- Email: [email protected]
On the one hand and on the other
THE LANCET
COMMENTARY would have been to produce summary measures, and to employ analysis of variance to track trends over time.5 Have these new data contributed to the screening debate, and are there implications for antenatal care? The study describes an interesting association, but we need to be sure that it is valid. Furthermore, in comparing differences in symptoms, we need to be wary of equating statistical significance with clinical significance. Notwithstanding these provisos, there remain major counterarguments to screening. TPOabs are a weak predictor of PPT and long-term thyroid disease.6 Further, this study did not show any relation between symptoms and abnormal thyroid function. This seriously questions the basis for any proposed intervention with thyroid hormone. Finally, there are no convincing data to suggest that this or any other intervention would alter outcome. Hence the case for antenatal screening for TPOabs remains to be made.
with normal mobility than in those with hypermobility. The authors deduce that there are at least two main pathophysiological pathways to the development of hand osteoarthritis, one being a systemic disorder causing a generalised disease of hand joints, and the other a disorder of ligament laxity leading primarily to joint instability and only secondarily to cartilage damage, expressed as osteoarthritis in the first carpometacarpal joint. Further, the authors say that >90º passive dorsiflexion of the fifth finger, found in 46% of the patients, was a sensitive (74%) and specific (100%) method of identifying those patients fulfilling two or more Beighton criteria. Sensitivity rose to 94% but with a lower specificity of 70% for those with four or more Beighton criteria. How does this help us in the study of osteoarthritis? Joint laxity is presumably a continuous variable. To dichotomise using a cut-off point of two or more Beighton criteria probably takes us no further forward in terms of understanding the pathophysiology of osteoarthritis than Stephen Ball does dividing the patterns into nodal versus non-nodal, Department of Medicine, Royal Victoria Infirmary, hyperostotic versus atrophic, or loose-jointed versus tightNewcastle upon Tyne NE1 4LP, UK jointed.2 Hypermobility as a cause for osteoarthritis would 1 Hall R. Pregnancy and autoimmune endocrine disease. Bailliere’s Clin seem to account for a large amount of risk in only a very Endocrinol Metab 1995; 9: 137–55. small number of patients or a small amount of risk in a 2 Harris B, Othman S, Davies J, et al. Association between postpartum larger proportion of patients. Premature hip osteoarthritis thyroid dysfunction and thyroid antibodies and depression. BMJ 1992; 305: 152–56. is not associated with the acetabular dysplasia and 3 Othman S, Philips D, Parkes A, et al. A long-term follow-up of posthypermobility of Down’s syndrome, hypermobility and partum thyroiditis. Clin Endocrinol 1990; 32: 559–64. hip or knee osteoarthritis are not common in groups such 4 Lazarus J, Hall R, Othman S, et al. The clinical spectrum of as physical education teachers or Africans or Asians with postpartum thyroid disease. Q J Med 1996; 89: 429–35. their varying degree of laxity, and osteoarthritis is not 5 Matthews J, Altman D, Campbell M, Royston P. Analysis of serial measurements in medical research. BMJ 1990; 300: 230–35. overexpressed in patients with homocystinuria or Marfan’s 6 Gerstein H. How common is post-partum thyroiditis? A methodologic syndrome. overview of the literature. Arch Intern Med 1990; 150: 1397–99. The age at which patients are examined (and therefore the duration of joint laxity) and other conditions are possible confounding factors. Hospital selection bias may also confound the results—for example, of 130 consecutive adults referred to a rheumatology clinic in Columbia, Missouri, 15% had hypermobility as judged by >5 points on the Beighton scale, whereas in 46 patients with generalised osteoarthritis examined in Oxford, only one patient had a joint score of >2.3 Another confounding factor is mode of diagnosis. Of 143 postmenopausal 0n the one hand and on the other women presenting with