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The association between comorbidities and
disease activity in spondyloarthritis eA
narrative review
Philipp Bosch
a
,
*
, Sizheng Steven Zhao
b
, Elena Nikiphorou
c
,
d
a
Clinical Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria
b
Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Science, School of
Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester,
United Kingdom
c
Center for Rheumatic Diseases, King's College London, London, United Kingdom
d
Rheumatology Department, King's College Hospital, London, United Kingdom
article info
Article history:
Received 23 June 2023
Received in revised form 19 July 2023
Accepted 19 July 2023
Keywords:
Spondyloarthritis
Axial Spondyloarthritis
Psoriatic arthritis
Comorbidities
Disease activity
abstract
Comorbidities, including cardiovascular disease, osteoporosis, and
depression, are more prevalent in patients with spondyloarthritis
(SpA) than in the general population. Clinical and laboratory
markers of disease activity are associated with numerous of these
comorbidities, and studies suggest that the treatment of SpA can
have a positive impact on comorbidities; conversely, managing
comorbidities can improve disease activity. Therefore, the
screening of comorbidities is considered a core component of a
rheumatology consultation, and treatment should be performed in
liaison with other health professionals (e.g. general physicians).
Validated tools and questionnaires can be used for not only the
detection but also the monitoring of potential comorbidities. Un-
derstanding whether a comorbidity is a separate disease entity,
linked to SpA or its treatment, or an extra-musculoskeletal mani-
festation of the disease is important to identify the most appro-
priate treatment options.
©2023 The Authors. Published by Elsevier Ltd. This is an open
access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
*Corresponding author.
E-mail address: philipp.bosch@medunigraz.at (P. Bosch).
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Rheumatology
journal homepage: www.elsevierhealth.com/berh
https://doi.org/10.1016/j.berh.2023.101857
1521-6942/©2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Please cite this article as: P. Bosch, S.S. Zhao and E. Nikiphorou, The association between comorbidities
and disease activity in spondyloarthritis eA narrative review, Best Practice &Research Clinical Rheu-
matology, https://doi.org/10.1016/j.berh.2023.101857
Introduction
Spondyloarthritis (SpA) is a heterogenous group of diseases comprising axial SpA (axSpA), psoriatic
arthritis (PsA), reactive arthritis, and arthritis associated with inflammatory bowel disease [1]. Like
other inflammatory rheumatic musculoskeletal diseases (RMDs), SpA is associated with comorbidities
that often have a negative impact on relevant patient outcomes and are closely linked to disease ac-
tivity [2,3]. To address this issue, the European Alliance of Associations for Rheumatology (EULAR) has
published points to consider for reporting, screening for, and preventing comorbidities in patients with
inflammatory RMDs [4]. Although there is a considerable amount of literature on the topic of
comorbidities in SpA, the relationship of comorbidities with disease activity and the implications for
treatment decisions are frequently not apparent. Therefore, the aim of this review is to give an over-
view of the most common comorbidities in SpA (with a focus on axSpA and PsA) and their relationship
with disease activity and treatment options.
What are comorbidities in SpA?
The term “comorbidity”is not straight forward and has been defined as “the existence or occurrence
of any distinct additional entity during the clinical course of a patient who has the index disease under
study”[5]. Although this definition implies an association between the comorbidity and the disease of
interest, it does not explain how the two are connected. For example, in SpA, psoriasis and uveitis are
usually described as extra-musculoskeletal manifestations, nonsteroidal anti-inflammatory drug
(NSAID)-induced kidney disease is defined as a potential complication of treatment, and hip dysplasia
is defined as a condition/comorbidity unrelated to the disease [6]. However, this “clustering”of
comorbidities becomes more complicated when considering a condition such as obesity, which could
be argued to be a comorbidity not directly related to SpA, a complication of the disease as a conse-
quence of a more sedentary lifestyle, a side effect of glucocorticoid treatment for peripheral disease, or
even an extra-musculoskeletal manifestation [7]. This review focuses on comorbidities that do not
strictly fall within the extra-musculoskeletal manifestation group while acknowledging that some
overlap may be unavoidable.
