Rheumatology News

Vol. 4 • No. 1 • 2016

The Leading Independent Newspaper from Elsevier

Ultrasound could help identify patients suitable for biologic tapering

IN THIS ISSUE

MRI findings beyond sacroiliitis not necessary for classifying nonradiographic axial SpA 3

BY NICOLA GARRETT Frontline Medical News From Arthritis Research & Therapy

U ltrasound evaluation at the time of clinical re- mission could be a useful tool to select the most appropriate rheumatoid arthritis (RA) patients to undergo biologic therapy tapering and discontinu- ation, Italian researchers say. In a study involving 42 RA patients in clinical remission who tapered their anti-tumour necrosis factor-alpha (anti-TNF-alpha) therapy according to ultrasound criteria, 69.1% maintained remission at 12 weeks. The findings suggested there was a meaningful, large patient population with established RA in remission for whom the anti-TNF-alpha dose can be decreased without clinical and functional worsening. Furthermore, 26 of the patients (89.7%) main- tained disease remission after 6 months of follow- up, reported the research team led by Dr Gianfranco Ferraccioli and Dr StefanoAlivernini of the Institute of Rheumatology, Catholic University of the Sacred Heart, Rome ( Arthritis Res Ther 2016. doi: 10.1186/ s13075-016-0927-z). The 30% of patients who relapsed (n=13) were re- treated and reached a good European LeagueAgainst Rheumatism (EULAR) response within 3 months, results from the observational study showed. According to the researchers, the daily manage- ment of patients receiving long-term biologic treat- ment remains a matter of debate, and it is currently unclear how to select the most appropriate patients for discontinuing biologic treatment. People with RA, even when in remission, tend to have residual synovitis. Previous research had shown that patients with negative signalling detected on power Doppler (PD) ultrasound were less likely to have disease flares. To determine if the detection of residual synovitis with PD signalling could help in selecting patients suitable for anti-TNF discontinuation, the research- ers selected 42 RA patients with disease duration of more than 12 months who were in sustained remission (Disease Activity Score less than 1.6 at three visits 3 months apart) who were receiving anti- TNF-alpha treatment plus methotrexate. Patients were first tapered on anti-TNF-alpha therapy (adalimumab 40 mg/4 weeks or etanercept 50 mg/2 weeks). Each patient underwent ultrasound evaluation of synovial hypertrophy (SH) and PD signal presence

Etanercept during pregnancy doubles the odds of major malformations

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Wearable device offers home-based knee OA pain relief Potential etanercept response biomarker identified

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in the second and third metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, the wrist (radiocarpal-intercarpal), bilateral knee, and second to fifth metatarsophalangeal (MTP) joints. After 3 months, patients with no power Doppler signalling on ultrasound discontinued anti-TNF- alpha therapy and were followed every 3 months while maintaining stable doses of methotrexate. Disease flares after anti-TNF-alpha discontinu- ation occurred in the joints with higher SH scores that were clinically involved at disease onset, despite the fact that no SH cut-off discriminated patients who relapsed from those who did not. In particular, the fifth MTP joint was informative (in both the tapering and discontinuation groups) and the second MCP joint was informative for the tapering group only. “This finding suggests the possible utility of fol- lowing US [ultrasound] with indices of joints ini- tially involved at disease onset with higher likelihood of relapse,” the researchers said. Results from subgroup of five patients who also underwent ultrasound-guided knee synovial tissue

biopsy to assess histologic features of residual syno- vitis revealed that the absence of ultrasound activity was associated with almost normal findings at the synovial level, they reported. Overall, the findings suggested there was a “mean- ingful, large patient population with established RA in remission for whom the anti-TNF-alpha dose can be decreased without clinical and functional worsening,” the researchers wrote. They suggested the combination of PD-US evalua- tion andAmerican College of Rheumatology/EULAR remission criteria could help identify patients on bio- logics who are likely to achieve drug-free remission. Use of three sequential ultrasound evaluations might identify an even higher proportion of patients likely to reach persistent drug-free remission, com- pared with current clinical methods of disease activ- ity assessment, they added. Gianfranco Ferraccioli declared receiving consulting fees and speaking fees from Wyeth, Roche, AbbVie, and Bristol-Myers Squibb. The other authors said that they have no competing interests.

End-stage renal disease risk in lupus nephritis remains unchanged of late 11 Fibromyalgia found in 20% with spondyloarthritis; could affect management decisions 12 The pain of inflammatory disease goes beyond the physical 15

NEWS 2

R heumatology N ews • Vol. 4 • No. 1 • 2016

High-dose vitamin D increases fall risk in study of 200 patients BY SHARON WORCESTER Frontline Medical News From JAMA Internal Medicine O lder adults treated with high-dose vi- 30 ng/mL at 6 and 12 months, but lower extremity function did not differ among the groups, the investigators reported in a study published online Jan. 4 in JAMA Internal Medicine.

Although vitamin D supplementation has been proposed as a possible strategy for delaying functional decline because of its effects on muscle strength, the current findings, which are consistent with some prior studies, suggest that high-doses of vitamin D confer no benefit with respect to function decline, compared with a standard-of-care dose of 24,000 IU of D 3 , and that high doses may increase falls in those with a prior fall event. Further research is needed to confirm the findings for daily dosing regimens, as well as to explore the physiology behind a possible detrimental effect of a high monthly bolus dose of vitamin D on muscle function and falls, they concluded. This study was funded by the Swiss National Science Foundation and the VELUX Founda- tions, as well as by investigator-initiated funds from Merck Sharp & Dohme AG, WILD, and DSM Nutritional Products. Dr Bischoff-Ferrari reported receiving speaker fees from and serving on advisory boards for Merck Sharp & Dohme AG, Amgen, WILD, DSMNutritional Products, Roche Diagnostics, Nestle, Pfizer, and Sanofi. in Leeds dactylitis instrument median score, and a significant decrease in the proportion of patients with enthesitis (25.7%). However, the median change in enthesitis score was 0. Response rates did not differ between pa- tients receiving methotrexate 15 mg/week or higher doses, although there was generally a higher proportion who met various response criteria among those taking greater than 15 mg/ week. However, the authors noted that there could be an underestimation of the dose ef- fect because the design of the TICOPA study, which randomised patients to a protocol for tight control of psoriatic arthritis disease activity or standard care, introduced a bias by intention- ally escalating treatment doses in patients who continue to have active disease. The investigators advised that the study results be interpreted in the context of the open-label design of the study, and placed alongside the other observational studies that support its use in psoriatic arthritis.

