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Rheumatoid arthritis
Original research
Biomechanical determinants of rheumatoid arthritis severity and excess cardiovascular disease: common origins of two complex diseases
  1. Stephen Philip Oakley1,2,
  2. Samantha Stott3,4,
  3. Kerri Gill1 and
  4. Lyanne Weston5
  1. 1Rheumatology, Hunter New England Local Health District, New Lambton, New South Wales, Australia
  2. 2School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
  3. 3Radiology, Hunter New England Local Health District, New Lambton, New South Wales, Australia
  4. 4School of Medicine and Public Health, The University of Newcastle, Newcastle, New South Wales, Australia
  5. 5Transplantation & Immunogenetics Service, Australian Red Cross Blood Service New South Wales and Australian Capital Territory, Alexandria, New South Wales, Australia
  1. Correspondence to Dr Stephen Philip Oakley; stephen.oakley{at}health.nsw.gov.au

Abstract

Objectives The determinants of rheumatoid arthritis (RA) severity and excess cardiovascular disease (CVD) are incompletely understood. Biomechanical factors are known to influence RA severity. Articular stiffness correlates with arterial and skin stiffness. This study explored the hypothesis that constitutional stiffness is a common determinant of RA severity and excess CVD.

Methods Fifty-eight patients with anti-CCP antibody (ACPA) positive RA and 57 controls were enrolled noting age, sex, body mass index, alcohol and tobacco exposure, Shared Epitope status and in RA disease duration, disease activity, ACPA titre and radiographic damage. Severe RA was defined as radiographic progression >1.3 mSharp points/year or requiring biological disease-modifying antirheumatic drugs (bDMARDs). Articular stiffness (Beighton Score and right 5th metacarpophalangeal (MCP) joint stress–strain responses), carotid-femoral pulse wave velocity and skin extensibility (percent increase distance two dots with manual traction dorsum right hand) were assessed.

Results Right 5th MCP stiffness correlated with Beighton Score and with arterial and skin stiffness. High radiographic rate was associated with greater MCP articular (t test p 0.014), arterial (p 0.044) and, in RA <5 years duration, greater skin stiffness (p 0.002) with similar trends in subjects requiring bDMARDs. In RA, arterial stiffness correlated with age (ß p<0.005), articular (ß p<0.001) and skin stiffness (ß p 0.037) and inversely with alcohol consumption (p 0.035).

Conclusions Articular, arterial and skin stiffness correlated with each other and with RA severity. As skin is not affected by RA, this association suggests that constitutional stiffness might be a common determinant of RA and CVD. Prospective studies of at-risk preclinical and early RA are required to determine if this relationship is causal.

Trials registration number ACTRN12617000170325.

  • Arthritis
  • Arthritis, Rheumatoid
  • Cardiovascular Diseases

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2024-004524

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The determinants of rheumatoid arthritis (RA) severity and associated excess cardiovascular disease (CVD) are incompletely understood.

    • Articular biomechanical factors are known to influence RA severity.

    • There is evidence for correlation of articular, arterial and skin stiffness reflecting what has been described as constitutional stiffness.

    • Constitutional stiffness is a plausible common determinant of RA severity and CVD.

    WHAT THIS STUDY ADDS

    • This study found evidence to support the construct of constitutional stiffness in RA and control subjects.

    • This study found that patients with higher rates of radiographic progression or requiring biological disease-modifying antirheumatic drug therapy to control RA had greater articular, arterial and skin stiffness.

    • As the skin is not affected by RA, this suggests that constitutional stiffness is a common determinant of RA severity and CVD.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Assessments of articular, arterial and skin stiffness might serve as useful predictors of RA severity and CVD to predict difficult-to-treat RA and better inform early therapeutic decisions.

    • Exploration of the determinants of constitutional stiffness may lead to new approaches to RA therapy.