Disease activity assessment in SpA
The 2017 treat-to-target recommendations and the 2023 EULAR management recommendations
for axSpA and PsA suggest using a treatment target (a composite score comprising different domains of
the disease) to assess and monitor disease activity and offer treatment alternatives to a patient if the
target (i.e. low disease activity or remission) is not reached [8e10]. For axSpA, the Ankylosing Spon-
dylitis Disease Activity Score (ASDAS) is recommended as the most appropriate tool for measuring and
monitoring disease activity. It comprises patient-reported outcomes (PROs), including the amount of
back pain, peripheral joint pain/swelling, and the duration of morning stiffness according to responses
in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the patient's global assessment of
the disease, and level of C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) [10,11].
For patients with PsA, either the Disease Activity Index for Psoriatic Arthritis (DAPSA) [12], or
Minimal Disease Activity (MDA) [13] is recommended [10]. Both composite scores include information
on joint tenderness, swelling, and pain and the global assessment reported by the patient. The DAPSA
also includes CRP as variable, whereas the MDA additionally requires the results of the Health
Assessment Questionnaire (HAQ), information regarding whether there is tenderness of at least one
enthesis, and the severity of psoriasis measured by the Psoriasis Area and Severity Index (PASI) or body
surface area (BSA).
Although these composite scores reflect disease activity, their values can easily get distorted in
patients with one or multiple comorbidities: Obesity may lead to elevated CRP and ESR values,
depression may have an impact on pain tolerance, and comorbidities in general can negatively affect
PROs [14e16]. All of these factors can contribute to an increase in the composite score values and lead
to a false assumption of raised inflammatory activity. It is, therefore, crucial to investigate the
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
2
underlying causes of elevated composite score values, rather than automatically attributing them
solely to SpA activity.
Magnetic resonance imaging (MRI) for the axial skeleton and ultrasound for peripheral joints may
also be used as additional tools for assessing disease activity, especially to distinguish inflammatory
pain from non-inflammatory pain [17e19].
Common comorbidities in spondyloarthritis
Hypertension and cardiovascular disease
Hypertension is the comorbidity with the highest prevalence in SpA (33.5%); is more common in
patients with axSpA (Odds ratio (OR): 1.58, 95% CI: 1.29 to 1.92) and patients with PsA (1.21, 95% CI: 1.15
to 1.27) than in the general population; and consequently leads to an overall higher risk of developing
cerebral, cardiac, and renal events for patients with SpA [3,20e23]. The mechanisms underlying this
comorbidity are not entirely clear, ranging from lack of physical activity due to pain and joint stiffness
and consecutive weight gain to fluid retention as a consequence of NSAID intake [24,25]. Hypertension
is associated with measures of disease activity in axSpA, as a recent study revealed an increase in
BASDAI by 0.42 (95%CI: 0.23 to 0.61) and an increase in the Bath Ankylosing Spondylitis Functional
Index (BASFI) by 1.15 (95%CI: 0.92 to 1.39) when patients with axSpA had uncomplicated hypertension
according to a univariable regression analysis. The results of BASFI remained statistically significant
even after adjusting for other cardiovascular risk factors (0.57 (95%CI: 0.25, 0.88)) [26].
Cardiovascular disease (CVD) entails several conditions, including ischaemic heart disease, heart fail-
ure, and peripheral vascular disease. Overall, CVD is present in 12% and 19.4% of patients with axSpA and
patients with PsA, respectively, exceeding the risk in the general population (OR 1.42 (95%CI: 0.99 to 2.03)
for axSpA and OR 1.7 (95%CI: 1.57 to 1.85) for PsA) [2,3,27]. CVD is one of the leading causes of mortality in
SpA, and recent studies suggest an 36e40% increased risk of cardiovascular (CV) death in patients with
axSpA compared with healthy controls [28,29]. Interestingly, the risk of CV death is not increased in pa-
tients with PsA despite the higher prevalence of CVD [28,30,31]. Disease activity is believed to be a major
influence and causal factor, as it is known that atheroma formation is closely linked to the inflammatory
burden of patients (especially through Interleukin (IL) 1
b
and IL-6) in association with monocyte and
macrophage activities [32,33]. This canbe underlined by the fact that anti-inflammatory therapy targeting
the IL-1
b
innate pathway with canakinumab has been shown to significantly lower the rate of CV events
compared with placebo in patients with recurrent CV events [34].