tamin D as part of a double-blind, ran- domised clinical trial achieved target 25-hydroxyvitamin D levels at 6 and 12 months, but did not achieve the primary end- point of improved lower extremity function. In fact, the highest dose used in the study – 60,000 IU of vitamin D 3 monthly – was associ- ated with an increased risk of falls, according to Dr Heike A. Bischoff-Ferrari of University Hospital Zurich, and her colleagues. In the 200 home-dwelling adults aged older than 70 years who participated in the 1-year study, monthly doses of 60,000 IU of vitamin D 3 and 24,000 IU of vitamin D 3 plus 300 mcg of calcifediol were significantly more likely than a 24,000 IU dose of vitamin D 3 alone to result in 25-hydroxyvitamin D levels of at least

For example, the adjusted changes in Short Physical Performance Battery scores – a measure of walking speed, suc- cessive chair stands, and balance – were 0.17, 0.16, and 0.16 at 6 months in the 24,000 IU, 60,000 IU, and 24,000 IU plus calcifediol groups, respectively, and 0.38, 0.10, and 0.11 at 12 months. However, the incidence of falls was 66.9%, 66.1%, and 47.9% in the groups, re- spectively, and the mean number of falls was higher in the 60,000 IU group (1.47) and 24,000 IU plus calcifediol group (1.24) than in the 24,000 IU group (0.94), they said, not- ing that a similar pattern was observed during study months 0–6 and months 7–12. Study subjects had a mean age of 78 years, 58% were vitamin D deficient with levels of less than 20 ng/mL at baseline, and 13% were severely deficient (levels less than 10 ng/mL). All had experienced a low-trauma fall in the previous 12 months and were thus considered

a high-risk group for vitamin D deficiency and functional decline. Vitamin D supplementa- tion was given via one 5-mL drink solution each month that provided 24,000 IU of vi- tamin D 3 – equivalent to the current recom- mendation of 800 IU/day – plus three placebo capsules; a 5-mL drink solution that provided 60,000 IU of vitamin D 3 – the equivalent of 2000 IU/day – plus three placebo capsules; or a 5-mL placebo drink, two capsules containing 12,000 IU of vitamin D 3 each, and one capsule containing 300 mcg of calcifediol, which is a potent liver metabolite of vitamin D.

Managing Editor

Anne Neilson anne.neilson@elsevier.com Carolyn Ng carolyn.ng@elsevier.com Jana Sokolovskaja j.sokolovskaja@elsevier.com

Methotrexate has a role in treating articular manifestations of psoriatic arthritis

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Designer

Commercial Manager Fleur Gill

fleur.gill@elsevier.com Stephen Yue s.yue@elsevier.com

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dose at 12 weeks of at least 15 mg/week in 175, 20 mg/week in 122, and 25 mg/week in 86. The proportions of patients achieving American College of Rheumatology (ACR) outcomes at 12 weeks were 40.8% for ACR20, 18.8% for ACR50, and 8.6% for ACR70. A to- tal of 22.4% achieved minimal disease activity, defined as meeting five of these seven criteria: 0–1 tender joints, 0–1 swollen joints, Psoriasis Area and Severity Index (PASI) of 1 or less or body surface area involvement of 3 or less, patient pain visual analog score (VAS) of 15 or less, patient global disease activity VAS of 20 or less, health assessment questionnaire of 0.5 or less, and 0–1 tender entheseal points. Other improvements that occurred at 12weeks included 27.2% reaching a PASI75, a 62.7%drop in dactylitis incidence, a significant drop of –59.7

BY NICOLA GARRETT Frontline Medical News From Journal of Rheumatology

International Editorial F rontline M edical N ews

P atients with psoriatic arthritis taking metho- trexate demonstrated an improvement in peripheral joint disease, skin disease, enthesitis, dactylitis, and nail disease over 12 weeks in a subanalysis of methotrexate users in the TICOPA (Tight Control of Psoriatic Arthritis) study. Out of the original 206 patients in the open- label, randomised, controlled TICOPA study, the subanalysis involved 188 who received methotrexate in its first 12 weeks. Substudy authors Dr Laura C. Coates and Dr Philip S. Helliwell of the Leeds Institute of Rheumatic and Musculoskeletal Medicine at the Univer- sity of Leeds (England) verified a maximum

Editor in Chief Mary Jo M. Dales Executive Editors Denise Fulton, Kathy Scarbeck Managing Editor Jeff Evans Senior Editors Therese Borden, Catherine Hackett, Gina L. Henderson, Sally Koch Kubetin, Mark S. Lesney, Renée Matthews, Lora T. McGlade, Catherine Cooper Nellist, Terry Rudd, Laura Nikolaides, Mary Ellen Schneider, Heidi Splete Associate Editors Felicia Rosenblatt Black, Mike Bock, Lucas Franki, Richard Franki, Gwendolyn B. Hall, Jane Locastro, Madhu Rajaraman Reporters Patrice Wendling, Bruce Jancin, Michele G. Sullivan, Alicia Gallegos, Mitchel L. Zoler, Doug Brunk, M. Alexander Otto, Deepak Chitnis, Whitney McKnight, Elizabeth Mechcatie, Gregory Twachtman R heumatology N ews is an independent newspaper that pro- vides the practicing specialist with timely and relevant news and commentary about clinical developments in the field and about the impact of health care policy on the specialty and the physician’s practice. The news and information in R heumatology N ews (Australian Edition) is sourced from R heumatology N ews (US Edition) published by Frontline Medical News. The ideas and opinions expressed in R heumatology N ews , Australian Edition do not necessarily reflect those of the Publisher. Elsevier Australia will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Please consult the full current Product Information before prescribing any medication mentioned in this publica- tion. For a digital edition visit elseviermedcomms.com.au To share your feedback with us, please email news.au@elsevier.com ISSN: 2202-221X

No relevant conflicts of interest were disclosed.