    Introduction

    Anticyclic citrullinated polypeptide antibody (ACPA) positive rheumatoid arthritis (RA) has origins in the respiratory tract arising from interaction between genetic and environmental factors inflammatory arthritis1 that is associated with 50%–100% excess cardiovascular disease (CVD).2 However, the known genetic and acquired risk factors fall short of accounting for the risk of developing RA.3 4 Progression from preclinical to clinical RA5 and the subsequent severity cannot be predicted accurately6 and the mechanisms of excess CVD are also incompletely understood. While greater inflammatory burden is associated with greater CVD,7 the advent biological disease-modifying antirheumatic drugs (bDMARDs) have not seen the expected reduction in CV events.8–10 While registry data suggest that TNF inhibitors halve CV events11 pooled randomised controlled trial (RCT) data suggest a modest 15% reduction.11 RCTs in non-RA subjects have shown 10%–15% risk reductions with canakinumab12 and colchicine13 that cannot confidently be extrapolated to RA.

    Impossibly large RCTs would be necessary to determine whether treatment reduces CV events in RA. There has thus been great interest in CV biomarkers such as arterial stiffness. Carotid-Femoral Pulse Wave Velocity (CF-PWV) is strongly predictive of CV events in non-RA subjects14 and is elevated in RA.15–18 However, placebo-controlled RCTs using CF-PWV have been inconclusive, finding better outcomes in placebo over tociluzumab19 or rapid changes in placebo and adalimumab arms due to changes in blood pressure (BP) rather than arterial structure.20 One RCT evaluating MRI assessments of aortic stiffness found improvements in both placebo and active treatment arms.21 Based on the performance metrics and life trajectories22 of CF-PWV, much larger RCTs would be required to detect treatment effects due to structural changes in the arterial wall.23 The emerging complexity of excess CVD in RA presents additional challenges. Half of 10-year CV risk can be attributed to conventional risk factors. Inflammation and autoimmunity account for another 30% leaving 20% unexplained.24 Perhaps most intriguing is evidence that CV risk is elevated prior to onset of RA.25–27

    One unexplored area in this field is the role of biomechanical factors in RA pathogenesis. Historically, bed rest and articular splints formed the foundation of management of RA flares. Clinicians see RA remit in limbs rendered paretic following stroke. Erosions develop at sites of greater biomechanical stress in the hands,28 are more severe in the dominant hand29 30 and occur earlier in the feet where greater loads are borne.31 These observations indicate that biomechanical factors influence disease activity locally. It is therefore plausible that connective tissue responses to biomechanical forces (stiffness) might also influence arthritis severity. We have observed that patients with RA with concurrent hypermobile Ehlers-Danlos (hEDS)32 require less intense treatment to achieve remission and incur less articular damage. This suggests that articular structures with lower stiffness may better accommodate biomechanical loads reducing articular inflammation. So, while autoimmunity lays the foundation for RA, articular stiffness may influence progression to and severity of clinical RA.

    Articular stiffness is known to correlate with arterial and skin stiffness33–35 reflecting what has been termed constitutional stiffness (CS).35 CS may thus represent a common cause of RA and CVD explaining why CV risk is elevated prior to the onset of RA, why more severe RA is associated with a greater risk of CVD and why the incidence of CVD in RA has not fallen as dramatically as expected since the advent of bDMARDs. While articular and arterial stiffness may be affected by inflammatory processes in RA, the skin is not. This presents an opportunity to explore the possible role of CS in RA pathogenesis.

    Aims

    This cross-sectional study of ACPA-positive RA and control subjects evaluated:

    1. The validity of the construct of CS in RA and controls.

    2. The relative contribution of CS to RA severity.

    3. The relative contribution of CS to arterial stiffness in RA and controls.

    Methods

    This study (ACTRN12617000170325) was conducted with the approval of the local ethics committee. Patients with ACPA-positive RA meeting the 2010 American College of Rheumatology-European Alliance of Associations for Rheumatology36 were recruited from a prior clinical trial23 (ACTRN12611000972921) and from clinical practice. Non-RA control subjects were recruited from the Hunter Medical Research Institute healthy volunteers (HV) register participating in another study evaluating the effect of Shared Epitope (SE) on vascular biomarkers (ACTRN12615000557538) along with hypermobile EDS controls (hEDS) recruited from clinical practice. Subjects with chronic inflammatory disease, hand osteoarthritis and neuromuscular diseases were excluded.