SpA, hypertension, and cardiovascular disease etreatment considerations
EULAR recommendations for CVD risk management are enforced to lower the disease activity of
patients with axSpA and patients with PsA to decrease CVD risk. Prescription of NSAIDs should be done
with caution in patients with PsA, especially in those with documented CVD, owing to the increased
risk of CV events. As NSAIDs are used as first-line treatment in patients with axSpA, no clear recom-
mendation was made for this patient group, and decisions should be guided by the individual clinical
presentation. Although Naproxen is frequently advocated as the NSAID with the safest CV risk profile,
the PRECISION trial showed that in patients with osteoarthritis or rheumatoid arthritis (RA), both
celecoxib and ibuprofen were noninferior in regard to a composite outcome of CV death, non-fatal
myocardial infarction, or non-fatal stroke after 18e30 months of NSAID treatment [35e37]. Gluco-
corticoid use should be kept to a minimum owing to its association with CV events.
CVD risk assessment should be performed at least every five years or after a major change in the
antirheumatic treatment. Validated prediction tools such as the “HeartScore”or “QRISK3”for assessing
the ten-year risk of fatal and non-fatal CVD or other CVD risk models recommended by national so-
cieties should be used. According to EULAR recommendations, it is advised to multiply the calculated
risk by 1.5 for patients with RA, unless the risk model already accounts for RA as a variable. A similar
approach is most likely applicable to patients with SpA, considering the high prevalence of CVD in the
population. Additionally, patients can be screened for bilateral atherosclerotic carotid plaques, which,
when present, increases the incidence of a future acute coronary syndrome significantly (1.1 per 100
patient years [95%CI: 0.6 to 1.7] without bilateral carotid plaques versus 4.3 per 100 patient years [95%
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
3
CI: 2.9 to 6.3] with bilateral carotid plaques). Antihypertensives and statins, as well as healthy lifestyle
recommendations, apply to patients with SpA as they do to the general population [4,38e41].
Infections
Infections are a relatively common comorbidity in SpA, with a prevalence of 18.2% in axSpA [3]. The
increased risk is mainly connected with the immunosuppressive treatment, and patients with SpA may
present with different types of infections (e.g. lower/upper respiratory infections and gastrointestinal
infections) and the reactivation of hepatitis B/C, tuberculosis (TB), varicella zoster (VZ), and human defi-
ciency virus (HIV) infections [42,43]. While respiratory infections in SpA are associated with chronic lung
disease,glucocorticoidtreatment, thenumber of previousbiologic disease-modifying anti-rheumaticdrug
treatments, and the history of previous airway infections, Human Leucocyte Antigen-B27 positivity ap-
pears to have a protective effect [44]. The latter may be due to an increased anti-viral immune response,
which has been reported for viruses such as HIV, hepatitis C, and influenza A [45e47].
Data on the role of disease activity in connection with infections in patients with SpA is scarce, but
from RA studies, it is apparent that patients with higher disease activity are at an increased risk of
infections compared with patients with low disease activity/remission (all receiving immunosup-
pression). One multicentre RA study reported that each 0.6 unit increase in the 28-joint Disease Ac-
tivity Score (DAS28) corresponded to a 4% and 25% increase in the risk of developing an outpatient
infection and infection requiring hospitalisation, respectively [48].
SpA and infections etreatment considerations
Although the treatment of infections in patients with SpA is not different from that in the general
public, specific screening and prophylactic measures should be taken when treating patients with
rheumatic inflammatory diseases. Before starting an immunosuppressive treatment, EULAR recom-
mendationsfor the screening and prophylaxis of chronicand opportunistic infections in adults withRMDs
suggest screening for latent TB, hepatitis B/C, and HIV. Furthermore, patients under immunosuppression
who are non-immune to the varicella zoster virus should be informed about a post-exposure prophylaxis
in case of contact with the virus. Pneumocystis jiroveccii pneumonia prophylaxis with trimethoprim/
sulfamethoxazole should be considered in patients receiving higher doses of glucocorticoids overlonger
periods of time (>15e30 mg of prednisone or equivalent for >2e4 weeks) [42]. Vaccination status and
indication for further vaccinations should be assessed yearly during the rheumatology consult [49].