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NEWS 3

Vol. 4 • No. 1 • 2016 • R heumatology N ews

MRI findings beyond sacroiliitis not necessary for classifying nonradiographic axial SpA

BY JEFF EVANS Frontline Medical News From Annals of the Rheumatic Diseases C urrent recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloar- thritis should still depend on the presence of subchondral bone marrow oedema, but ad- ditional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consen- sus review by experts from the Assessment in SpondyloArthritis International Society MRI working group. The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of theAssessment in SpondyloArthritis Interna- tional Society (ASAS) ( Ann RheumDis 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642), where members unanimously approved it. The group’s goal was to examine whether new data published on axial SpA in the 5 years fol- lowing the 2009 publication of theASAS recom- mendations were “sufficient tomerit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.” Overall, the working group determined that the addition of “structural damage changes of

lesion or combination of lesions,” the working group wrote. The panelists found that there was no con- sistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses. In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr Atul Deodhar of Oregon Health and Science University, Port- land, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumour necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for pa- tients to receive coverage from their insurance carrier to use a TNFi”. There is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.

benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for defini- tions for each MRI structural damage lesion and the setting of thresholds for any defined

the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.” Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear

Second dose of herpes zoster vaccine beneficial to seniors

BY DEEPAK CHITNIS Frontline Medical News

Although the practical implications of the current findings are not fully understood, the similarity of [enzyme-linked immunosorbent spot] responses to those observed in the successful efficacy trial of ZV in vaccinees [at least] 60 years of age supports further investigation of administration of ZV at an early age vs at a later age and further investigation of a booster dose for elderly individuals at an appropriate interval after initial immunisation against HZ.

From the Journal of Infectious Diseases T he herpes zoster vaccine should be administered earlier rather than later in order to achieve optimal immune response, but an additional booster shot for individu- als 70 years or older is also advisable. This is according to a recent study published in the Journal of Infectious Diseases , which looked at four distinct cohorts – 200 sub- jects at least 70 years old who had already received the herpes zoster vaccine (ZV) 10 years or more prior (Group 1), 200 subjects at least 70 years old who had never received ZV (Group 2), 100 subjects ages 60–69 years old who had never received ZV (Group 3), and 100 subjects 50–59 years old who had never received ZV (Group 4) – to determine the efficacy of relatively late ZV admin- istration on inducing an adequate immune response. “During ageing there is a progres- sive decline in immune responsive- ness to vaccination and a shortening of the duration of vaccine-induced immunity,” wrote Dr Myron J. Levin of the University of Colorado, Den- ver, and his associates, who added that “as an initial step in investigating the potential for reversing this de- cline in efficacy, we determined that a booster dose of ZV administered

The geometric mean count of VZV-specific effector memory cells per million peripheral blood mononuclear cells in Group 1 was 47 at baseline, 88 at week 1, 90 at week 6, and 65 at week 52, vs 36 at baseline, 65 at week 1, 73 at week 6, and 37 at week 52 in Group 2 (P < 0.05). Similar disparities were seen between Groups 3 and 4, too, with Group 4 having consistently and significantly higher geometric mean counts at each collection of blood samples throughout the study. “All age groups developed an increase in GMT [geometric mean titer] at week 1 after ZV receipt that peaked at week 6,” the authors explained. However, “the booster dose of ZV administered to adults [at least] 70 years old after [at least] 10 years elicited a GMT and geometric mean fold-rise in VZV antibody titer that was noninferior to that of ZV administered as a first dose to sub- jects [at least] 70 years old.”

to adults [at least] 70 years of age elicits a varicella-zoster virus (VZV) antibody response that is noninferior to that of ZV administered as a first dose.” Dr Levin and his coinvestiga- tors separated subjects into one of the four aforementioned cohorts, enrolling individuals who had a history of varicella and had been US residents for at least 30 years, but had no history of herpes zoster prior to enrollment. All individuals received a single, subcutaneous, deltoid region ZV injection of 0.65 mL on the first day of the study, with subsequent blood samples collected and analysed at 1, 6, and 52 weeks after receiving ZV. Sub- jects in Group 2 were matched with subjects in Group 1 based on age to compare results. Baseline levels of both interferon gamma (IFN-gamma) and inter- leukin 2 (IL-2) were significantly higher in Group 1 than in Group 2.

The indication of that, the authors conclude, is that cell-mediated immunity is affected by ZV and enhanced by a stronger, or more re- cent, dose. This lends credence to the theory that although it is better to get a ZV shot earlier in life, those who are approaching age 70 years can – and, in many cases, should – get a booster shot to strengthen and maintain that immunity. “Although the practical implica- tions of the current findings are not fully understood, the similarity of [enzyme-linked immunosorbent spot] responses to those observed in

the successful efficacy trial of ZV in vaccinees [at least] 60 years of age supports further investigation of ad- ministration of ZV at an early age vs at a later age and further investigation of a booster dose for elderly individuals at an appropriate interval after initial immunisation against HZ,” Dr Levin and his coauthors concluded. The study was funded by Merck, Sharp & Dohme. Dr Levin reported having received grants, personal fees, and royalty payments from Merck. Several other coauthors disclosed individual potential.

