Management of pregnancy in women with rheumatoid arthritis

Rheumatoid arthritis (RA) is a common condition which occurs more frequently in women than men.1 Its prevalence is about 2% in Australia, and this is predicted to increase to 3% by 2032.2 Therefore, the need to manage pregnancy in a woman with RA is not an uncommon clinical scenario. Clinicians must be aware of the teratogenicity of certain disease-modifying antirheumatic drugs (DMARDs) used to treat RA, and must ensure that women taking these drugs are using reliable contraception. Clinicians also have an important role to play in prepregnancy counselling to facilitate informed decision making. We,3 and others,4 have identified unmet information needs among women with RA, including needs relating to contraception, pregnancy planning, pregnancy and early parenting. The aim of our review is to highlight pertinent issues in managing pregnancy in women with RA.

Effect of RA on fertility and pregnancy

Despite having normal ovarian reserves,5 women with RA have fewer children than women in a control group,6 and take longer to conceive.7 The reasons for smaller family size have not been fully elucidated but may include personal choice, uncontrolled inflammatory disease, sexual dysfunction secondary to RA and the effects of non-steroidal anti-inflammatory drugs on ovulation and implantation.8 Clinicians should be aware of the possibility of subfertility, discuss this issue with prospective parents, and refer to reproductive specialists, when appropriate.

A recent registry-based study reported increased rates of spontaneous abortion in women with RA, although previous studies suggested no increased risk.9 Increased rates of prematurity, pre-eclampsia, caesarean delivery and infants with a low birth weight have been reported in women with RA.10–13 A Dutch study found that women taking prednisolone had higher rates of preterm delivery, and those with high disease activity were more likely to have caesarean delivery and infants with a low birth weight, but patients with well controlled RA had pregnancy outcomes comparable with those of the general population.14

Effect of pregnancy and lactation on RA

It was reported as early as 1938 that RA disease activity improved in 90% of women during pregnancy,15 and numerous subsequent studies have reported similar observations. A more recent prospective study of pregnant women with RA supports this finding, but suggests that rates of remission are more modest than traditionally thought, and that complete remission is uncommon.16 In this study, 39% of patients had flared by 26 weeks postpartum, confirming another long-held observation that women with RA are at increased risk of flare in the postpartum period. Women should be educated about the likelihood of postpartum flares and safe strategies to manage these events.

Because prolactin, a pituitary hormone integral to breastfeeding, is proinflammatory in animal models,17 the effect of breastfeeding on postpartum RA activity has been investigated. Despite two small studies suggesting that breastfeeding was associated with postpartum flares of RA,18,19 subsequent larger studies have not confirmed this association.20,21

Prepregnancy counselling

Given the teratogenicity of several DMARDs, treating practitioners have an obligation to ensure that patients with RA are counselled regularly about the importance of reliable contraception while taking these agents.22 One study found that 28% of women taking methotrexate (MTX) or leflunomide (LEF) used ineffective contraception.23 Another reported that despite 84% of women receiving correct contraceptive advice, one-third of women taking MTX or LEF were not using any contraception.24

It is estimated that up to 49% of pregnancies in the general population are unintended.25 If an unplanned pregnancy occurs in the setting of exposure to teratogenic drugs, the medications should be ceased immediately and the patient referred to a genetic counsellor and maternal–fetal medicine specialist for discussion of risk and further management.

Women with RA may question their practitioner about the possibility of RA inheritance. Controlled cohort studies have shown a relative risk of RA of 1.5–4.5 in first-degree relatives.26 Despite this modest increase in relative risk, patients can be reassured that the absolute risk of RA in their offspring remains small.

Good disease control before conception results in the best chance of low disease activity during pregnancy and a reduced risk of postpartum flare.16 Teratogenic medications need to be ceased and the several months it may take to ensure stability on a new drug regimen should be taken into account when planning pregnancy. Recommendations about cessation of medications before conception also extend to men on MTX and LEF (although there are no reports of teratogenicity in the children of men on either drug),27,28 and sulfasalazine (SSZ), which is known to reversibly impede spermatogenesis and reduce sperm motility and quality.29 A preconception referral to a maternal–fetal medicine specialist or obstetrician with an interest in high-risk pregnancy should also be considered.

Safety of drug therapy in pregnancy

Because of ethical concerns, pregnant and lactating women are specifically excluded from premarketing drug trials. Most pregnancy drug safety data are, therefore, derived from animal studies or postmarketing surveillance, case reports and large registries. In Australia, the Therapeutic Goods Administration pregnancy classification is used to categorise the safety of drugs in pregnancy (https://www.tga.gov.au/australian-categorisation-system-prescribing-medicines-pregnancy). It is not a hierarchical system, ie, it is not implied that a category B drug is safer than a category C drug. Although the pregnancy classification is widely used, in certain situations it is of limited use to clinicians in determining suitability of therapy. For example, while hydroxychloroquine (HCQ) and MTX are both category D drugs, only HCQ is considered safe in pregnancy, according to Australian practice guidelines.30

Of the DMARDs in current use, MTX and LEF are contraindicated in pregnancy and breastfeeding, and HCQ and SSZ are compatible with pregnancy.31 Of the biological agents, tumour necrosis factor (TNF) inhibitors may be continued until pregnancy is confirmed, with use in later gestation determined on a case-by-case basis,32 but all other biological agents should be avoided. If TNF inhibitors are used during pregnancy, live vaccinations should be avoided in the infant until 6 months of age, because of the risk of immunosuppression.33

Given the evolving nature of drug safety data, online resources are particularly helpful for clinicians. MotherToBaby (www.mothertobaby.org), a service of the Organization of Teratology Information Specialists, and LactMed (http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm), run by the United States National Library of Medicine, are two useful and regularly updated websites.

Not just loading and age: the dynamics of osteoarthritis, obesity and inflammation

Body fat is not an inert structure

Obesity is a well recognised risk factor for osteoarthritis (OA).1 It is commonly believed that obesity affects joints through loading. However, there must be additional mechanisms since, for decades, obesity has been known to be a strong risk factor for hand OA. Given that we do not walk on our hands, an effect of obesity through loading of the joints cannot be the whole explanation. An understanding of the potential mechanisms by which obesity affects joints is important for optimising the treatment and prevention of OA.

Work over the past decade using magnetic resonance imaging has enabled the assessment of factors affecting joints across the spectrum of the disease, from normal asymptomatic joints to symptomatic OA.1 This has made it possible to examine the effect of obesity on joints, and to untangle the issue of whether obesity causes OA or whether OA-related pain causes obesity through modification of lifestyle behaviours and consequent weight gain. This work has shown that obesity is a causative factor in the development of OA, with increased weight being associated with early articular cartilage damage, well before symptoms develop.1 Obesity is an important risk factor for OA across a wide range of joints, including hands, back, hip and knee.