    Assessments

    Cardiovascular risk factors and RA severity

    Age, sex, height, weight, body mass index (BMI), current smoking status and cumulative exposure in pack years, present weekly alcohol consumption and key comorbidities were noted in all subjects and peripheral blood DNA samples analysed for the presence of SE alleles37 (Australian Red Cross Blood Service LABType SSO, Luminex system and One Lamda HLA Fusion Software). RA disease duration, rheumatoid factor and second-generation assay ACPA titre at commercial laboratories categorised as low (<100 U/L), moderate (101–200 U/L) or high (> 200 U/L). DAS28 scores38 were calculated and treatment noted. Articular damage was quantified from hand and foot radiographs by a radiologist using the modified Sharp van der Heidje method39 blind to all other assessments. RA severity was summarised as the Rate of Radiographic Damage (RRD) calculated as mSharp score divided by disease duration in years and treatment intensity (bDMARD or no DMARD).

    Biomechanical assessments

    Overall articular stiffness was assessed using Beighton scores (BS)40 and Beighton Questionnaire scores (BSQ).41 Lower scores represent greater articular stiffness. Subjects then underwent biomechanical assessment of the right fifth finger metacarpophalangeal joint (R5-MCPJ) a joint rarely affected by OA and largely spared in RA. Measurements were undertaken using a Meccano device (figure 1) to measure the strain as angular displacement (AD) degrees extension in response to a range of torque moment stresses. Lower AD indicates greater articular stiffness. Skin stiffness was measured as Clinical Skin Extensibility Score (CSES) calculated as the percentage increase in distance between two dots on the dorsal right hand drawn apart by manually applied tension (SKSTR-PC) divided by skin thickness measured using Harpenden callipers.33 Lower values indicate greater skin stiffness. A second observer (SO) measured peripheral and central BPs and arterial stiffness (CF-PWV metre/second) with the SphygmoCOR Excel system.42 Large reductions in CF-PWV occur between two baseline assessments simply due to reduction in BP.23 CF-PWV was measured twice 1–7 days apart and the second set used in the analysis. CF-PWV was measured twice on the second occasion to calculate intraobserver reproducibility. COVID-19 lockdowns disrupted study recruitment for 3 years. The final 25 subjects had all assessments conducted by a single investigator (SO). Sufficient results were available for interobserver reproducibility for articular and skin assessments.

    Figure 1
    Figure 1

    Schematic diagram and photograph of the Meccano device measuring stress (dorsal angular displacement) in response to strain (torque moment 0.26 Nm) produced by three 200 g weights in a 155 g cradle at the right fifth metacarpophalangeal joint (MCPJ) of a volunteer.

    Analytical methods

    With no prior data for sample size calculations, a recruitment target was set at 100 RA cases, 50 HVs and 25 hEDS. HV and hEDS were combined to form a non-RA Control group. Reproducibility was summarised by intraclass correlation coefficient (ICC).

    Constitutional stiffness

    R5-MCPJ stiffness was compared with BS and BSQ. Stress–strain response curves were generated for subjects with BS of 0, 1–3 and >3 and optimally discriminant stress ascertained by Kruskal-Wallis and analysis of variance. R5-MCPJ AD and BS were then compared with arterial and skin stiffness to determine and evaluate construct of CS. Analyses of skin stiffness were additionally undertaken separately in subjects with RA disease duration of 5 years or less to minimise the potential effects of corticosteroid skin toxicity.