NEWS 4

R heumatology N ews • Vol. 4 • No. 1 • 2016

Family history of cardiovascular disease is key in psoriasis patients

adjusted for age, gender, socioeconomic status, comorbid cardiovascular disease, smoking, and the use of cardiovascular medications, patients with mild psoriasis and a positive family history for cardiovascular disease had a 28% greater risk of a premature cardiovascular event than the general population during follow-up out to roughly age 40. Those with a positive family history and severe psoriasis as defined by the use of systemic therapies had a 62% increase in risk. Both of these elevated risks were sta- tistically significant. Among young adult Danes with a positive family history for cardiovascular disease, there were 222MACE events during 62,225 person- years of follow-up in the mild psoriasis group and 31 events during 6848 person-years in the 4504 subjects with severe psoriasis. The resultant incidence rates in both groups were significantly higher than in the control group, who experienced 28,846 MACE events during 16.1 million person-years of follow-up. In contrast, fewer than 10 MACE events occurred in Danish psoriasis patients without a family history of cardiovascular disease. A positive family history was also associated with increased MACE in the nonpsoriatic general population, although it didn’t confer as great a risk as in the Danes with psoriasis. A point worthy of consideration, Dr Egeberg noted, is that the epidemiology of psoriasis in Denmark apparently differs in several impor- tant ways from psoriasis in the US and some other countries. For one, the prevalence is higher in Scandinavian countries – 7.1% in a Danish national cross-sectional study ( Int J Dermatol 2013;52:681–3) and 8% in neigh- bouring Norway – as compared with 2–3% in much of the rest of the world. Moreover, according to the same cross-sec- tional study, the prevalence of traditional car- diovascular risk factors, such as smoking and the components of the metabolic syndrome, isn’t higher in Danish psoriasis patients than in

BY BRUCE JANCIN Frontline Medical News At the EADV congress, Copenhagen

T he increased risk of MI and stroke in patients who develop psoriasis as young adults is essentially confined to those having a positive family history of cardiovas- cular disease, according to a Danish national study presented at the annual congress of the European Academy of Dermatology and Venereology. “We found a significantly increased risk of MACE [major adverse cardiovascular events] in patients with psoriasis only when a fam- ily history of cardiovascular disease was pre- sent. This just highlights why it’s important that future studies of cardiovascular risk in psoriasis should include family history. Also, an increased focus on cardiovascular disease in relatives may be appropriate in the car- diovascular risk assessment of patients with psoriasis,” said Dr Alexander Egeberg of the University of Copenhagen. He presented a population-based study involving 15 years of follow-up of 30,278 Danes diagnosed with psoriasis in their 20s and a control group consisting of nearly 2.7 million of their Danish contemporaries who were not. None had personal history of acute MI or stroke at baseline. Family medical his- tory, including whether cardiovascular disease occurred in first-degree relatives, was available for all subjects. Dr Egeberg and coinvestigators mapped the incidence of acute MI, ischaemic stroke, or cardiovascular death in psoriasis patients and the general population controls during follow-up. “When you look at the patients who devel- oped psoriasis and didn’t have a positive fam- ily history of cardiovascular disease, there are almost no cardiovascular events for the entire country,” Dr Egeberg observed. In contrast, in a multivariate analysis

the country’s general population. That’s in con- trast to the situation in the United Kingdom, where Dr Joel M. Gelfand of the University of Pennsylvania and associates reported a decade ago in a landmark study that the prevalence of hypertension, obesity, hyper lipidaemia, dia- betes, and smoking were all higher in persons with psoriasis than in the general population. Similar findings were subsequently reported in US psoriasis patients. Despite their absence of elevated levels of the standard cardiovascular risk factors, Danish psoriasis patients as a group do face a clinically significant increase in cardiovascular risk, compared with the general population, as shown in yet another Danish national cohort study in which the rate ratios for cardiovas- cular death for mild and severe psoriasis were 1.14 and 1.57, respectively, compared with controls. In an even more recent Danish nationwide study, the overall death rate was found to be

25.4 per 1000 person-years in patients with severe psoriasis, 17.0 in those with mild pso- riasis, and 13.8 per 1000 person-years in the general population. Dr Egeberg said his new Danish findings suggest that even in psoriasis patients with a greater burden of systemic inflammation as expressed in severe disease, that burden alone doesn’t translate into increased cardiovascular risk. Rather, elevated cardiovascular risk ap- pears to be a consequence of heritable factors, Dr Egeberg said. An important caveat regarding this study, he continued, is that the mean age at which participants were diagnosed with psoriasis was 26.6 years. It’s unclear whether the study findings extend to individuals who develop the dermatologic disease later in life. Dr Egeberg reported having no financial con- flicts regarding this study, supported by Danish national research funding.

Etanercept during pregnancy doubles the odds of major malformations

Women in all three groups were about 33 years old on average, and about 80% were white. The women were enrolled toward the end of their first trimester. Disease severity, comorbidities, and use of vitamins, alcohol, and tobacco were similar be- tween etanercept and disease control women. About 40% of the etanercept and disease control women, but just one in the healthy pregnancy group, were exposed to systemic corticoster- oids while pregnant. There were 33 major structural de- fects in children born towomen taking etanercept versus 7 in the disease con- trol group. That translated to a more than doubling of risk with etanercept (odds ratio, 2.37; 95% confidence interval, 1.02–5.52), and a more than doubling of risk versus the 10 major structural defects in children born to healthy control women (OR, 2.91; 95% CI, 1.37–6.76). A subanalysis excluded chro- mosomal anomalies, but “did not [change] our conclusions,” Dr Chambers said.