Having established the importance of obesity as a causative factor for OA, it is important to consider potential mechanisms and to recognise that measures of obesity, such as weight and body mass index, have limited usefulness because they do not provide information regarding body composition. For example, body composition may be very different in two men with an identical body mass index of 30 kg/m²: one may have a very high proportion of muscle, while the other may have a very high proportion of fat. Several studies have examined the effect of body composition, particularly fat mass, on joint health.1 A large body of evidence has shown that an increase in fat mass is associated with pre-clinical OA.1 Increased fat mass is also associated with faster loss of knee cartilage and an increased likelihood of joint replacement. An increase in fat mass is also associated with more back pain and disability2 and foot pain.3

The findings that increased fat mass is associated with early through to late OA, independent of obesity, suggest that the effect of obesity on the joint may be via metabolically driven inflammation. It is well recognised that body fat is not an inert structure but rather a highly metabolically active tissue that produces inflammatory molecules, including cytokines and adipokines, that have been shown to damage joints.4 Circulating levels of inflammatory cytokines5 and low-grade synovitis are associated with cartilage loss.6 Higher levels of the adipokine leptin are also independently related to increased cartilage loss, suggesting a systemic mechanism for the effect of obesity on knee cartilage.7 Thus the old paradigm of OA being a degenerative, wear-and-tear disease of older age, and not an inflammatory disease, has been challenged.

So what are the implications of these findings? For weight-bearing joints, as obesity affects joints through both mechanical loading and metabolically driven inflammation, the effects are synergistic; the joint that is being loaded, rather than being healthy, is also subjected to low-grade inflammation — a double “hit”. Thus if a patient is carrying 20 kg extra weight, they are not carrying 20 kg of inert fat. The individual is carrying 20 kg of metabolically active tissue that is not only overloading the joint, but also producing inflammatory molecules resulting in a more vulnerable joint being loaded. The inflammatory mechanisms may also contribute to some of the obesity-related risk for non-weight-bearing joints.

The inflammatory mechanism for obesity-related damage to joints highlights the importance of preventing obesity in early life to avoid early joint damage. Such damage sets up a vicious cycle of further joint damage through both inflammation and loading. It may also contribute to the increased risk of cardiovascular disease seen in those with OA.9 Preventing early weight gain is potentially a more achievable and effective option than weight loss in later life.9,10 Once disease is established, weight maintenance may be a more feasible goal than weight loss for minimising pain and structural progression in joints such as the knee.1,9 With our increasingly obese population and its associated burden of osteoarthritis, novel therapies aimed at targeting inflammatory pathways warrant further investigation.

Australian clinical trial activity and burden of disease: an analysis of registered trials in National Health Priority Areas

To improve Australia’s health, clinical research programs should devote substantial activity to advancing practice in areas of high clinical need. Clinical trials are designed to provide high-quality evidence of the effectiveness of new interventions to establish best clinical practice. However, few studies have examined the extent to which Australian clinical trials address priority areas of clinical need.

The Australian Institute of Health and Welfare (AIHW) National Health Priority Areas (NHPAs) were introduced to encourage appropriate targeting of health services and clinical research to improve health. Currently, there are nine NHPAs: cancer control, cardiovascular health, mental health, injury prevention and control, diabetes mellitus, obesity, arthritis and musculoskeletal conditions, dementia and asthma. These NHPAs account for approximately three-quarters of the total estimated burden of disease in Australia (1 915 600 of 2 632 800 disability-adjusted life-years [DALYs]).1

Previous studies have reported a disparity between the level of National Health and Medical Research Council (NHMRC) grant funding for studies investigating NHPA conditions relative to their disease burden.2,3 The founding of clinical trial registries, including the Australian New Zealand Clinical Trial Registry (ANZCTR) in 2005, provides the first opportunity to examine how well clinical trial activity in Australia is targeted to NHPAs.

Methods

We conducted a retrospective analysis using ANZCTR and ClinicalTrials.gov (CT.gov) data to report on Australian trial activity and characteristics for NHPAs; and to compare the level of trial activity to the relative burden of disease for each NHPA.

Ethics approval was not required for this analysis of publicly available trial data.

Data sources

Trial registration is voluntary in Australia.4

The ANZCTR is an online public registry of clinical trials maintained by the NHMRC Clinical Trials Centre, the University of Sydney. It collects information about trial interventions, investigated health conditions, planned recruitment, outcomes, funding and sponsorship using the World Health Organization-defined 20-item minimum dataset.5 Health conditions are coded using the United Kingdom Clinical Research Collaboration Health Research Classification System (http://www.hrcsonline.net). Additional data are collected about trial design, including randomisation and blinding. The ANZCTR 2011 Data Quality and Completeness Audit reported that, on average, at least 93 of 94 data fields for 148 trials were complete.6

CT.gov is an online public registry of clinical trials maintained by the United States National Library of Medicine (https://clinicaltrials.gov). It records similar data items to the ANZCTR.

Trial sample and characteristics

The trial sample included all trials of health-related interventions registered on the ANZCTR or CT.gov between 1 January 2008 and 31 December 2012 that included Australia as a country of recruitment. To avoid entering duplicate trial data, trials that listed a CT.gov or ANZCTR registration number as a secondary identifier were only included in the ANZCTR trial list.

Condition categories and codes were used to classify individual trials as addressing one or more NHPA conditions, or other, non-NHPA conditions. For each trial, we extracted information for: purpose of intervention (treatment, prevention, diagnosis, education/counselling/training, other/missing); allocation of intervention (randomised, non-randomised); trial phase (I–IV, not applicable, missing), blinding (blinded, open, other/missing), planned recruitment (reported as target sample size, and classified as < 100, 100–1000, > 1000 participants); participant age range (< 18 years, 18–69 years, ≥ 70 years); and countries of recruitment (Australia only, Australia and overseas).

Analysis

To measure trial activity, we recorded the total number and planned recruitment of registered trials investigating NHPA conditions. To assess whether trial activity reflected the burden of disease for each NHPA, we compared the relative trial activity targeted to each NHPA, measured as a proportion of the total trial activity, with the “expected” distribution of trial activity estimated from the relative burden of disease for that NHPA. Burden of disease was estimated from published estimates of DALYs for each NHPA expressed as a percentage of the total burden of disease and injury in Australia (%DALY).1

To describe disparities in relative trial activity by NHPA, we identified NHPAs where the observed trial activity was less than 50% or more than 200% of expected values. The χ2 goodness-of-fit test was also used to test for statistically significant differences between observed and expected trial activity for each NHPA. For these analyses, a two-sided P < 0.006 was regarded as statistically significant using the Bonferroni adjustment for multiple comparisons (nine comparisons).

For assessment of trial recruitment across NHPA, we also conducted a sensitivity analysis to examine trial recruitment to NHPA from Australian sites, where Australian recruitment was estimated from the planned recruitment from all ANZCTR trials plus 10% of the planned recruitment from CT.gov trials that included at least one Australian site. The figure of 10% was estimated from a randomly selected sample of 100 CT.gov registered trials that included at least one Australian site and represents the number of Australian sites as a proportion of all sites for each trial.

We also calculated the frequency distribution of trial characteristics for each NHPA. SAS, version 9.3 (SAS Institute) was used for data analyses.

Results

There were 5143 intervention trials registered during 2008–2012 that planned to recruit in Australia (ANZCTR, 3379; CT.gov, 1764). Of these, 3032 (59%) related to NHPA conditions (ANZCTR, 1908; CT.gov, 1124). Total planned recruitment for the trial sample was 2 404 609 participants, including 1 532 064 (64%) for NHPA trials (ANZCTR, 670 832; CT.gov, 861 232).

Trial activity in NHPA

The three disease areas that contribute the largest %DALY — cancer, cardiovascular diseases and mental disorders — also attracted the largest number of trial registrations and the largest planned recruitment (Box 1; Box 2).