    Correlates of RA severity and arterial stiffness

    R5-MCPJ stress–strain responses were evaluated to select optimally discriminant stress loads by rank sum and t tests. Multivariate analyses then explored the relative contribution of articular stiffness (R5-MCP AD), age, tobacco exposure, alcohol consumption and SE status to RA severity. The analysis was repeated using CF-PWV and then SKSTR-PC in the place of R5-MCPJ. Similar modelling was then undertaken to evaluate determinants of arterial stiffness (CF-PWV) in RA and non-RA controls. Finally, multivariate modelling explored the contribution of articular, arterial and skin stiffness to RA severity and arterial stiffness accounting for known determinants of RA severity and CVD. CF-PWV was compared between RA and controls subjects accounting for articular, arterial and skin stiffness (in separate multivariate models along and other possible influences by multivariate analysis). Analyses of CF-PWV were adjusted for central mean arterial BP. To minimise confounding effects of corticosteroids on the skin, subjects with RA >5 years duration were not included in analyses of skin stiffness.

    Results

    Fifty-eight subjects with ACPA-positive RA and mean disease duration of 7.2 years (range 0.1–40) were recruited (table 1). Eighty-one percent had ACPA >50 IU/L and 79% were in remission (DAS28-CRP <2.6). Nineteen subjects (33%) were receiving bDMARD therapy. Radiographic mSharp scores were skewed highly to lower values (mean 15, median 3, range 0–97) as were estimates of RRD (mean 18, median 1.3, range 0–672). The right fifth MCPJ was spared from radiographic damage where only two subjects scored a single point for joint space narrowing. Fifty-seven controls were recruited (47 HV and 10 hEDS). The hEDS group were all female, 20 years younger than HVs and had lower stiffness for all biomechanical assessments. While CSES trended to significance, raw SKST-PC measurements were significantly lower in AH subjects and were therefore used in subsequent analysis. Overall, the combined control group was comparable to the RA group in terms of age, sex, height, systolic BP and concurrent medical conditions. However, controls had lower BMI, had lower tobacco exposure, consumed more alcohol and had lower SE expression.

    View this table:
    Table 1

    Characteristics of rheumatoid arthritis (case) and control groups

    Overall, the control and RA groups had comparable R5-MCPJ assessments and skin stiffness. However, controls had slightly greater overall articular stiffness (BS 1.9 vs 0.9) and lower arterial stiffness (CF-PWV 9.1 vs 10.1 m/s). Intraobserver reproducibility was excellent (Intraclass Correlation Coefficient ICC 0.94) for R5-MCPJ AD0.33 and for CF-PWV (ICC 0.99), moderate for BS (kappa 0.67) and low for skin stretch percent increase (SK-STR-PC, ICC 0.27). Interobserver reproducibility was similar for AD0.33 (ICC 0.97) and SK-STR (ICC 0.23) with no systematic differences between observers.

    Constitutional stiffness

    Figure 2a presents stress–strain curves illustrating that R5-MCPJ AD was significantly greater (lower stiffness) in subjects with greater BS (lower overall articular stiffness) at all stress loads for controls and for the upper stress loads in RA. BS correlated with R5-MCPJ AD0.33 more strongly in controls (Spearman rho 0.53) than in RA (rho 0.30). However, this difference was less pronounced when AD0.33 was compared with historical hypermobility (BSQ) in controls (rho 0.56) and RA (rho 0.41).

    Figure 2
    Figure 2

    Constitutional stiffness. Mean strain responses (degrees angular displacement (AD) y-axis) right fifth finger metacarpophalangeal joint (R5-MCPJ) in response to a range of strains (torque moment x-axis) are shown in comparison to overall articular stiffness (a), arterial stiffness (b) and skin stiffness (c and d) in rheumatoid arthritis (RA) and controls. Lower AD indicates greater articular stiffness. Scatter plots with linear regression lines compare arterial stiffness with articular stiffness (e) and with skin stiffness (f) in RA and control. Articular stiffness is expressed as 90 minus AD in response to 0.33 Nm and skin stiffness as 40 minus the percent increase skin stretch so that greater values indicate greater stiffness. ANOVA, analysis of variance; CF-PWV, carotid-femoral pulse wave velocity.