“etanercept is not meeting the crite- ria for causality. There’s no pattern” in major defects and “no biological plausibility” because the drug doesn’t seem to cross the placenta when the fetus is most vulnerable to adverse outcomes. “It is difficult to draw the con- clusion that this drug is causing harm. With true teratogens, you tend to see reduced birth weights and an increased risk of spontane- ous abortion, which is not the case with etanercept. We are seeing only this one finding that kind of stands alone, and everything else looks pretty good,” she said. The etanercept study investigated pregnancy outcomes in 370 women exposed to the drug while pregnant, mostly women with rheumatoid ar- thritis, but also women with psoriasis and ankylosing spondylitis. Their outcomes were compared with 164 pregnant women with the same diseases but no etanercept exposure – the disease control group – and 296 healthy pregnant women.

BY M. ALEXANDER OTTO Frontline Medical News At the American College of Rheumatology annual meeting, San Francisco E tanercept during pregnancy more than doubled the risk of major congenital malformations in a study by the Organization of Teratol- ogy Information Specialists. The group keeps a prospective registry on exposures to biologics during pregnancy. It is finishing up its adalimumab investigation and hasn’t found much to worry about, and continues to gather data on abatacept, tocilizumab, tofacitinib, apremilast, and certolizumab pegol. Etanercept , however, seems to be a different story; major malfor- mations turned up in the group’s recently completed investigation. Even so, Organization of Teratology Information Specialists (OTIS) in- vestigator Dr Christina D. Chambers, PhD, of the University of California, San Diego, was careful to note at the annual meeting of the Ameri- can College of Rheumatology that

Major structural defects generally refer to problems that need a surgical fix, including spina bifida, atrial sep- tal defects, cleft palates, hypospadias, polydactyly, and craniosynostosis. Minor defects that don’t need sur- gery, like a missing earlobe, occurred in six children exposed to etanercept and showed two different patterns that involved “three specific minor malformations” not seen in either of the control groups, Dr Chambers said. She did not elaborate on what those patterns were, but noted that the parents usually had them, too, “suggesting a genetic component as opposed to a drug effect.” Children in the three study groups had no statistically significant dif- ferences in 1-year malignancy rates,

serious infections, and hospitalisa- tions, even when exposed to etaner- cept in the third trimester. Children exposed to etanercept, however, were more likely to be born preterm and more likely to be small for gestational age in weight, length, and head circumference. They were also more likely than disease control children to screen positive for developmental issues at 1 year, but none of those differences were statistically significant. Dr Chambers disclosed funding from 14 companies, including Amgen, the maker of etanercept, and Jans- sen, Pfizer, Roche, Sanofi/Genzyme, GlaxoSmithKline, and AbbVie, the maker of adalimumab.

A life with RA is made up of many moments.

For one whole month, we captured on camera many moments of the life of a Simponi patient, Sarah Ryan†. In all those moments Simponi

featured in just one. Bet you won’t notice which one.

1

See the person behind the patient

PBS Information: Authority Required. Refer to PBS Schedule for full information

Please refer to the Product Information before prescribing. Product Information is available from www.janssen.com.au/Simponi_PI

SIMPONI (golimumab, rmc). Indications: Moderate to severely active rheumatoid arthritis (RA) in adult patients, in combination with methotrexate; active and progressive psoriatic arthritis (PsA) in adult patients, alone or in combination with methotrexate; active ankylosing spondylitis (AS) in adult patients, *active ulcerative colitis (UC) in adult patients . Contraindications: Severe infections such as tuberculosis (TB) and sepsis, opportunistic infections; concurrent anakinra or abatacept; moderate or severe heart failure (NYHA class III/IV), hypersensitivity to golimumab or any excipients. Precautions: May affect immune response; chronic, current, history or risk of infections, TB; Hep B reactivation; Hep B screening; surgery (infection risk); history or current malignancies, *hepatosplenic T-cell lymphoma; colon dysplasia/carcinoma; skin cancers, periodic skin examination, risk of malignancies in children, especially with concurrent immunosuppressants; CNS demyelinating disorders; haematological cytopaenias; live vaccines not recommended;*concurrent therapeutic infectious agents not recommended; hypersensitivity reactions*, latex sensitivity; autoimmunity. Not recommended in pregnancy (Category C) or while breastfeeding. Contraception recommended and discontinue breastfeeding including at least 6 months after last dose. Adverse Effects: URTIs, infections, allergic reactions, GI effects, increased ALT and AST, dizziness, headache, asthenia, hypertension, pruritus, neoplasms (including melanoma), visual disorders, CHF, lupus-like syndrome, for others see full Product information. Dosage: RA, PsA, AS: 50 mg subcutaneous injection once a month, on the same date each month; *UC: 200mg at Week 0, 100mg at Week 2 then 100mg every 4 weeks. Presentation: Solution for injection containing 50 mg golimumab in Smartject Injector pen or pre-filled syringe; *Solution for injection containing 100 mg golimumab in Smartject Injector pen or pre-filled syringe. Date of preparation: 20 March 2014. * Please note changes in the Product Information

Reference: 1. SIMPONI Product Information (7 July 2014) † Disclaimer: This patient story is fictional. A model was used in the photographs. © Janssen-Cilag 2015. Janssen-Cilag Pty Ltd. ABN 47 000 129 975. 1-5 Khartoum Road, Macquarie Park NSW 2113 AU-SIM0319. McCann Healthcare SIM0181_RN. Date prepared: March 2015.