acute distal radial fracture, on The interaction of biochemistry and biomechanics in the radiography 25% had carpometacarpal arthritis was, but pathogenesis of osteoarthritis has been the subject of only 28% of these women had basal thumb pain.4 debate over many years. Particularly contentious has been the importance of joint hypermobility. The argument runs Any visitor to a zoo will have noticed the difference in thus: “Is osteoarthritis more common in lax joints? If so, is hand shape between monkeys and human beings. The it because normal cartilage is exposed to greater than proposal that joints that have undergone the most recent normal forces, to which the joint cannot adapt, or is there change during human evolution are those that are most an underlying abnormality of soft tissues susceptible to osteoarthritis is supported that is shared by articular collagen and soft by findings in 32 human and 32 rhesus tissue and that leads both to hypermobility macaque skeletons: only 3·3% of the and to osteoarthritis?” macaques had thumb-base osteoarthritis, Jonssen and colleagues from Reykjavik1 compared with 37% in the human examined this issue in relation to skeletons, whereas prevalence of osteoarthritis of the hand in 50 consecutive osteoarthritis in the distal interphalangeal women, selected on the basis of a Hypermobile digit—prone to joints was much closer at 26·7% in human combination of symptoms from the thumb osteoarthritis? beings and 50% in monkeys. This low risk base and a diagnosis of hand osteoarthritis, and in 94 ageof thumb-base osteoarthritis in rhesus macaques tends to matched women. 31 patients and 30 controls satisfied two support the suggestion that the more recently evolved or more Beighton hypermobility criteria, but 17 of the joints are more prone to articular failure. This hypothesis patients fulfilled four or more of the criteria, compared could be interestingly extended to comparing marmosets with nine of the controls. At the interphalangeal joints, and tamarinds (earlier to evolve) with gorillas and oranghowever, osteoarthritis seemed to be commoner in people utangs, but the work would have to be accompanied by
Vol 348 • October 5, 1996
907
THE LANCET
COMMENTARY analysis of the relative gripping habits of the various groups of monkeys and apes. If this sort of study takes us no further with regard to pathogenesis, does it help us with management of patients? 660 musicians were interviewed at Rochester, New York, about work-related symptoms, such as joint pain and swelling. They were also examined for joint hypermobility with the Beighton criteria.6 The conclusion was that among musicians who play instruments requiring repetitive motion, hypermobility of the wrists is likely to be an asset—only 5% of those musicians with hypermobile wrists and fingers reported musculoskeletal symptoms, compared with 18% of those without hypermobility. But undue laxity of joints not used for playing music might be a disadvantage—23% of those with hypermobile spines had back symptoms, compared with 11% of those without spinal hypermobility. Symptoms arising from hypermobility seem to be related to the aspirations of possessors of the joints.
Michael L Snaith Institute of Bone and Joint Medicine, University of Sheffield, Sheffield S10 2RX, UK 1
2 3 4
5
4
Jonsson H, Valtysdottir S Th, Kjartansson O, Brekken A. Hypermobility associated with osteoarthritis of the thumb base: a clinical and radiological subset of hand osteoarthritis. Ann Rheum Dis 1996; 55: 540-43. Peyron JG. General and local aspects of osteoarthritis. J Rheumatol 1983; suppl 9, 17-18. Bridges AJ, Smith E, Reid J. Joint hypermobility in adults referred to rheumatology clinics. Ann Rheum Dis 1992; 51: 793-96. Armstrong AL, Hunter JB, Davus TRC. The prevalence of degenerative arthritis of the base of the thumb in post-menopausal women. J Hand Surgery 1994; 19B: 340-41. Keith KT, Lim JR, Shepstone L, Dieppe PA. The evolutionary origins of osteroarthritis: a comparative skeletal study of hand disease in two primates. J Rheumatol 1995; 22: 2132-34. Larsson L-G, Baum J, Midolkar GS, Kollia GD. Benefits and disadvantages of joint hypermobility among musicians. N Engl J Med 1993; 329: 1079-82.