    R5-MCPJ AD was significantly greater (lower stiffness) in RA subjects with lower (arterial stiffness (CF-PWV<9.3 m/s) at all stress loads while similar non-significant trends were seen in controls (figure 2b). Linear regression compared CF-PWV to R5-MCPJ stiffness expressed as 90 minus AD0.33 so that greater values indicate greater stiffness (figure 2e). There was significant correlation between arterial and articular stiffness in RA (β 0.06, p 0.002) with similar non-significant trends in controls (β 0.03, p 0.115). Arterial stiffness was significantly lower in hEDS controls compared with HVs (7.6 vs 9.5 m/s, p 0.017). Arterial stiffness was significantly lower in controls with BS greater than 3 (CF-PWV 7.1 m/s) compared with BS 1–3 (CF-PWV 9.8 m/s, p 0.004) and BS 0 (CF-PWV 9.4 m/s, p 0.013) while this trend was not significant in RA.

    There were non-significant trends to greater R5-MCP AD (lower stiffness) in subjects with lower skin stiffness (skin stretch >9.7%) in both groups (figure 2c). When subjects with RA of greater than 5 years duration were excluded, this effect became significant at the lower stress loads (figure 2d).

    High arterial stiffness (CF-PWV >9.3 m/s) was associated with high skin stiffness (SKST-PC <9.7%) in controls (OR 1.92, p 0.242) and RA (OR 2.21, p 0.157). However, the association was much stronger in RA less than 5 years duration where 58% (11/9) of subjects with high arterial stiffness had high skin stiffness while none (0/6) with low arterial stiffness (<9.3 m/s) had high skin stiffness. Linear regression compared CF-PWV with skin stiffness expressed as 40 minus SKST-PC so that greater values represent greater stiffness (figure 2f). There was positive correlation approaching significance in controls (β 0.10, p 0.081) and in RA less than 5 years duration (β 0.18, p 0.057) and the regression plots were similar in appearance to the statistically significant plots comparing arterial and articular stiffness (figure 2e).

    Correlates of RA severity

    RRD was dichotomised by median divide to high (>1.3 mSharp/year) and low (<1.3 mSharp/year). Stress–strain curves show low MCPJ stiffness in subjects with low RRD subjects statistically significant at lower stress loads (figure 3a). Similar non-significant trends to lower articular stiffness were seen in RA not requiring bDMARD (figure 3b). Sixty percent of RA subjects with high overall articular stiffness (BS 0) had high RRD compared with 33% of those with moderate (BS 1–3) and none with low (BS>3) articular stiffness (figure 3c). Subjects with high RRD had greater articular stiffness (R5-MCPJ AD0.12 13 versus 21 degrees, p 0.0081, figure 3d), greater arterial stiffness (10.9 vs 9.3 m/s, p 0.007, figure 3e) and greater skin stiffness in RA less than 5 years duration (9% vs 13% skin stretch, p 0.003, figure 3f). Multivariate analyses (table 2) confirmed that articular, arterial and skin stiffness (in RA<5 years) all correlated with RRD while age, tobacco exposure, alcohol consumption, SE status did not. Models not presented found no effect from BMI or ACPA titre.

    Figure 3
    Figure 3

    Correlates of rheumatoid arthritis (RA) severity. The top two panels show right fifth metacarpophalangeal joint (MCPJ) mean strain (angular displacement (AD) y-axis) in response to a range of stress torque moments (x-axis). Lower AD indicates greater articular stiffness. Subjects with high rate of radiographic disease (RRD) had lower AD while greater stiffness was seen in subjects receiving biological disease-modifying antirheumatic drug (bDMARD) therapy (b). Sixty percent of subjects with high overall articular stiffness (Beighton score 0) had high RRD compared with 33% with scores of 1–3 and none with scores over 3 (c). Right fifth MCPJ (d), arterial (e) and skin (f) stiffness were all significantly greater in subjects with high RRD. CF-PWV, carotid-femoral pulse wave velocity; RRD, rate of radiographic damage.