The proportions of registered trials that investigated dementia or injury interventions were less than half those expected from their %DALYs (65/185 [35%] and 137/360 [38%], respectively; Box 1). The proportions of obesity and asthma trials were also lower than expected (195/386 [51%] and 68/123 [55%], respectively). In contrast, the proportion of registered arthritis and musculoskeletal diseases trials was about twice as high as expected on the basis of the %DALY (Box 1).

The proportions of planned recruitment to trials investigating obesity and dementia were also substantially lower than expected from their %DALYs (33 948/180 346 [19%] and 24 248/86 566 [28%], respectively), and was also low for asthma (29 468/57 711 [51%]) (Box 1).

When this analysis was repeated using estimated recruitment from Australian sites only, a similar pattern was observed, with the exception of recruitment to diabetes trials. For diabetes trials, total trial planned recruitment was relatively high (185 929/132 253 [141%]) compared with Australian sites (44 201/66 607 [66%]).

Trial characteristics

Overall, 2335 of 3032 (77%) NHPA trials used a randomised design and 1509 (50%) planned recruitment of ≤ 100 participants (Box 3). Of the 2931 NHPA trials that reported information about blinding, 1504 (51%) reported using it (Box 3).

About three-quarters of NHPA intervention trials investigated treatments (2321 [76%]) and 397 (13%) investigated prevention interventions (Box 3). The ratio of treatment to prevention trials ranged from less than 2 : 1 for obesity trials to 14 : 1 for cancer trials.

Most NHPA trials excluded children, whereas 2252 (75%) specified a maximum participant age of ≥ 70 years, or did not specify a maximum age (Box 3). International recruitment sites were reported in 1081 (36%) of NHPA trials (169 ANZCTR trials, 912 CT.gov trials) and varied by condition (Box 3).

Discussion

This study provides the first overview of clinical trial activity in Australia. We found that more than half of Australian registered intervention trials and planned trial recruitment are targeted to NHPA conditions.

Trial activity for cancer, cardiovascular diseases and mental disorders was high relative to other NHPA conditions, consistent with their position as the three major contributors to disability and premature death in Australia. In contrast, trial activity for obesity and dementia interventions was substantially less than the level expected from their contribution to the total DALY.

To interpret these results, the number of trials can be considered to provide a proxy measure for the number of active research questions being investigated to identify more effective interventions in each area. Planned trial recruitment provides a measure of the number of patients actively participating in research to determine best practice in each area.

These findings suggest there is a need to further examine research activity for obesity, dementia and asthma to determine if and how clinical trials research in these areas should be increased. However, this study does not allow us to define the optimum level of trial activity for each condition. Clearly, not all important research questions for NHPAs are amenable to investigation through clinical trials. For conditions where trial activity is already high relative to other disease areas, further increases may still represent good value for money by improving health care. For example, if promising new interventions are available; or practice variations or controversies exist with gaps in evidence to guide best practice. Conversely, for some conditions where trial activity is currently low, research priorities may warrant other study designs, such as those used in translational research or behavioural science, to develop new interventions.

This study also provides the first opportunity to assess the extent to which Australian trials are designed to provide robust, high-quality evidence for guiding practice. The use of randomisation and blinding provides a measure of trial quality; trial size provides an indicator of study power. Trials enrolling more than 100 participants are generally required to assess clinically meaningful health outcomes and to weigh up the benefits and harms of the new strategy, whereas smaller trials are generally designed to assess surrogate outcomes. About three-quarters of Australian trials used a randomised design; however, only around half reported blinding, or planned recruitment of more than 100 participants. These findings are slightly more favourable than those of a recent analysis of 79 413 intervention trials registered on CT.gov between 2000 and 2010, which reported that 70% used a randomised design, 44% used a blinded design and 38% enrolled 100 or more participants.7

One commonly raised concern about clinical trials research is the applicability of trial data to routine clinical practice populations and settings. Our finding that more than two-thirds of trials in NHPA areas did not exclude participants aged 70 years or older is encouraging.

The main strength of our study is that it provides a unique, timely overview of Australian clinical trials to inform current debate on the achievements, limitations and future directions for clinical trials research in Australia. Clinical researchers can use the same methods to further explore gaps for conditions within specific disease areas, as has been performed for cancer trials.8

There are two main limitations to our study that could affect our estimates of trial activity in different directions. First, we relied on trial registrations to estimate trial activity. As trial registration is not compulsory in Australia, we may have underestimated trial activity. Additionally, we only included international trials registered on the ANZCTR or CT.gov. A search using the WHO International Clinical Trials Registry Platform Search Portal (http://www.who.int/ictrp/search/en) showed that 11 096 of 11 412 (97%) trials with Australian sites are registered on these two registries. The total number of registered trials may therefore be 3% higher than our study estimate.

Second, our estimates of trial participation may overestimate the number of Australians participating in clinical trials, because 1622 of 5143 trials (32%) included sites outside Australia. Nevertheless, by including Australian sites, these trial recruitment figures capture participation in trials that can be expected to provide evidence relevant to Australian practice.

Despite these limitations, we believe our findings are valuable in informing initiatives to increase clinical trial activity.9,10 It is well documented that trial research is often not available to guide many routine clinical decisions about selecting interventions.11 To guide practice, large trials with adequate long-term follow-up are needed to identify small incremental improvements in health outcomes and/or adverse events. Our findings on trial size suggest that further efforts are needed to promote and support the conduct of large trials, or support the conduct of small high-quality trials that can later contribute data to meta-analyses.

Overall, we demonstrate the feasibility and value of using publicly available trial registry data to examine the profile of trials research for particular conditions and identify gaps in trial activity to inform trial initiatives. The ANZCTR provides a valuable resource for researchers to ensure new studies build on, or contribute to, existing trials.

1 Number of registered Australian intervention trials and total planned recruitment in National Health Priority Areas, as a percentage of total trial activity, and comparison to the expected number based on %DALY, Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012

	DALY		Trials					Planned recruitment
National Health Priority Area	Rank	%	Rank	Observed no. (%)	Expected no.	Observed/ expected %	P*	Rank	Observed no. (%)	Expected no.	Observed/ expected %	P*

Cancer control	1	19.0%	1	871 (16.9%)	977	89%	0.007	2	427 188 (17.8%)	456 876	94%	< 0.001
Cardiovascular health	2	18.0%	3	646 (12.6%)	926	70%	< 0.001	1	577 178 (24.0%)	432 830	133%	< 0.001
Mental health	3	13.3%	2	693 (13.5%)	684	101%	0.82	3	196 826 (8.2%)	319 813	62%	< 0.001
Obesity	4	7.5%	6	195 (3.8%)	386	51%	< 0.001	7	33 948 (1.4%)	180 346	19%	< 0.001
Injury prevention and control	5	7.0%	7	137 (2.7%)	360	38%	< 0.001	5	125 256 (5.2%)	168 323	74%	< 0.001
Diabetes mellitus	6	5.5%	5	282 (5.5%)	283	100%	1.00	4	185 929 (7.7%)	132 253	141%	< 0.001
Arthritis and musculoskeletal conditions	7	4.0%	4	410 (8.0%)	206	199%	< 0.001	6	109 107 (4.5%)	96 184	113%	< 0.001
Dementia	8	3.6%	9	65 (1.3%)	185	35%	< 0.001	9	24 248 (1.0%)	86 566	28%	< 0.001
Asthma	9	2.4%	8	68 (1.3%)	123	55%	< 0.001	8	29 468 (1.2%)	57 711	51%	< 0.001

DALY = disability-adjusted life-years. %DALY = DALYs expressed as a proportion of the total burden of disease in Australia.1 Observed number of trials is expressed as a percentage of total 5143 registered intervention trials. Observed planned recruitment is expressed as a % of total 2 404 609 planned recruitment. Expected number of trials is calculated by applying %DALY to total 5143 registered intervention trials. Expected planned recruitment is calculated by applying %DALY to total 2 404 609 planned recruitment. * χ2 goodness-of-fit test for comparison of observed versus expected values.