NEWS 6

R heumatology N ews • Vol. 4 • No. 1 • 2016

Wearable device offers home- based knee OA pain relief

US FDA announces new plan to combat opioid abuse BY ALICIA GALLEGOS Frontline Medical News US Food and Drug Administra- tion officials are calling for a sweeping overhaul of the agency’s approach to opioid medications, in- cluding renewed efforts to improve how opioids are approved, labelled, and prescribed. The initiative focuses on new policies to help reverse the opioid abuse epidemic, while still provid- ing patients in pain with access to effective relief, Dr Robert M. Califf, FDA deputy commissioner for medi- cal products and tobacco, said in a Feb. 4 announcement. “Things are getting worse, not better, with the epidemic of opioid misuse, abuse and dependence,” said Dr Califf, who has been nomi- nated but not confirmed as FDA commissioner. “It’s time we all took a step back to look at what is work- ing and what we need to change to impact this crisis.” Under the new plan, the FDA will convene an advisory committee be- fore approving new drug applications for opioids that do not have abuse- deterrent properties and develop changes to immediate-release opioid labeling. The agency also plans to expand access to abuse-deterrent formulations of opioid products and improve the availability of naloxone and medication-assisted treatment options for patients with opioid use disorders. In a Feb. 4 editorial published in the New England Journal of Medicine , Dr Califf noted that the number of annual deaths from opioid overdoses now exceeds the number of annual deaths from mo- tor vehicle accidents (doi:10.1056/ NEJMsr1601307). “Regardless of whether we view these issues from the perspective of patients, physicians, or regula- tors, the status quo is clearly not acceptable,” Dr Califf wrote in the editorial. “As the public health agency responsible for oversight of pharmaceutical safety and effective- ness, we recognise that this crisis demands solutions. We are commit- ted to action, and we urge others to join us.” perspective of patients, physicians, or regulators, the status quo is clearly not acceptable. Regardless of whether we view these issues from the

week 16 as a result of the intravenous loading regimen, not to the 75-mg subcutaneous maintenance dose. The safety profile of secukinumab in the present studies was consistent with previous studies of secukinum- ab for ankylosing spondylitis and moderate-to-severe plaque psoriasis, Dr Baeten and his associates said. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients. Overall, the results suggest that interleukin-17A plays a role in the pathogenesis of ankylosing spondy- litis, and they validate inhibition of this cytokine as a potential thera- peutic approach, the study authors concluded. The study was sponsored by Novartis Pharma. Dr Baeten has received a grant fromNovartis to study the impact of IL-17A blockade in experimental models of spondyloarthritis. He also has been a consultant for Novartis for the design and conduct of the secukinumab program in ankylosing spondylitis and psoriatic arthritis. reduced 25.5% with the PEMF device and 3.6% with the placebo device. The standardised treatment effect size induced by PEMF therapy was –0.73 (95% confidence interval, –1.24 to –0.19), the investigators reported. WOMAC pain subscale and total scores fell 23.4% and 18.4% with the PEMF device versus a 2.3% reduc- tion for both scores with the placebo device. The standardised effect size was –0.61 for WOMAC pain (95% CI, –1.12 to –0.09) and –0.34 for WOMAC total score (95% CI, –0.85 to 0.17). At 1month, the mean Short Form-36 physical health score was significantly better in the PEMF group than in the placebo group (55.8 vs 53.1; P = 0.024), while SF-36 mental health scores were nearly identical (43.8 vs 43.6; P = 0.6). Patients were allowed per protocol to take prescribed analgesic therapy as needed, but eight patients from the PEMF group stopped these medica- tions, while one patient from the pla- cebo group stopped medication and three started a new therapy for chronic pain. No adverse events were reported during the study. “Given that our data are limited to a low number of participants and the long-term efficacy of the wearable de- vice is unknown, the generalisability of the results needs to be confirmed in a larger clinical trial with a longer dura- tion of treatment,” Dr Bagnato and his coauthors concluded. “However, the use of a wearable PEMF therapy in knee OA can be considered as an alternative safe and effective therapy in knee OA, providing the possibility for home-based management of pain, compared with previous studies.”

BY NICOLA GARRETT Frontline Medical News From the New England Journal of Medicine S ecukinumab, an interleukin 17-A inhibitor approved for the treatment of moderate to severe psoriasis, significantly reduced the signs and symptoms of ankylosing spondylitis in two phase III trials, researchers reported Dec. 23 in the New England Journal of Medicine . The results of the double-blind MEASURE 1 and MEASURE 2 trials extend the positive results of the phase II study, according to Dr Dominique Baeten of the Academic Medical Centre at the University of Amsterdam and his colleagues ( N Engl J Med 2015 Dec 23. doi: 10.1056/NEJMoa1505066). “Although head-to-head trials would be required to fully assess the efficacy and safety of secuki- numab versus TNF-inhibitors, the [20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response crite- ria] response rates achieved with secukinumab at week 16 in our studies were similar to those re- ported in phase III studies of anti- TNF agents in which most of the BY PATRICE WENDLING Frontline Medical News From Rheumatology A wearable pulsed electromagnetic fields device reduced pain inten- sity and improved physical func- tioning in patients with painful knee osteoarthritis (OA) in a double-blind, randomised trial. The commercially available device (ActiPatch, Bioelectronics Corp.) did not improve patients’ mental health, but significantly reduced patients’ intake of NSAIDs and analgesics, compared with placebo. “Although NSAIDs remain the gold standard for the treatment of pain in OA, there is increasing need to find conservative and alternative ap- proaches, in order to avoid the toxicity associated with the chronic use of the analgesics, mostly in the elderly popu- lation,” wrote Dr Gian Luca Bagnato of the University of Messina (Italy) and his colleagues. Pulsed electromagnetic fields (PEMF) therapy has been shown to reduce chondrocyte apoptosis and MMP-13 expression of knee cartilage and favourably affect cartilage ho- meostasis in animal models, but data regarding osteoarthritis (OA) pain and function in humans are mixed. A recent systematic review found no effect in all 14 trials analysed, but when only high-quality randomised clinical trials were included, PEMF