Speaking about pharmacovigilance One aim of postmarketing surveillance is to quantify rare side-effects, but such analyses are an inexact science, drawing as they do on case-reports and cohort and casecontrol studies. Communication of messages about risk/benefit is also an inexact science. Communicating with certainty messages that are uncertain was the topic of a workshop in Verona on Sept 23-25, convened by the WHO Collaborating Centre for International Drug Monitoring in Uppsala, the University of Verona Institute of Pharmacology, and the Council for International Organisations for Medical Science (CIOMS). An early task was to identify the major players in pharmacovigilance (figure), the members of the workshop reflecting the different players. Effective communication requires not only drug knowledge but also understanding about how the groups relate to each other. So another job was to examine a communications model proposed by Bruce Hugman, a communications expert who works with the Uppsala centre. The model analyses the purpose of communicating, the sender’s and recipient’s setting and motives, the content and style of the message itself, and the media used for dissemination. How did the model fare when applied to intergroup communications? This part of the work was complex, so two players and one message, drawn from events in late 908
1995, were selected: the transmission from a regulatory authority to clinicians of the risk/benefit message about venous thromboembolism associated with thirdgeneration oral contraceptives. The aim was to inform prescribers of a small but significant increase in risk, and to influence behaviour by decreasing use in high-risk groups. These actions would contribute data to a debate and help to solve individual treatment decisions. The medium that the UK regulatory authority used was a warning letter to doctors. It was leaked to the mass media before the professional media reported the peer-reviewed data. A “pill scare” was inevitable. Interestingly, no such scare occurred in Sweden. Cultural factors might explain the difference. In the UK, the culture in drug regulation is one of secrecy and paternalism, whereas that in Sweden is one of openness and consultation. The workshop also gave the opportunity to hear others’ views. Hearing that the media is seen as unaccountable, inaccessible, elitist, and incapable of change is both enlightening and worrying. Understanding the needs and motivations of other players is salutary. One hope was that a better communicator will be a better player. The “Verona Initiative” will move ahead under the umbrella of CIOMS. The next stages will be research proposals into the effects of communications in pharmacovigilance, how to educate the consumer from a young age, how to harness computer technologies for information dissemination and gathering, and the development of guidelines for good communications practice. A larger symposium is planned, which will also look at how the developing world handles pharmacovigilance messages. Transparency in the dissemination of risk/benefit information is the ultimate goal, to empower consumers to make fully informed choices about what drugs they take.
David McNamee The Lancet, London, UK
Vol 348 • October 5, 1996
COMMENTARY would have been to produce summary measures, and to employ analysis of variance to track trends over time.5 Have these new data contributed to the screening debate, and are there implications for antenatal care? The study describes an interesting association, but we need to be sure that it is valid. Furthermore, in comparing differences in symptoms, we need to be wary of equating statistical significance with clinical significance. Notwithstanding these provisos, there remain major counterarguments to screening. TPOabs are a weak predictor of PPT and long-term thyroid disease.6 Further, this study did not show any relation between symptoms and abnormal thyroid function. This seriously questions the basis for any proposed intervention with thyroid hormone. Finally, there are no convincing data to suggest that this or any other intervention would alter outcome. Hence the case for antenatal screening for TPOabs remains to be made.
with normal mobility than in those with hypermobility. The authors deduce that there are at least two main pathophysiological pathways to the development of hand osteoarthritis, one being a systemic disorder causing a generalised disease of hand joints, and the other a disorder of ligament laxity leading primarily to joint instability and only secondarily to cartilage damage, expressed as osteoarthritis in the first carpometacarpal joint. Further, the authors say that >90º passive dorsiflexion of the fifth finger, found in 46% of the patients, was a sensitive (74%) and specific (100%) method of identifying those patients fulfilling two or more Beighton criteria. Sensitivity rose to 94% but with a lower specificity of 70% for those with four or more Beighton criteria. How does this help us in the study of osteoarthritis? Joint laxity is presumably a continuous variable. To dichotomise using a cut-off point of two or more Beighton criteria probably takes us no further forward in terms of understanding the pathophysiology of osteoarthritis than Stephen Ball does dividing the