2 Relationship between trial characteristics and %DALY for each NHPA, Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012

The diagonal line represents the line of equality where %DALY is equal to trial number as a percentage of total registered trials (A) or planned trial participation as % of total planned trial participation (B). Dots below the line show NHPAs where the variable falls below the %DALY. The size of dots corresponds to the size of planned trial participation (A) or number of trials (B) for the NHPA.

%DALY = disability-adjusted life-years expressed as a proportion of the total burden of disease in Australia.1 NHPA = National Health Priority Area.

3 Australian intervention trial characteristics, overall and by National Health Priority Area (NHPA),* Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012

Characteristic	All trials	NHPA trials	Cancer	Cardio- vascular	Mental health	Obesity	Injury	Diabetes	Arthritis/ musculoskeletal	Dementia	Asthma

Total	5143	3032	871	646	693	195	137	282	410	65	68
Randomisation
Yes	3990 (78%)	2335 (77%)	564 (65%)	494 (77%)	579 (84%)	163 (84%)	125 (91%)	253 (90%)	321 (78%)	53 (82%)	59 (87%)
No	1137 (22%)	691 (23%)	304 (35%)	150 (23%)	113 (16%)	31 (16%)	12 (9%)	28 (10%)	89 (22%)	12 (18%)	9 (13%)
Missing	16	6	3	2	1	1		1
Intervention type
Treatment	3834 (75%)	2321 (76%)	732 (84%)	444 (69%)	494 (71%)	108 (55%)	103 (75%)	210 (75%)	357 (87%)	50 (77%)	46 (68%)
Prevention	781 (15%)	397 (13%)	52 (6%)	131 (20%)	98 (14%)	67 (34%)	25 (18%)	46 (16%)	34 (8%)	5 (8%)	10 (15%)
Diagnosis	152 (3%)	78 (3%)	29 (3%)	26 (4%)	11 (2%)	3 (2%)	2 (2%)	8 (3%)	4 (1%)	4 (6%)	0
Educational/ counselling/training	263 (5%)	171 (6%)	39 (5%)	26 (4%)	73 (11%)	10 (5%)	4 (3%)	15 (5%)	9 (2%)	5 (8%)	7 (10%)
Other/missing	113 (2%)	65 (2%)	19 (2%)	19 (3%)	17 (2%)	7 (4%)	3 (2%)	3 (1%)	6 (2%)	1 (2%)	5 (7%)
Age group (years)
Minimum age < 18†	987 (19%)	490 (16%)	122 (14%)	60 (9%)	156 (23%)	29 (15%)	42 (31%)	28 (10%)	57 (14%)	7(11%)	26 (38%)
Missing	5	2	1							1
Maximum age ≥ 70†	3652 (71%)	2252 (75%)	774 (89%)	558 (87%)	397 (57%)	69 (36%)	98 (72%)	199 (71%)	316 (77%)	59 (94%)	41 (60%)
Missing	18	10	2	2		1			2	2
Blinding
Blinded	2639 (53%)	1504 (51%)	270 (31%)	347 (55%)	405 (61%)	93 (51%)	89 (67%)	141 (52%)	249 (64%)	47 (72%)	48 (72%)
Open	2322 (47%)	1427 (49%)	589 (69%)	281 (45%)	260 (39%)	91 (49%)	43 (33%)	129 (48%)	139 (36%)	18 (28%)	19 (28%)
Missing	182	101	12	18	28	11	5	12	22	0	1
Planned recruitment
1–100	2689 (52%)	1509 (50%)	361 (41%)	325 (50%)	361 (52%)	132 (68%)	66 (48%)	133 (47%)	228 (56%)	22 (35%)	33 (49%)
101–1000	2066 (40%)	1274 (42%)	427 (49%)	244 (38%)	300 (43%)	58 (30%)	61 (45%)	119 (42%)	161 (39%)	35 (55%)	31 (46%)
> 1000	383 (7%)	246 (8%)	83 (10%)	77 (12%)	30 (4%)	5 (2%)	10 (7%)	30 (11%)	21 (5%)	6 (10%)	3 (5%)
Missing	5	3	1		2					2	1
Country of recruitment
Australia only	3521 (68%)	1951 (64%)	349 (40%)	401 (62%)	578 (83%)	184 (94%)	113 (82%)	192 (68%)	286 (70%)	37 (57%)	47 (69%)
Australia and overseas	1622 (32%)	1081 (36%)	522 (60%)	245 (38%)	115 (17%)	11 (6%)	24 (18%)	90 (32%)	124 (30%)	28 (43%)	21 (31%)

Data are no. (%) unless otherwise specified. * Trials may be classified under more than one NHPA (eg, obesity and diabetes). † Includes trials that did not specify age limits.

Update on the diagnosis and management of gout

Gout is a common clinical problem encountered by both general and specialist physicians. Despite its high prevalence and the availability of safe and effective therapies, the optimal approach to its diagnosis and treatment remains uncertain, as a result of which practice varies between clinicians.1 In this article, we provide an up-to-date review of the diagnosis and management of gout, and outline recent developments in the literature.

The key principles in gout management are:

establishing a definitive diagnosis;
the swift treatment of acute attacks; and
preventing further attacks and joint damage by using urate-lowering therapies appropriately.

Diagnosis

To establish a definitive diagnosis, monosodium urate (MSU) crystals must be demonstrated by polarised light microscopy in synovial fluid or in a tophus. A clinical diagnosis is possible without synovial fluid analysis, but must be considered only provisional. Individual clinical and laboratory features — such as hyperuricaemia, first metatarsal joint involvement, maximal inflammation within 24 hours and local erythema — are of low diagnostic utility, with two exceptions: a prompt response to colchicine (positive predictive value [PPV], 86%) and the presence of tophi (PPV, 91%).2

New imaging techniques have recently been explored as diagnostic alternatives to arthrocentesis and synovial fluid analysis. Dual-energy computed tomography (DECT) uses differences in the attenuation of x-rays with different energy characteristics to identify urate deposits, while the double contour sign (DCS) seen in an ultrasound examination indicates deposition of hyperechoic MSU on the surface of the hyaline cartilage. A recent systematic review identified eight studies (case–control or cross-sectional) that compared the use of DECT or DCS with the gold standard for MSU detection, synovial fluid analysis by polarised light microscopy. The pooled sensitivities for DCS and DECT were 0.83 and 0.87, respectively; the pooled specificities were 0.76 and 0.84.3 Overall, the evidence for the utility of the newer imaging techniques is promising, but their cost and availability and the current lack of standardisation argue against using them in routine clinical practice at this time.

