 infection previously unexposed adults have a biphasic illness (15). A non-specific febrile illness develops approximately 1 week after infection, which coincides with the period of viraemia. This subsides to be followed by the development of rash, arthralgia and sometimes arthritis towards the end of the third week. This sequence of events would be compatible with an immune complex-mediated disease and there is some evidence for raised levels of circulating immune complexes in symptomatic patients (7). B19 DNA has been demonstrated in the synovial tissue of a patient with B19 associated arthritis (16) but this does not differentiate between viral invasion and immunologically - mediated deposition of viral DNA. Klouda et al found that possession of HLA-DR4 predisposed patients infected with B19 to develop a persistent arthritis (17) but this has not been substantiated by others (18) and a thorough epidemiological study found no association between arthritis and H L A - D R types (11). B19 infection in adults commonly causes arthralgia or a short-lived arthritis and this may be immune complex mediated. A few patients will have a persistent disease indistinguishable from R A and some of these are seropositive. Whether a patient's H L A status is important in determining the outcome remains unclear. Our own experience and review of the literature suggests that even those patients with persistent arthritis have a relatively mild disease. The finding of IgM anti-B19 antibodies in the first few months of an RA-like polyarthritis may therefore allow clinicians to give the patient a more reassuring prognosis. Acknowledgements: Our thanks to J. Shirley and R.
McEwan for measurement of the human parvovirus antibody levels.
550
H.G. Taylor, A.A. Borg, P.T. Dawes
REFERENCES 1.
Cossart, Y.E., Cant, B., Field, A.M., Widdows, D. Parvoviruslike particles in human sera. Lancet 1975, i, 72-73. 2. Serjeant, G.R., Mason, K., Topley, J.M., Serjeant, B.E., Pattison, J.R., Jones, S.E., Mohamed, R. Outbreak of aplastic crises in sickle-cell anaemia associated with parvovirus-like agent. Lancet 1981, 2, 595-597. 3. Rao, K.R.P., Patel, A.R., Anderson, M.J., Hodgson, J., Jones, S.E., Pattison, J.R. Infection with parvovirus-like virus and aplastic crisis in chronic hemolytic anaemia. Ann Intern Med 1983, 98, 930-932. 4. Anderson, M.J., Lewis, E., Kidd, I.M., Hall, S.M., Cohen, B.J. An outbreak of erythema infectiosum associated with human parvovirus infection. J Hyg (Camb) 1984, 93, 85-93. 5. Reid, D.M., Reid, T.M.S., Brown, T., Rennie, J.A.N., Eastmond, C.J. Human parvovirus-associated arthritis : a clinical and laboratory description. Lancet 1985, i, 422-425. 6. Cohen, B.J., Buckley, M.M., Clewly, J.P., Jones, V.E., Puttick, A.H., Jacoby, R.K. Human parvovirus infection in early rheumatoid and inflammatory arthritis. Ann Rheum Dis 1986, 45, 832-838. 7. White, D.G., Mortimer, P.P., Blake, D.R., Woolf, A.D., Cohen, B.J., Bacon, P.A. Human parvovirus arthropathy. Lancet 1985, i, 419-421. 8. Luzzi, G.A., Kurtz, J.B., Chapel, H. Human parvovirus arthropthy and rheumatoid factor (letter). Lancet 1985, i, 1218. 9. Naides, S.J., Scharosch, L.L., Foto, F., Howard, E.J. Rheumatological manifestations of human parvovirus B19 infection in adults. Initial two-year experience. Arthritis Rheum 1990, 33, 1297-1309. 10. Rowe, I.F., Deans, A.C., Midgley, J., Anderson, M.J., Keat, A.C. Parvovirus infection in hospital practice. Br J Rheumatol 1987, 26, 13-16.
11. Woolf, A.D., Campion, G.V., Chishick, A. et al. Clinical manifestations of human parvovirus B19 in adults. Arch Intern Med 1989, 149, 1153-1156. 12. Cohen, B.J., Mortimer, P.P., Pereira, M.S. Diagnostic assays with monoclonal antibodies for the human serum parvovirus-like virus (SPLV). J Hyg(Lond) 1983, 91, 113-131. 13. Arnett, F.C., Edworthy, S.M., Bloch, D.A. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31,315-323. 14. Anonymous. Arthritis and parvovirus infection (Editorial). Lancet 1985, i, 436-438. 15. Anderson, M.J., Higgins, P.G., Davis, L.R. et al. Experimental parvoviral infection in humans. J Infect Dis 1985, 152, 257-265. 16. Dijkmans, B.A.C., van Elsacker-Niele, A.M.W., Salismans, M.M.M., van Albada-Kuipers, G.A., de Vries, E., Weiland, H.T. Human parvovirus B19 DNA in synovial fluid. Arthritis Rheum 1988, 31, 279-281. 17. Klouda, P.T., Corbin, S.A., Bradley, B.A., Cohen, B.J., Woolf, A.D. HLA and acute arthritis following parvovirus infection. Tissue Antigens 1986, 28, 318-319. 18. Dykmans, B.A.C., Breedveld, F.C., de Vries, R.R.P. HLA antigens in human parvovirus arthropathy (letter). J Rheumatol 1986, 13, 1192-1193.
Received: 15 May 1992; Revision-accepted: 3 August 1992 Correspondence to: Dr. H.G. TAYLOR, Department of Rheumatology, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom.