patterns into nodal versus non-nodal, Department of Medicine, Royal Victoria Infirmary, hyperostotic versus atrophic, or loose-jointed versus tightNewcastle upon Tyne NE1 4LP, UK jointed.2 Hypermobility as a cause for osteoarthritis would 1 Hall R. Pregnancy and autoimmune endocrine disease. Bailliere’s Clin seem to account for a large amount of risk in only a very Endocrinol Metab 1995; 9: 137–55. small number of patients or a small amount of risk in a 2 Harris B, Othman S, Davies J, et al. Association between postpartum larger proportion of patients. Premature hip osteoarthritis thyroid dysfunction and thyroid antibodies and depression. BMJ 1992; 305: 152–56. is not associated with the acetabular dysplasia and 3 Othman S, Philips D, Parkes A, et al. A long-term follow-up of posthypermobility of Down’s syndrome, hypermobility and partum thyroiditis. Clin Endocrinol 1990; 32: 559–64. hip or knee osteoarthritis are not common in groups such 4 Lazarus J, Hall R, Othman S, et al. The clinical spectrum of as physical education teachers or Africans or Asians with postpartum thyroid disease. Q J Med 1996; 89: 429–35. their varying degree of laxity, and osteoarthritis is not 5 Matthews J, Altman D, Campbell M, Royston P. Analysis of serial measurements in medical research. BMJ 1990; 300: 230–35. overexpressed in patients with homocystinuria or Marfan’s 6 Gerstein H. How common is post-partum thyroiditis? A methodologic syndrome. overview of the literature. Arch Intern Med 1990; 150: 1397–99. The age at which patients are examined (and therefore the duration of joint laxity) and other conditions are possible confounding factors. Hospital selection bias may also confound the results—for example, of 130 consecutive adults referred to a rheumatology clinic in Columbia, Missouri, 15% had hypermobility as judged by >5 points on the Beighton scale, whereas in 46 patients with generalised osteoarthritis examined in Oxford, only one patient had a joint score of >2.3 Another confounding factor is mode of diagnosis. Of 143 postmenopausal 0n the one hand and on the other women presenting with acute distal radial fracture, on The interaction of biochemistry and biomechanics in the radiography 25% had carpometacarpal arthritis was, but pathogenesis of osteoarthritis has been the subject of only 28% of these women had basal thumb pain.4 debate over many years. Particularly contentious has been the importance of joint hypermobility. The argument runs Any visitor to a zoo will have noticed the difference in thus: “Is osteoarthritis more common in lax joints? If so, is hand shape between monkeys and human beings. The it because normal cartilage is exposed to greater than proposal that joints that have undergone the most recent normal forces, to which the joint cannot adapt, or is there change during human evolution are those that are most an underlying abnormality of soft tissues susceptible to osteoarthritis is supported that is shared by articular collagen and soft by findings in 32 human and 32 rhesus tissue and that leads both to hypermobility macaque skeletons: only 3·3% of the and to osteoarthritis?” macaques had thumb-base osteoarthritis, Jonssen and colleagues from Reykjavik1 compared with 37% in the human examined this issue in relation to skeletons, whereas prevalence of osteoarthritis of the hand in 50 consecutive osteoarthritis in the distal interphalangeal women, selected on the basis of a Hypermobile digit—prone to joints was much closer at 26·7% in human combination of symptoms from the thumb osteoarthritis? beings and 50% in monkeys. This low risk base and a diagnosis of hand osteoarthritis, and in 94 ageof thumb-base osteoarthritis in rhesus macaques tends to matched women. 31 patients and 30 controls satisfied two support the suggestion that the more recently evolved or more Beighton hypermobility criteria, but 17 of the joints are more prone to articular failure. This hypothesis patients fulfilled four or more of the criteria, compared could be interestingly extended to comparing marmosets with nine of the controls. At the interphalangeal joints, and tamarinds (earlier to evolve) with gorillas and oranghowever, osteoarthritis seemed to be commoner in people utangs, but the work would have to be accompanied by
Vol 348 • October 5, 1996
907
THE LANCET
COMMENTARY analysis of the relative gripping habits of the various groups of monkeys and apes. If this sort of study takes us no further with regard to pathogenesis, does it help us with management of patients? 660 musicians were interviewed at Rochester, New York, about work-related symptoms, such as joint pain and swelling. They were also examined for joint hypermobility with the Beighton criteria.6 The conclusion was that among musicians who play instruments requiring repetitive motion, hypermobility of the wrists is likely to be an asset—only 5% of those musicians with hypermobile wrists and fingers reported musculoskeletal symptoms, compared with 18% of those without hypermobility. But undue laxity of joints not used for playing music might be a disadvantage—23% of those with hypermobile spines had back symptoms, compared with 11% of those without spinal hypermobility. Symptoms arising from hypermobility seem to be related to the aspirations of possessors of the joints.