Treatment of acute attacks

Non-steroidal anti-inflammatory drugs (NSAIDs), low-dose colchicine, and glucocorticoids (oral, intramuscular or intra-articular) are all effective therapeutic options for the management of acute gout. In the absence of clear evidence supporting the superiority of a particular agent, the choice should be determined by patient factors such as age, comorbidities, concomitant medications and personal preference. If used, a low-dose colchicine regimen (1 mg immediately, 0.5 mg 1 hour later) is as effective as traditional higher-dose therapy, and is associated with fewer adverse effects.4 Novel agents, including the anti-interleukin-1 antibody canakinumab, have been investigated, but are not yet part of the standard management of acute gout.5

Urate-lowering therapies

Urate-lowering therapy should be initiated in any patient with established gout who is experiencing frequent acute attacks (generally more than two to three per year), or who presents evidence of tophi, gouty arthropathy, stage 2 chronic renal impairment or nephrolithiasis.6 In these patients, the core strategy for preventing gout flares and subsequent joint destruction and disability is to reduce the patient’s serum uric acid (SUA) levels. An SUA concentration of less than 0.36 mmol/L is the minimum target for reducing the frequency of gout attacks. However, a stricter SUA goal (< 0.30 mmol/L) is recommended for patients with tophi, severe disease or joint damage, as it is associated with more rapid tophus reduction and a longer interval before the recurrence of acute attacks after treatment is stopped.7

Allopurinol is the first-line medication for reducing SUA levels because of its efficacy, safety, availability and cost.8 Monthly up-titration of allopurinol should occur until the target SUA level is achieved, with the maximum dose determined by tolerability rather than renal function.9,10 In patients with renal impairment, a lower starting dose and more gradual up-titration are advisable, but a treat-to-target SUA strategy remains vital.9

Second-line agents, such as probenecid, febuxostat and benzbromarone, may be used if allopurinol is not tolerated or the patient’s response is inadequate despite appropriate dosing. Febuxostat and benzbromarone are available in Australia under individual hospital-based Special Access Schemes. Febuxostat is a non-purine, non-competitive xanthine oxidase inhibitor that is probably as effective as allopurinol in its ability to lower SUA levels and reduce the frequency of gout flares.11,12 The uricosuric agent benzbromarone was more effective and better tolerated than probenecid in a single trial.13 Combining a xanthine oxidase inhibitor with a uricosuric agent can be considered when monotherapy fails to achieve the target SUA level.

Pegloticase is an intravenously administered porcine uricase that has been found to be superior to placebo in achieving target SUA levels, but it is associated with adverse events that include frequent acute gout attacks and anaphylaxis.14 Phase III trials of a further uricosuric agent, lesinurad, have recently been completed.15 Neither of these new urate lowering agents are currently approved for use in Australia.

Prophylaxis

When urate-lowering therapy is started, prophylaxis should also be routinely initiated to reduce the risk of disease destabilisation and flares. NSAIDs, low-dose colchicine and low-dose glucocorticoids are all options for prophylaxis, alone or in combination. Novel prophylactic therapies, such as the interleukin-1 inhibitor rilonacept, have not yet been demonstrated to have benefit–risk profiles superior to those of already available agents.16 The optimal duration of prophylaxis is unclear, but it should be continued at least until the target SUA level is reached; the presence of tophi may warrant its prolongation until they have resolved. Urate-lowering therapy itself should be continued for life, and should not be stopped during acute attacks of gout.

In summary, the gold standard diagnostic tool for gout remains the identification of MSU crystals in synovial fluid or a tophus by polarised light microscopy. Emerging new diagnostic imaging techniques and novel therapies show promise, but in most cases the judicious use of existing therapies remains the key determinant of success in managing gout.

Spinal gout mimicking osteomyelitis

A 41-year-old Australian man with a history of gout presented with severe thoracic back pain and fevers, causing him to be bed-bound for a week. There was no infectious or traumatic precipitating event. This magnetic resonance image of the spine showed a lytic lesion on the T1 spinous process with inflammatory changes in the adjacent soft tissues and surrounded by a small collection of fluid. There was no spinal cord involvement.

The patient was treated for vertebral osteomyelitis and gout until a spinal aspirate showed monosodium urate crystals. He made a full recovery.

Febuxostat-associated rhabdomyolysis in chronic renal failure

Clinical record

A 68-year-old man of European descent presented to our emergency department with rhabdomyolysis and acute-on-chronic kidney disease. He had a history of stage 3 chronic kidney disease (CKD3) — based on 17 tests in the year before this admission, his estimated glomerular filtration rate (eGFR) was 35 ± 7 mL/min/1.73m2 (CKD3: eGFR = 30–59 mL/min/1.73m2), his serum creatinine concentration was 179 ± 42 µmol/L (reference interval [RI], 60–120 µmol/L) — and of polyarticular tophaceous gout, type 1 diabetes mellitus, hypertension, ischaemic heart disease (coronary artery bypass grafting in 1998) and peripheral vascular disease.

His gout, diagnosed 13 years before this presentation, had been treated with allopurinol and then colchicine. Both, however, caused anaphylactic reactions. He had had multiple short courses of prednisolone to treat acute attacks on a background of naproxen. A month before this presentation, naproxen was withdrawn and treatment with a new hypouricaemic drug, febuxostat(40 mg daily) initiated. This drug was obtained through the Special Access Scheme of the Therapeutic Goods Administration. Two doses of febuxostat were withheld 12 days before this admission when he was admitted to hospital for 8 days with Haemophilus influenzae pneumonia and acute-on-chronic kidney disease, with his serum creatinine concentration peaking at 245 µmol/L. He was treated with intravenous ceftriaxone and azithromycin for 5 days, after which his renal function values had returned to baseline levels. He was discharged home and prescribed oral amoxicillin, which was to be continued for 5 days.

When he presented to our emergency department, the man was lethargic, oliguric, dehydrated and with acute-on-chronic kidney disease (serum creatinine concentration, 669 µmol/L; eGFR, 7 mL/min/1.73m2), but he was haemodynamically stable. There were no symptoms suggesting infection, and he was afebrile. Elevated serum creatine kinase activity (48 200 U/L; RI, 20–200 U/L) and the presence of myoglobin in his urine were consistent with rhabdomyolysis. The man was hyperkalaemic (potassium, 6 mmol/L; RI, 3.5–5.0 mmol/L) with tall T waves in his electrocardiogram; this responded to oral resonium and nebulised salbutamol. His serum creatinine concentration continued to rise despite intravenous hydration, peaking 48 hours after admission at 833 µmol/L (eGFR, 6 mL/min/1.73m2). His bicarbonate levels declined from 22 mmol/L to 15 mmol/L (RI, 24–31 mmol/L), reflecting worsening metabolic acidosis.

At the time of his admission, he was taking (in addition to febuxostat) aspirin (100 mg daily), simvastatin (40 mg daily), gemfibrozil (600 mg twice daily), frusemide (40 mg daily), metoprolol (100 mg twice daily), moxonidine (200 mg twice daily), insulin and omeprazole (20 mg daily).