Obesity
Obesity (body mass index (BMI) >30 kg/m
2
) is a highly frequent comorbidity in the general pop-
ulation, sometimes also referred to as a “global pandemic”with considerable differences between
countries and ethnicities [50,51]. According to recent systematic literature reviews (SLRs) on comor-
bidities in SpA that included studies irrespective of the geographical location, approximately 13.5% of
patients with axSpA and 27.4% of patients with PsA are considered obese. In general, obesity is well-
known to be associated with numerous diseases, ranging from CVD to different types of cancer to
mental disorders [52e54]. In addition, SpA can be found among these diseases. A UK population-based
study with over 75,000 patients with psoriasis found that the risk of developing PsA increased with
BMI. Relative risk (RR) for developing PsA was 1.09 (0.93e1.28) for BMIs from 25 to 29.9 kg/m
2
, 1.22
(1.02e1.47) for BMIs from 30.0 to 34.9 kg/m
2
, and 1.48 (1.20e1.81) for BMIs 35.0 kg/m
2
[55,56]. The
pathophysiological link to the development of autoimmune diseases may lie in a low-grade inflam-
matory state caused by the release of adipocytokines and pro-inflammatory molecules in adipose
tissue [57,58]. Furthermore, numerous studies report that obesity and overweight are associated with
different measures of disease activity in axSpA [59e61]. A recent SLR with meta-analysis reported a
mean difference of 0.38 (95% CI e0.56, 0.21; P <0.0001) in BASDAI between patients with normal
BMI and patients with overweight/obesity [61]. Similar results can also be found in PsA; a study from
the USA reported that higher disease activity measured by the Routine Assessment of Patient Index
Data (RAPID3) score and a higher impact of the disease according to the PsA Impact of Disease (PSAID)
were found in patients with obesity [62].
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
4
SpA and obesity etreatment considerations
Explaining to patients the negative impact of obesity not only on general health but also on their
RMD and discussing effective measures for weight loss and physical activity should be key parts of a
medical consult. Data also suggest that patients with SpA who are obese have a poorer response to
immunosuppressive treatment and have a lower chance of reaching a state of low disease activity or
remission [63,64]. Notably, it appears that this negative impact on treatment response is mainly
observed in patients with RA and patients with SpA receiving tumour necrosis factor alpha inhibitors
(TNFi). Conversely, this effect did not seem to be present in patients with RA receiving IL-6 inhibitors or
abatacept and in patients with PsA receiving IL-17 and IL-23 inhibitors. Consequently, this opens the
discussion of whether other immunosuppressive treatments should be preferred to TNFi in patients
with RA/SpA who are obese.
Signposting patients to dieticians or weight-loss programmes, as well as encouraging regular
physical activity, can help patients lose weight and optimise their BMI. The minimum recommendation
for adults with RMDs is to participate in a moderate-intensity aerobic physical activity for a minimum
of 30 min on 5 days per week or vigorous-intensity aerobic activity for a minimum of 20 min on 3 days
per week [65]. However, the amount of physical activity and exercises should be tailored to the needs
and ability of the individual patient.
Depression
Depression is a common disease in patients with RMDs, including SpA [66].Theprevalenceof
depression is estimated to be 5% in the general population, whereas current data suggest depression
to be present in up to 10.9% and 11.9% of patients with axSpA and patients with PsA, respectively
[2,3,67]. A recent study performing a cluster analysis along with a consecutive multivariable
regression analysis in patients with axSpA revealed a distinct depression and anxiety cluster that was
associated with 0.9 unit poorer global health (95%CI: 0.1 to 1.7), reduced quality of life (0.25 unit
lower Euro Quality of Life; 95%CI: 0.37 to 0.12), and a 0.9 unit higher BASDAI (95% CI: 0.1 to 1.8)
[68]. Similarly, patients with PsA who have depression also report higher disease activity [69]. While
SpA features such as chronic pain, fatigue, a decrease in physical activity, and psoriasis can be seen as
risk factors for developing depression, studies have also found an immune-pathophysiological link
showing that patients with active depression have elevated levels of CRP, IL-1
b
, IL-6, and tumour
necrosis factor alpha [70,71]. Furthermore, it was observed that patients with axSpA with moderate
to severe depression, as assessed by the Hospital Anxiety and Depression Scale (HADS), had a
significantly poorer response to treatment after initiating a biological agent than patients without
signs of depression [72].