    View this table:
    Table 2

    Multiple linear regression models for correlates of rheumatoid arthritis severity and arterial stiffness

    Correlates of arterial stiffness

    Arterial stiffness correlated with articular stiffness and skin stiffness in RA and control (discussed above). Multivariate analysis (table 2) found that CF-PWV correlated most strongly with age in both groups and with mean arterial pressure in the control group. R5-MCPJ stiffness correlated with arterial stiffness in RA subjects. Ten degrees lower AD0.33 (greater stiffness) was associated with 0.8 m/s greater CF-PWV. Alcohol consumption correlated with lower CF-PWV in RA so that CF-PWV was 0.1 m/s lower for each standard (10 g) alcoholic drink consumed each week. No effects were found for tobacco exposure, SE status, ACPA titre and BMI. Similarly, a 5-point increase in skin stiffness (40 minus percent stretch) was associated with 1.10 m/s greater CF-PWV. RA subjects had 0.75 m/s greater CF-PWV than controls (p 0.025) after accounting for age, alcohol consumption, R5-MCPJ stiffness and mean arterial pressure.

    Discussion

    This study explored the potential contribution of connective tissue biomechanical properties to RA pathogenesis. The results support the construct of CS and found that it was the strongest correlate of RA severity and arterial stiffness. After accounting for CS and age, RA subjects had CF-PWV 0.75 m/s greater than controls.

    Right fifth MCPJ assessments were found to be representative of total body articular stiffness. The stronger correlation with historical hypermobility (BSQ) in RA suggests that these assessments were not confounded by osteoarthritis or RA. The study then found correlation between articular, arterial and skin stiffness supporting existing evidence for the previously described construct of CS.33–35

    Greater articular, arterial and most significantly skin stiffness were associated with more severe RA. As the skin is not affected by RA, this suggests that greater CS may be causally related to RA severity while articular hypermobility is protective. By contrast, other known risks for more severe RA did not correlate with our measures of RA severity suggesting that these effects may not be as strong.

    Articular and skin stiffness were the strong correlates of arterial stiffness after adjusting for age, the strongest known correlate of CF-PWV.22 It is known that 1 m/s greater CF-PWV is associated with 14% increase risk of CV events.14 By extension, our results suggest that 10° degrees lower R5 MCPJ AD0.33 is associated with 16% greater CV risk, a 5-point increase in skin stiffness with 22% greater CV risk14 and each alcoholic beverage per week with 1.5% lower CV risk. The 0.75 m/s greater PWV in RA versus control remaining after accounting for age, MAP and articular stiffness translates to a 12% greater CV risk14 possibly due to cumulative inflammatory burden not evaluated in this study.

    Limitations

    This cross-sectional study could not evaluate the effects of cumulative inflammatory burden and potential confounding from corticosteroids most notably the skin. The intensity of treatment was determined by clinical decisions possibly influenced by factors other than disease activity. Prospective studies in preclinical and early RA are required to determine whether CS is a causal determinant of progression to and severity of RA.

    Unifying hypothesis

    These observations may be brought together into a unifying hypothesis that while autoimmunity and inflammation lay the foundation for RA these processes interact with connective biomechanical properties to determine the risk and severity of RA and the associated excess CVD. Figure 4 illustrates in greater detail how inherited and acquired determinants of CS might interact with a primed immune system leading to inflammatory arthritis and CV events. While this study provides modest and preliminary support for this hypothesis, a substantial, although fragmented, body of supportive evidence already exists.