Febuxostat was considered to be the likely dominant precipitating factor and was withdrawn, as were simvastatin and gemfibrozil; he had used these two medications for 12 years, but febuxostat had only recently been prescribed. Further, application of the Naranjo adverse drug reaction (ADR) probability scale1 indicated that febuxostat possibly caused rhabdomyolysis in our patient.

Haemodialysis of the patient was commenced, and he had five cycles over the next 11 days. His renal function gradually returned to baseline (Figure). He was discharged on Day 23. Some months later, treatment with benzbromarone was started, a uricosuric drug that was also obtained through the Special Access Scheme. After taking benzbromarone for one-and-a-half months, his plasma urate concentration was 0.26 mmol/L (RI, 0.25–0.50 mmol/L).

Uncontrolled gout is a significant disorder because of the debilitating attacks of acute gout, the ensuing joint damage that causes pain, deformity and loss of function, and the organ damage involved, particularly renal dysfunction. The xanthine oxidase inhibitor allopurinol is an effective medication for reducing plasma urate concentrations to below 0.36 mmol/L, and this effect, if maintained, will almost always eliminate recurrent acute attacks of gout and the risk of joint and organ damage.2–4 As the active form of the drug is cleared exclusively by the kidney, the starting dose needed by patients with impaired renal function is lower.4 Risk of hypersensitivity, manifested as toxic epidermal necrolysis, is an uncommon but significant problem; a macular-papular rash is seen in as many as 2% of patients. These problems may be more common in those with impaired renal function or also using diuretic medications.5

There are alternative approaches for lowering urate levels in patients with hypersensitivity reactions. Uricosuric drugs, such as probenecid, are effective in patients with normal to moderately impaired renal function, but are not effective in those with severe renal impairment.6 Benzbromarone is a more effective uricosuric agent in individuals with renal impairment, but must be imported into Australia under the Special Access Scheme, as it is not registered in this country.7

The availability of a second xanthine oxidase inhibitor, febuxostat, is therefore welcome, especially for patients who do not tolerate allopurinol well. Febuxostat is registered in the United States and Europe, and was recently also registered in Australia (December 2014). The medication is generally well tolerated and dose adjustment is not necessary in patients with mild to moderate renal dysfunction. Liver function abnormalities and cardiovascular thrombotic reactions have been identified by postmarketing studies, but their incidence is very low. Only a few case reports have described hypersensitivity reactions. Cost is an issue, as febuxostat is more expensive than allopurinol, and should therefore not be the agent of first choice.

Rhabdomyolysis is noted as a rare side effect in the product information for febuxostat (following post-marketing experience), but there has only been a single published case report.8 In our patient, a serious additional decline in renal function was marked by substantially elevated creatine kinase activity, suggesting that rhabdomyolysis had caused this decline. It is likely that the concomitant statin and fibrate hypolipidaemic medications (ie, simvastatin and gemfibrozil) that the patient had taken uneventfully for several years contributed to his myositis. Dehydration associated with the patient’s recent pneumonia probably also contributed to renal deterioration.

It is notable that in our case and that of Kang and colleagues,8 patients with chronic kidney disease had been taking statins both before and together with febuxostat. The combination of chronic kidney disease and statin therapy may represent a risk for febuxostat-induced rhabdomyolysis and renal injury.

The options for reducing this patient’s plasma urate levels — a critical goal, given his deteriorating renal function, progressive joint damage, and recurrent and severely painful acute gout — are quite limited. Febuxostat is now clearly contraindicated. Probenecid has limited efficacy when the glomerular filtration rate falls below 30 mL/minute. Benzbromarone, which is more effective than probenecid in patients with impaired renal function, can be obtained in Australia under the Special Access Scheme, and is a reasonable option. However, the patient’s hepatic function would need to be carefully monitored, as the medication was withdrawn from the market in Europe and North America after rare reports of serious hepatic toxicity.7 Recombinant forms of uricase (such as rasburicase, pegloticase) would undoubtedly be effective in reducing urate levels, but repeated use would be prohibitively expensive; further, there is a risk of developing antibodies to pegloticase, which results in reduced efficacy and the possibility of adverse effects.9 Desensitisation to allopurinol, although complex, time-consuming and not without risk, also remains an option.10

Lessons from practice

Options for reducing plasma urate levels to prevent recurrent acute and tophaceous gout are limited, especially in patients with impaired renal function.
Febuxostat is an effective alternative xanthine oxidase inhibitor to allopurinol.
Although the product information for febuxostat indicates that there is no need for dose adjustment in patients with moderate renal impairment, prescribers need to be cautious.
Chronic kidney disease and concomitant statin therapy may represent a risk for febuxostat-induced rhabdomyolysis and subsequent renal injury.

Figure

Time course of serum creatine kinase activity and estimated glomerular filtration rate (eGFR) in our patient. Arrows: Dialysis was undertaken on Days 3, 7, 10, 12 and 15.

[Comment] Spondyloarthropathy: interleukin 23 and disease modification

Prevention of progressive loss of normal articular structure and preservation of functional capability are central goals of therapeutic discovery in rheumatology. Despite the remarkably effective inhibition of structural damage in rheumatoid arthritis that was achieved with biological agents targeting tumour necrosis factor, and the ability to reduce signs and symptoms of disease in spondyloarthropathy with the same treatments, prevention of disease progression and bone pathology in seronegative spondyloarthropathies has been immensely challenging.

The scope, funding and publication of musculoskeletal clinical trials performed in Australia

According to the recently published 2010 Global Burden of Disease study, musculoskeletal (MSK) conditions have the fourth greatest impact on the health of the world’s population, accounting for 6.8% of the total disease burden.1 In considering disability alone, low back pain has the greatest impact on health, outranking ischaemic heart disease, chronic obstructive pulmonary disease and major depressive illness, with other MSK conditions ranked sixth and osteoarthritis ranked 11th.1

In Australia, MSK conditions are the leading contributor to total disability burden (27.4%), and are second only to cancer (15.3% versus 16.2%) when death is also considered.2 They are the most common reason for accessing health care services,3 and in financial terms, contribute to 7.5% of total health expenditure (costing around $4 billion).4 Given their large burden on the Australian population, osteoarthritis, rheumatoid arthritis and osteoporosis were designated National Health Priority Areas (NHPAs) in 2002.5 Importantly, the burden from MSK conditions is increasing as the population ages. There is therefore an urgent need to prioritise research on the most effective and affordable strategies to deal with these conditions.

High-quality trials to test these strategies should be informed by factors such as burden of disease, greatest needs of the population, evidence syntheses showing that more research is required, and identification of novel or promising interventions. To facilitate the conduct of large, high-quality Australian MSK clinical trials that address the most pertinent questions with an emphasis on improving the translation of research findings into clinical practice, we have formed the Australian Musculoskeletal Clinical Trials Group (AUSMUSC). To determine the current scope of Australian MSK clinical trials, we identified the MSK trials currently being performed in Australia, including their source of funding and where they are being published.

Current scope of musculoskeletal trials in Australia

Definition of Australian musculoskeletal trials

MSK trials were defined as trials in humans which investigate interventions for the treatment or prevention of inflammatory and non-inflammatory arthritis, regional conditions (back, neck, shoulder/arm, elbow/forearm, hip/thigh, knee/leg, wrist/hand or ankle/foot), gout, osteoporosis or related conditions, autoimmune diseases including systemic lupus erythematosus and scleroderma, and fibromyalgia. We included all trials with an MSK focus (treatment and/or outcome) even if the participants had another primary condition. Pain trials were excluded if the site of pain was not specified and injury trials other than fractures were also excluded. Trials were considered “Australian” if Australian participants were recruited, and “Australian investigator-initiated” if there was an Australian primary contact.