Michael L Snaith Institute of Bone and Joint Medicine, University of Sheffield, Sheffield S10 2RX, UK 1
2 3 4
5
4
Jonsson H, Valtysdottir S Th, Kjartansson O, Brekken A. Hypermobility associated with osteoarthritis of the thumb base: a clinical and radiological subset of hand osteoarthritis. Ann Rheum Dis 1996; 55: 540-43. Peyron JG. General and local aspects of osteoarthritis. J Rheumatol 1983; suppl 9, 17-18. Bridges AJ, Smith E, Reid J. Joint hypermobility in adults referred to rheumatology clinics. Ann Rheum Dis 1992; 51: 793-96. Armstrong AL, Hunter JB, Davus TRC. The prevalence of degenerative arthritis of the base of the thumb in post-menopausal women. J Hand Surgery 1994; 19B: 340-41. Keith KT, Lim JR, Shepstone L, Dieppe PA. The evolutionary origins of osteroarthritis: a comparative skeletal study of hand disease in two primates. J Rheumatol 1995; 22: 2132-34. Larsson L-G, Baum J, Midolkar GS, Kollia GD. Benefits and disadvantages of joint hypermobility among musicians. N Engl J Med 1993; 329: 1079-82.
Speaking about pharmacovigilance One aim of postmarketing surveillance is to quantify rare side-effects, but such analyses are an inexact science, drawing as they do on case-reports and cohort and casecontrol studies. Communication of messages about risk/benefit is also an inexact science. Communicating with certainty messages that are uncertain was the topic of a workshop in Verona on Sept 23-25, convened by the WHO Collaborating Centre for International Drug Monitoring in Uppsala, the University of Verona Institute of Pharmacology, and the Council for International Organisations for Medical Science (CIOMS). An early task was to identify the major players in pharmacovigilance (figure), the members of the workshop reflecting the different players. Effective communication requires not only drug knowledge but also understanding about how the groups relate to each other. So another job was to examine a communications model proposed by Bruce Hugman, a communications expert who works with the Uppsala centre. The model analyses the purpose of communicating, the sender’s and recipient’s setting and motives, the content and style of the message itself, and the media used for dissemination. How did the model fare when applied to intergroup communications? This part of the work was complex, so two players and one message, drawn from events in late 908
1995, were selected: the transmission from a regulatory authority to clinicians of the risk/benefit message about venous thromboembolism associated with thirdgeneration oral contraceptives. The aim was to inform prescribers of a small but significant increase in risk, and to influence behaviour by decreasing use in high-risk groups. These actions would contribute data to a debate and help to solve individual treatment decisions. The medium that the UK regulatory authority used was a warning letter to doctors. It was leaked to the mass media before the professional media reported the peer-reviewed data. A “pill scare” was inevitable. Interestingly, no such scare occurred in Sweden. Cultural factors might explain the difference. In the UK, the culture in drug regulation is one of secrecy and paternalism, whereas that in Sweden is one of openness and consultation. The workshop also gave the opportunity to hear others’ views. Hearing that the media is seen as unaccountable, inaccessible, elitist, and incapable of change is both enlightening and worrying. Understanding the needs and motivations of other players is salutary. One hope was that a better communicator will be a better player. The “Verona Initiative” will move ahead under the umbrella of CIOMS. The next stages will be research proposals into the effects of communications in pharmacovigilance, how to educate the consumer from a young age, how to harness computer technologies for information dissemination and gathering, and the development of guidelines for good communications practice. A larger symposium is planned, which will also look at how the developing world handles pharmacovigilance messages. Transparency in the dissemination of risk/benefit information is the ultimate goal, to empower consumers to make fully informed choices about what drugs they take.
David McNamee The Lancet, London, UK
Vol 348 • October 5, 1996