Courtesy BioElectronics Corporation

27.12 MHz, a pulse rate of 1,000 Hz, and a burst width of 100 microsec. Persistent pain was defined as a minimal mean score of 40 mm for global pain on the VAS (visual analog scale) and daily pain during the month prior to enrollment despite maximal tolerated doses of conventional medi- cal therapy, including acetaminophen and/or an NSAID. The patients’ mean age was 67.7 years and mean OA dura- tion 12 years. The primary efficacy endpoint was reduction in pain intensity at 1 month on the VAS and WOMAC (Western Ontario and McMaster Universities Arthritis Index). The mean WOMAC total score at baseline was 132.9. At 1 month, VAS pain scores were

provided significantly better pain relief at 4 and 8 weeks and better function at 8 weeks than did placebo ( Rheumatol- ogy 2013;52:815–24). Not only has the quality of trials var- ied, so has the PEMF pulse frequency and duration used in trials, “further limiting the possibility of comparing efficacy and safety,” Dr Bagnato and associates observed. The current study evenly ran- domised 60 patients with radiologic evidence of knee OA and persistent pain to wear the PEMF or a placebo device for a minimum of 12 hours, mainly at night, with the device kept in place with a wrap. The active device emits a form of non-ionising electro- magnetic radiation at a frequency of

Secukinumab cut ankylosing spondylitis symptoms in MEASURE trials

Secukinumab not only is effective in patients who have not received TNF agents previously but also may be effective in patients in whom previous anti-TNF treatment failed.

150 mg and 75 mg and for placebo, respectively, (P < 0.001 for both comparisons with placebo). In MEASURE 2, 219 patients re- ceived subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the place- bo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. In this trial, ASAS20 rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P < 0.001 for the 150-mg dose and P = 0.10 for the 75-mg dose). The researchers noted that the ineffectiveness of the 75-mg dose in MEASURE 2 suggests that the efficacy of secukinumab at the 75- mg dose in MEASURE 1 may have been due to the greater exposure at

patients had not received previous anti-TNF therapy (response rates of 58% to 64% at weeks 12 to 24), even though 30% to 40% of the patients in our studies had had no response to previous anti-TNF treatment,” the authors wrote. “Thus, secukinumab not only is effective in patients who have not received TNF agents previously but also may be effective in patients in whom previous anti-TNF treatment failed,” they added. In MEASURE 1, 371 patients received intravenous secukinumab (10 mg/kg of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. The study’s primary endpoint of ASAS20 response rates at week 16 were 61%, 60%, and 29% for sub- cutaneous secukinumab at doses of

7 ORTHOPEDICS

Vol. 4 • No. 1 • 2016 • R heumatology N ews

Functional dependence linked to risk of complications after spine surgery

Thigh muscle weakness a risk factor for knee replacement in women

Dr Patel reported findings from 24,357 patients: 23,620 (97.0%) functionally independent, 664 (2.7%) partially de- pendent, and 73 (0.3%) totally dependent. Dependent patients were significantly older and had higher rates of all comorbidi- ties (P < 0.001), with the exception of obesity (P = 0.214). In addition, 30-day complication rates were higher for all com- plications (P < 0.001) other than neurological (P = 0.060) and surgical site complications (P = 0.668). When the researchers controlled for type of procedure and for disparities in patient preoperative variables, multivariate analyses demonstrated that functional dependence was independently associated with sepsis (odds ratio 6.40; P < 0.001), pulmonary (OR 4.13; P < 0.001), venous thromboembolism (OR 4.27, P < 0.001), renal (OR 3.32; P < 0.001), and cardiac complications (OR 4.68; P = 0.001), along with mortality (OR 8.31; P < 0.001). “The very strong association between functional dependence and mortality was quite surprising,” Dr Patel said. “It was, to the contrary, also surprising to see that, despite wide vari- ance in medical comorbidities and functional status, surgical complications such as infection and neurological injury were similar in all groups.” He characterised the study as “the first large-scale assessment of functional status as a predictor of patient outcomes after cervical spine surgery. It fits in line with other studies utilising large databases. Big data analysis of outcomes can be used to identify risk factors for complica- tions including death after surgery. Identifying these factors is important if we are going to improve the care we provide. Accu- rately quantifying the impact of these risk factors is also critical when we risk stratify and compare hospitals and physicians.” He acknowledged certain limitations of the study, including the fact that it is a retrospective study “with a heterogeneous population of patients, surgeons, hospitals, and procedures. This adds uncertainty to the analysis at the level of the indi- vidual patient but does provide generalisability to a broader patient population.”

BY DOUG BRUNK Frontline Medical News At CSRS 2015, Toronto

BY NICOLA GARRETT Frontline Medical News From Arthritis & Rheumatology

F unctional dependence following elective cervical spine procedures was associated with a significantly increased risk of almost all 30-day complications analysed, includ- ing mortality, a large retrospective analysis of national data demonstrated. The findings suggest that physicians should “include the patient’s level of functional independence, in addition to more traditional medical comorbidities, in the risk-benefit analysis of surgical decision making,” Dr Alpesh A. Patel said in an interview in advance of the annual meeting of the Cervical Spine Research Society. “Those individuals with dependence need to be counselled appropriately about their increased risk of complications including mortality.” Dr Patel, professor and director of orthopaedic spine surgery at Northwestern University Feinberg School of Medicine, Chi- cago, and his associates retrospectively reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACSNSQIP) data files from 2006 to 2013 and limited their analysis to patients undergoing elective anterior cervi- cal fusions, posterior cervical fusions, cervical laminectomy, cervical laminotomy, cervical discectomy, or corpectomy. They divided patients into one of three groups based on the follow- ing preoperative functional status parameters: independent, comprising those not requiring assistance or any equipment for activities of daily living (ADLs); partially dependent, includ- ing those with equipment such as prosthetics, equipment, or devices and requiring some assistance from another person for ADLs; and totally dependent, in which patients require total assistance for all ADLs. The researchers used univariate analysis to compare patient demographics, comorbidities, and 30-day postoperative complications among the three groups, followed by multivariate logistic regression to analyse the independent association of functional dependence on 30-day complications when controlling for procedure and comorbidity variances.