NHMRC funding for musculoskeletal trials over the past 5 years

We searched the National Health and Medical Research Council (NHMRC) website to identify successful MSK trial grants (including project and program grants) within the past 5 years (those with funding commencing in 2009–2013).6 The number of successful MSK trial project grants and the amount of funding awarded was compared with the number of grants and amount of funding awarded for all NHMRC-funded clinical trials, and for all NHMRC project grants.

NHMRC project grants have provided funding of more than $17.6 million for 29 MSK trials over the past 5 years (range, 2–9 trials per year) (Box). This represents 0.8% of all project grants funded, 0.8% of the total funding allocated to project grants ($17.6 million out of > $2 billion) and 5.0% of the total amount of NHMRC funding allocated to clinical trials ($17.6 million out of $354 million).

Appendix 1 summarises details for the 29 MSK trials funded by NHMRC project grants. Over a third (11 trials), were for interventions for osteoarthritis (eight for the knee, two for the hip and one for the big toe). Interventions included drug treatments, physical therapies and exercise, footwear, acupuncture and surgery. There were three trials for low back pain and one trial for sciatica, which investigated treatment with either drugs or psychotherapy; and one trial for neck pain and two for whiplash, which investigated treatment with either exercise or dry needling.

The remaining trials varied widely by condition and intervention.

One program grant for MSK trials has been awarded over the past 5 years. It funded eight trials which investigated interventions related to physiotherapy for regional conditions (Appendix 1).

Australian musculoskeletal trials registered in the past 2 years

We searched the Australian New Zealand Clinical Trials Registry (ANZCTR) and World Health Organization Clinical Trials Registry Platform to identify all MSK trials (randomised, non-randomised and single-arm), registered within the past 2 years (2011–2012), that are currently recruiting, planning to recruit or had recruited participants in Australia. For the ANZCTR registry we used the advanced search facility and included both randomised and non-randomised allocation to intervention. We searched all trials categorised by the conditions: musculoskeletal, alternative and complementary medicine, anaesthesiology, inflammatory and immune system, injuries and accidents, metabolic and endocrine, other, physical medicine and rehabilitation, public health and surgery. We did not limit by sex, age group or recruitment status, and did not exclude healthy volunteers.

For the WHO Clinical Trials Registry, we also conducted an advanced search of both randomised and non-randomised trials, restricting our results to those that listed musculoskeletal, injury, inflammation, endocrine, rehabilitation, surgery, alternative medicine, immune diseases, or public health as the “condition”. Since the condition category is not restricted to a set number of conditions as it is in the ANZCTR registry, we performed this search using the key words arthritis, osteoporosis, scleroderma, vasculitis, gout, spondyloarthritis, lupus, back, neck, shoulder, arm, elbow, forearm, wrist, hand, hip, thigh, knee, leg, ankle and foot. Registered trials that listed NHMRC funding were crosschecked with the NHMRC search results.

We identified 191 MSK trials that were recruiting Australian participants registered in the past 2 years (132 registered in the ANZCTR and 59 in the WHO clinical trials registry) (Appendix 2). There were 83 trials (44%) with industry sponsorship and 63 (33%) that listed an overseas industry contact person. One hundred and twenty-eight trials (67%) appeared to be trials initiated within Australia (all but one were registered within the ANZCTR).

The median trial size for Australian investigator-initiated trials was generally smaller than that of all registered trials combined (median, 65 participants; range, 10–1650 participants versus median, 100 participants; range, 10–16 300 participants). Of the Australian investigator-initiated trials, two-thirds (n = 86, 67.2%) had a recruitment size of = 100 participants. Over a third (n = 45, 35%) were for osteoarthritis. Two-thirds of these (n = 30) related to various aspects of joint replacement or arthroscopy. Another 12 trials (9%) were for osteoporosis or related conditions, six trials were for rheumatoid arthritis and one trial was for gout. There were 53 trials (41%) for regional conditions, most commonly low back pain (n = 12, 9%), shoulder and arm pain (n = 10, 8%) and neck pain (n = 8, 6%).

Overall, the most common intervention studied was physical therapy and/or exercise (n = 55, 43%), while 33 (26%) were for drug therapies, 23 (18%) were related to surgery, 12 (9%) investigated a patient education intervention and four trials (3%) investigated a psychological intervention. There were no trials investigating interventions to improve uptake of research findings or guidelines into practice.

Australian musculoskeletal randomised controlled trials published in top international journals in the past 2 years

We chose journals based on their 2011 impact factor rankings according to Journal Citation Reports (Thomson Reuters) in each of the following subject categories: medicine, general and internal, rheumatology, orthopaedics, rehabilitation and sports sciences. As there was no specific category for osteoporosis we searched the subject category endocrinology and metabolism for journals that include osteoporosis within their scope, and we searched subject category orthopaedics to identify journals that included spine pain within their scope. We included journals where at least one MSK randomised controlled trial (RCT) had been published in 2011 or 2012. Several journals appeared in more than one category and for ease of description we included them in the heading that we thought best described their scope. We limited inclusion to the primary publication of RCTs.

We searched Ovid MEDLINE 2011 and 2012 using the search term “randomised controlled trial” and the journal name. Two authors independently screened the search results and retrieved the full text if necessary. We also searched all issues of journals online and for those with a search facility we searched papers using the term “trial”.

We identified 565 published papers reporting the primary results of MSK RCTs in the top 37 (ranked by impact factor) general medical and MSK-specific journals in the past 2 years (Appendix 3). Fifty-seven of these (10.1%) included Australian participants (Appendix 4), and 30 (5.3%) were initiated in Australia. Australian investigator-initiated trials were published across a range of journals, particularly in rheumatology, orthopaedics and rehabilitation.

Almost half (14) were for osteoarthritis and a further 14 were for regional conditions (Appendix 5). Nearly half (14) involved physical therapy interventions, while drug and surgery interventions accounted for 12. There were no published trials investigating interventions to improve uptake of research findings or guidelines into practice.

Where are the gaps?

Our data indicate that Australian MSK trialists are productive and internationally competitive. The NHMRC has funded an average of 5.8 new MSK trials per year through the project grant scheme over the past 5 years; 128 Australian-initiated trials were registered in the past 2 years; and about one in 20 MSK RCTs published in leading general medical and MSK-specific journals in the past 2 years was initiated in Australia.

A significant number of Australian-initiated trials were for osteoarthritis. While this is commensurate with its known burden on the population, and its status as an NHPA, there were proportionally fewer trials for osteoporosis and rheumatoid arthritis, both also designated NHPAs. Despite the ranking of back pain as the leading cause of disability worldwide and in Australia, there were also comparatively fewer trials for back pain, and a paucity of trials for other MSK conditions. Integrating other MSK conditions such as back pain into the NHPA framework could increase their profile and result in more systematic development and implementation of programs aimed at promoting best practice treatment of these conditions.8

NHMRC funding for MSK trials was found to be disproportionately low in relation to the size of the burden from MSK conditions in Australia and internationally. A 2000–2008 review of NHMRC funding found that some of Australia’s NHPAs are better funded than others.9 The NHMRC has estimated that more than $216 million has been invested in arthritis and osteoporosis research in the past decade.10 While the data may not be directly comparable, as estimated funding is based on identification of chief investigator-provided keywords and titles contained in the NHMRC research database, this appears to be less than the amount invested in other NHPAs such as diabetes (> $475 million) and cardiovascular disease ($795 million). In contrast to one NHMRC MSK program grant in the past 5 years, three have been awarded for diabetes and eight for cardiovascular clinical research.