    Figure 4
    Figure 4

    Common origins of two complex diseases. Greater constitutional stiffness results in greater microstructural damage in articular and arterial connective tissues providing access to primed immune systems leading to more severe inflammatory arthritis and cardiovascular disease. Constitutional stiffness is determined by range of inherited and acquired factors already known to predict or influence risk and severity of both rheumatoid arthritis and cardiovascular disease. (IL interleukin, MMP matrix metalloprotein, TNF tumour necrosis factor, JAK janus activated kinase, STAT signal transducer and activator of transcription)

    Genetic/inherited factors

    The contribution of genes to articular stiffness is clearly seen in hEDS which exhibits strong polygenic inheritance.32 The hEDS phenotype represents one end of a continuum of CS that may prevent and mitigate the severity of RA while greater articular stiffness does the opposite. Arterial stiffness is strongly predictive of CV events and similarly exhibits strong polygenic inheritance.43 While the heritability of RA is estimated to be around 60%, only half of this is explained by immunological gene loci.4 It is plausible that shared polygenic molecular determinants of arterial and articular stiffness influence the risk and severity of CVD and RA.

    Environmental/acquired factors

    Age and menopause are significant in the epidemiology of both CVD and RA. The prevalence of both diseases increases through life. Premenopausal women are protected against CVD44; however, the prevalence rises to approximate that of men after menopause.45 Menopausal hormone replacement therapy (HRT) lowers CV risk only when commenced early after menopause.46 It is also notable that RA pursues a more aggressive course after menopause,47 oral contraceptives protect against RA48 and RA typically remits during the high oestrogen state of pregnancy.48

    The influence of age and oestrogen on CS may go some way to explaining these trends. Articular, arterial and skin stiffness all increase through life. Perhaps the best insights can be found from comparing lifetime trends in RA and arterial stiffness. Figure 5 shows previously published data49 on the effects of age, sex and menopause on RA incidence permitting calculation of a crude estimate of RA prevalence. In men, RA prevalence increases exponentially through life until the rate slows after a peak in the seventh decade due to immune senescence The trend is similar for women; however, peak incidence occurs 15 years earlier at menopause. Extrapolation of the RA prevalence curves from the point of peak incidence predicts trajectories that would occur in the absence of immune senescence. These exponential curves are remarkably similar to life trends for CF-PWV in the general population.50 The exponential increase in CF-PWV through life has been explained in terms of a positive feedback loop of material fatigue. Each cardiac cycle imposes tensile stress on the vascular wall incurring microtrauma making the arterial wall less elastic and more easily damaged.51 Similar processes occurring in articular structures may explain the similar trajectories in the prevalence of RA through life.

    Figure 5
    Figure 5

    The effects of age, sex and menopause on rheumatoid arthritis (RA) prevalence and arterial stiffness (carotid-femoral pulse wave velocity (CF-PWV)). In men, RA prevalence (black lines) calculated from incidence data* (bars) increases exponentially through life until the rate slows in the seventh decade with immune senescence. Extrapolation of the curve from the age of peak incidence predicts trajectories that would occur in the absence of immune senescence (broken black lines) that mirror the life trajectories for CF-PWV** (blue lines). The trend is similar for women; however, peak incidence occurs 15 years earlier at menopause. *Reproduced from Goemaere et al,49 with permission from The Journal of Rheumatology Publishing Co. Ltd. **Reproduced from McEniery et al,50 2005 with permission from Elsevier.

    Hormonal effects are then superimposed on these life trends. Skin stiffness has been shown to decrease during the high oestrogen state of pregnancy.52 Similar changes in articular structures might reduce RA disease activity during pregnancy. By contrast, menopause represents an inflection point where RA incidence peaks, the prevalence of CVD and RA increase more rapidly and RA severity is greater.47 Studies of annual CF-PWV through perimenopause have found a striking increase of 1 m/s over a 12-month period that is five times the background rate53 of increase and would be associated with 14% increase in CV events.14 Oestrogen replacement therapy prevents this increase.54 Our study suggests that this might be associated with considerable increases in articular stiffness coinciding with peak incidence of RA in women at menopause.49 This apparent window of opportunity for CV protection46 suggests that HRT prevents but does not reverse arterial stiffening. It is plausible that menopause and hormonal therapy influence the development and severity of RA through similar biomechanical mechanisms.