W omen with knee osteoarthritis who had low thigh muscle strength were more likely to need a knee replacement in a case-control study of participants in the Osteoarthritis Initiative (OAI). In particular, predictors of knee replacement included knee extensor weakness in the year prior to knee replacement and longitudinal deterioration in knee extensor strength over a 2-year observation period prior to surgery. Measurement of knee exten- sor strength in women with knee osteoarthritis may then indicate who could benefit from weight training exercises to potentially delay or prevent the need for knee replacement surgery, said the researchers, led by Dr Adam Culvenor of Paracelsus Medical University in Salzburg, Austria.

Dr Patel reported having no conflicts of interest.

The optimal knee extensor strength threshold for differentiat- ing those with and without knee replacement risk was approxi- mately 200 N or 0.9 Nm/kg; or prevention of any loss of knee extensor strength over 2 years. “There appears to be a considerable window for women below this threshold to obtain realistic strength gains and potentially lower the risk of knee replacement,” the study authors concluded. In the multicentre, longitudinal, case-control study of 4796 participants in the OAI (60% of whom were women), the investigators identified 136 participants who had received a knee replacement and matched them with controls who had not received a knee replacement and were similar in age, body mass index (BMI), and radiographic stage. The mean age of the women was 65 years and the mean BMI was 29 kg/m 2 . The results showed that knee extensor strength at the examina- tion prior to knee replacement (time T 0 ), which occurred 2 years or less before surgery, was significantly lower in females who had received a knee replacement than in matched controls (pain- adjusted odds ratio, 1.72; 95% confidence interval, 1.16–2.56; P = 0.007). Measurement of the longitudinal change in knee extensor and flexor strength between T 0 and 2 years prior to T 0 (T -2 ) also provided similar results (pain-adjusted OR, 4.30; 95% CI, 1.34–13.79; P = 0.014). The findings were independent of age, BMI, and radiographic disease severity, the researchers noted. The investigators found no relationship between knee extensor or flexor muscle strength in men and subsequent need for knee replacement surgery. The relationship between thigh muscle strength and knee replacement for women did not extend to measurements made at T -2 or T -4 or the change in thigh muscle strength between T -2 and T -4 . The OAI receives funding from the National Institutes of Health, Merck Research Laboratories, Novartis, GlaxoSmithKline, and Pfizer. The work was also funded by a grant from the European Union Seventh Framework Programme. One author disclosed consulting or preparing educational sessions for pharmaceutical companies and for receiving research support. Two authors reported being employees of Chondrometrics GmbH, a company providing MR image analysis services to academic researchers and to industry.

Benefits, risks of total knee replacement for OA illuminated in trial

nonsurgical intervention (50 patients) or receive the comprehensive nonsur- gical intervention alone (50 patients) at two specialised university clinics in Denmark. The 12-week nonsurgical intervention comprised a twice-weekly group exercise program to restore neu- tral, functional realignment of the legs; two 1-hour education sessions regard- ing osteoarthritis characteristics, treat- ments, and self-help strategies; a dietary (weight-loss) program; provision of indi- vidually fitted insoles with medial arch support and a lateral wedge if patients had knee-lateral-to-foot positioning; and as-needed pain medication for pain – acetaminophen and ibuprofen – and pantoprazole, a proton-pump inhibitor. The primary outcome measure in the trial was the between-group difference at 1 year in improvement on four subscales of the Knee Injury and Osteoarthritis Outcome Scores (KOOS) for pain, symptoms, activities of daily living, and quality of life. The surgical group showed a significantly greater improvement (32.5 out of a possible 100 points) than the nonsurgical group (16.0 points) in this outcome. The surgical group also showed significantly greater improvements in all

five individual subscales and in a timed chair-rising test, a timed 20-metrewalk test, and on a quality-of-life index, the investigators said. However, it is important to note that patients who had only the nonsurgical intervention showed clinically relevant improvements, and only 26% of them chose to have the surgery after the con- clusion of the study. As expected, the surgical group had more serious adverse events than did the nonsurgical group (24 vs 6), including three cases of deep venous thrombosis and three cases of knee stiffness requiring brisement forcé while the patient was anesthetised, Dr Skou and his associates said. This study was supported by the Obel Family Foundation, the Danish Rheu- matism Association, the Health Science Foundation of the North Denmark Region, Foot Science International, Spar Nord Foundation, the Bevica Foundation, the Association of Danish Physiotherapists Research Fund, the Medical Specialist Heinrich Kopp’s Grant, and the Danish Medical Association Research Fund. Dr Skou and his associates reported hav- ing no relevant financial disclosures.

BY MARY ANN MOON Frontline Medical News

From the New England Journal of Medicine T otal knee replacement was superior to nonsurgical treatment in reliev- ing pain, restoring function, and improving quality of life for patients with moderate to severe knee osteoarthritis, according to a report published online Oct. 22 in the New England Journal of Medicine . Even though the number of total knee replacements performed each year is large and steadily increasing – with more than 670,000 done in 2012 in the US alone – no high-quality randomised, controlled trials have ever compared the effective- ness of the procedure against nonsurgical treatment, said Søren T. Skou, PhD, of the Research Unit for Musculoskeletal Function and Physiotherapy, Institute of Sports Science and Clinical Biomechan- ics, University of Southern Denmark, Odense, and his associates. Dr Skou and his colleagues remedied that situation by randomly assigning 100 adults (mean age, 66 years) who were eligible for unilateral total knee replace- ment to either undergo the procedure and then receive a comprehensive