We think it is unlikely that we missed any NHMRC-funded MSK trials, although we have no information about unsuccessful grant applications (as this information is not publicly available). However, it is possible that we underestimated the number of other NHMRC-funded trials, as before 2011 there was no specific category for clinical trials and identification was reliant on a key word and title search of the NHMRC database using the terms clinical trial, clinical study, clinical studies, randomised trial or controlled trial. It is also unlikely that we missed relevant registered Australian MSK trials. While most registered MSK trials are likely to denote themselves as MSK, we also searched other potentially relevant categories. It is also unlikely that we missed relevant Australian MSK trials published in the past 2 years. Two independent reviewers used two different but complementary strategies to identify potentially relevant papers. The scope of trials was also broadly similar across all three components of our scoping project, further supporting the validity of our findings.

There was a wide range of interventions under study, most commonly drug treatments or physical therapies. While the range of current Australian MSK trials likely reflects the interests and expertise of Australian MSK trialists, our review suggests that not all Australian MSK trials reflect priorities based on the greatest burden of disease, the most novel and/or promising interventions and the greatest needs of the population. Many trials may be too small to be of value; many appear to be driven (either directly or indirectly) by commercial imperatives rather than genuine clinical novelty or patient-centred research priorities, and most are unlikely to influence clinical practice. While a significant number included a placebo or usual care comparator, there were no placebo-controlled surgical trials and only one comparing surgery with conservative care. In addition, we identified only one multicentre trial (which involved two states).

Where to from here?

Identifying and addressing evidence–practice gaps has been identified as a major NHMRC priority,11 yet none of the Australian trials we identified was testing interventions to improve uptake of research findings or guidelines into practice. This is in keeping with a previous study that found scarce high-quality implementation trials addressing nine evidence–practice gaps relating to other conditions, and no indication that this had improved over time.12 The NHMRC has now established a Research Translation Faculty to address the challenge of research translation in Australia.13 As part of this process, steering groups across major health areas have been tasked with identifying major evidence–practice gaps. While the role of each steering group is to develop a single case for action that the NHMRC could address, this process may also serve to identify priorities for MSK trials based on population needs, to complement and enhance current investigator-initiated trials.

More investment to support the conduct of MSK trials in Australia is needed. This includes infrastructure funding in both the public and private sectors, more support for clinical researcher training and supervision and, importantly, greater buy-in from clinicians and patients. Many studies have identified suboptimal clinician buy-in for clinical research, particularly those directed towards closing evidence–practice gaps.12,14,15 The lack of clinician buy-in for clinical research directed specifically at improving care suggests the need for a global culture shift towards clinician (and patient) participation in research as a matter of course.

There is also an onus on MSK trialists to ensure that they ask the most important questions. Evidence suggests that this is not consistently the case.16 In discussing the mismatch between what clinical researchers do and what patients need in oncology, Liberati has suggested that inclusion of patients and patient advocacy groups, who spend much time in raising awareness and money to support research in the hope of improving care, should be at the centre of redefining the research agenda.17 The Arthritis Research UK clinical studies initiative has already taken a strategic approach to prioritising clinical study funding for MSK disorders.18 Consultations with consumer representatives and all relevant health care professionals and scientists have led to nationally agreed priorities for MSK clinical trials. It is time to replicate this approach in Australia to ensure that only worthwhile MSK trials are performed and funded.

Funding awarded for National Health and Medical Research Council (NHMRC) musculoskeletal (MSK) trial project grants and clinical trials, and total funding for NHMRC project grants and clinical trials over the past 5 years

Year trial commenced	NHMRC* project grants awarded	No. of project grants for MSK trials (% of all project grants)	Total NHMRC funding for project grants	Total NHMRC funding for clinical trials	NHMRC funding for project grants for MSK trials (% of all clinical trials)

2009	688	4 (0.6%)	$357 248 846	$44 705 943	$2 171 800 (4.9%)
2010	683	6 (0.9%)	$390 715 106	$55 812 016	$4 526 514 (8.1%)
2011	758	2 (0.3%)	$415 484 352	$64 833 882	$906 723 (1.4%)
2012	771	8 (1.0%)	$454 826 481	$83 365 267	$4 140 806 (5.0%)
2013	731	9† (1.2%)	$457 858 034	$105 677 755	$5 866 460 (5.6%)
Total	3631	29 (0.8%)	$2 076 132 819	$354 394 863	$17 612 303 (5.0%)

* The NHMRC categorises project grants as clinical trials based on information provided by chief investigators in the grant application. This relies on key word searches for the terms clinical trial, clinical study, clinical studies, randomised trial or controlled trial. The use of grant synopses and an application question asking if the grant is a clinical trial has enabled more grants to be identified as clinical trials in the past 2 years.7 It is therefore possible that total funding for NHMRC funded clinical trials may be underestimated for grants awarded in 2009–2011. † One project grant in 2013 was for a clinical trial in addition to a large cross-sectional study of young women.

Arthroscopy to treat osteoarthritis of the knee?

To the Editor: In their editorial, Buchbinder and Harris conclude that “The use of arthroscopy for knee osteoarthritis has been allowed to continue, exposing patients to an intervention that is at best ineffective, and at worst, harmful”.1

Each year, HCF funds more than 5000 knee arthroscopies in private hospitals alone, and the primary diagnosis is osteoarthritis (coded
as gonarthrosis [arthrosis of the knee]) in more than 1000 of these procedures.

As such, HCF will endeavour to contribute to the debate by surveying members who have a primary diagnosis of gonarthrosis to collect data on self-assessed benefits of knee arthroscopies. It would be fair to say that the patient’s view of the benefits of the procedure is a leading indicator and should form an integral part of assessing the success of knee arthroscopies for osteoarthritis.

Arthroscopy to treat osteoarthritis of the knee?

In reply: We thank Adams for providing private health insurance data that confirm the continued use
of arthroscopic surgery for patients with osteoarthritis.

We agree that the patient’s view of the benefits of the procedure is fundamental to assessing treatment success. We do not doubt that many patients are happy with the results of arthroscopic knee surgery, but this does not necessarily imply that the surgery has had any specific effect, as satisfaction rates are high after many ineffective placebo treatments. Indeed, high-quality randomised controlled trials have consistently failed to demonstrate clinically relevant self-assessed benefits of arthroscopy compared with sham surgery1 or non-surgical comparators.2–4 Potential risks of arthroscopy are also an important consideration. These include thrombosis, infection, complications of anaesthesia, and increased progression of osteoarthritis and likelihood of joint replacement.5

Satisfaction surveys do not justify the ongoing use of ineffective interventions. While some may find it acceptable to fund care based on perceived effectiveness, in this instance to do so might be doing more harm than good.