    Alcohol consumption protects against the development of RA55 56 and slows radiographic progression.57 While the mechanisms are unclear, widespread articular hypermobility, most pronounced in the hands, has been reported in women with chronic alcoholism.58 Similarly, there is evidence that low-to-moderate alcohol consumption lowers CV risk59 and has been associated with lower arterial stiffness.60 61 It thus appears plausible that the protective effects of alcohol against the development of RA and CVD may be mediated by direct effects on determinants of stiffness common to both tissue compartments.

    It is well established that smoking plays a causal role in the pathogenesis of RA via mucosal immunity.62 Smoking is best known for its association with arterial stiffness63 and greater skin stiffness.64,65 It is plausible that smoking might also contribute to RA pathogenesis through effects on articular stiffness.

    Obesity is associated with greater risk of RA, progression from preclinical to clinical RA66 and with more severe RA.67 It is also associated diabetes mellitus which is in turn associated with greater tendon, arterial and skin stiffness through non-inflammatory mechanisms such as collagen deposition, changes in the extracellular matrix and advanced glycation end products.68 69

    Other forms of arthritis may similarly be influenced by CS. Subluxation of the first carpometacarpal joint precedes the development of osteoarthritis70 likely due to greater articular instability in this multiaxial joint. However, the opposite is seen in uniaxial interphalangeal joints71 where hypermobililty protects against osteoarthritis. Conversely, inflammatory hand osteoarthritis typically develops at menopause72 when there are significant increases in arterial53 and likely articular stiffness. It is notable too that non-inflammatory gluteus medius tendinopathy occurs almost exclusively in postmenopausal women.73 Biomechanical factors are important in the pathogenesis of psoriatic arthritis74 and milder disease has been reported in patients with ankylosing spondylitis with concurrent hypermobility.75

    While advances in immune therapies have transformed treatment of RA, many challenges remain. ACPA-positive RA has well-defined immunological origins and inflammatory processes that interact with structural articular tissues. Biomechanically informed exploration of this interaction may improve prediction of the risk of RA and CVD, early identification of easily controlled RA and difficult-to-treat RA.76 and open new avenues for scientific inquiry.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Hunter New England Local Health District Research Governance Ethics Committee (HREC Reference Number: 15/09/16/3.03). Participants gave informed consent to participate in the study before taking part.

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    Footnotes

    • Contributors SPO: protocol design, funding application, ethics committee submissions, research governance oversight, manuscript writing, subject recruitment, and study assessments and guarantor for the authenticity of the study. SS: reading and grading of X-rays. KG: study coordination, biomechanical assessments of skin and articular stiffness. LW: laboratory HLA typing for Shared Epitope.

    • Funding This study was indirectly supported by two Abbvie Investigator-Initiated Grants from which participants in the present study were recruited. (1) Title: The Hunter HEART Trial (Humira and Endothelial function in Early RA). Abbvie Investigator-Initiated Grant number: IMM-11-0067; ANZ Clinical Trial Registry number: ACTRN12611000972921. (2) Title: The Hunter HEART-2 Trial (Humira and Endothelial Function in Early RA Trial - 2). Abbvie Investigator-Initiated Grant number: iis-csa-oakley-10552-abbvie; ANZ Clinical Trial Registry number: ACTRN12615000557538.

    • Competing interests SPO has received speaker fees and honoraria (Abbvie, Pfizer, UCB, Janssen, Lilley, Novartis, Roche, Bristol Meyers Squibb) and an educational travel grant (Pfizer).

    • Provenance and peer review Not commissioned; externally peer reviewed.