SpA and depression etreatment considerations
Owing to depression's high prevalence and impact on SpA, patients should be screened for
depression in rheumatology clinics on an annual basis [73]. The UK National Institute for Health and
Care Excellence (NICE) suggests a number of screening questions for patients in a hospital setting (see
Table 1)[74]. Prompt initiation of treatment is key, although the specific health care provider
responsible may vary across national pathways. When treating patients who are taking antidepres-
sants (especially selective serotonin reuptake inhibitors), rheumatologists should be aware of the
increased risk of gastrointestinal, uterine, cerebral, and perioperative bleeding (OR: 1.41; 95% CI:
1.2 7 e1.57), which can be further increased by the addition of a therapy with NSAIDs or glucocorticoids
[75]. Nevertheless, adequate disease control through immunosuppressive treatment is essential and
has been shown to improve depressive symptoms in patients with axSpA [76]. Furthermore, to improve
coping with SpA, rheumatologists should aid patients in developing self-management strategies and
involve them in the decision-making process. Obtaining self-efficacy can have numerous benefits for
patients with SpA, as emphasised by the recent EULAR recommendation for the implementation of
self-management strategies [77].
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
5
Osteoporosis
The global prevalence of osteoporosis is estimated to be 18.3%, whereas the prevalence of osteo-
porosis among young healthy men is around 5% [78,79]. Data from the Assessment of Spondyloarthritis
international Society-COMOrbidities in SPondyloArthritis (ASAS-COMOSPA) study reports a prevalence
of 13.4% in patients with peripheral SpA or axSpA, with the cohort consisting of young (mean age: 44
years), predominantly male (65%), participants. Other studies report even higher estimates for axSpA
(8.8%e34.4%) and similar results for PsA (9.3e12.9%) [2,3,80,81]. This relatively high frequency of
osteoporosis especially in patients with axSpA makes them prone to fragility fractures of the vertebrae
[81].
Although disease duration and ankylosis appear to be risk factors for vertebral fractures, data from
the Devenir des Spondylarthropathies Indiff
erenci
ees R
ecentes (DESIR) cohort showed that even young
patients with axSpA with a symptom duration of under three years have a low bone mineral density
(BMD; Z score 2) and, consecutively, a higher risk of fractures [82e84]. The underlying cause of the
high prevalence of osteoporosis is assumed to be multifactorial, including a more sedentary lifestyle,
glucocorticoid treatment, malabsorption in patients with additional inflammatory bowel disease, and
high levels of pro-inflammatory cytokines [85,86]. The latter is especially reflected by the positive
association of CRP and ESR with low BMD values in axSpA [87,88].
SpA and osteoporosis - treatment considerations
Although treatment should aim to minimise the risk of fragility fractures in patients with SpA, the
first difficulty may already arise in diagnosing osteoporosis. Owing to osseous remodelling processes,
including ligament calcification and syndesmophyte development, dual-energy X-ray absorptiometry
(DXA) results may be false negative for osteoporosis, especially when using an anterior-posterior view
in patients with advanced axSpA [89,90]. Lateral lumbar or hip DXA could, therefore, result in less
biased results in advanced axSpA cases. Additional imaging techniques such as trabecular bone score
(TBS) reveal more insights into the bone structure and have been associated with disease activity
measures, including ASDAS; however, their clinical use in SpA is still unclear [91].
Although the EULAR points to consider for reporting, screening for, and preventing selected
comorbidities advise documenting past osteoporotic fractures, risk factors, and treatment, recom-
mendations on when and how to screen specifically patients with SpA for osteoporosis are lacking [4].
Furthermore, screening recommendations for the general population are most likely inadequate owing
to the beforementioned risk of low BMD in younger patients as well.
Although specific treatment recommendations for osteoporosis in patients with SpA are not
available, the control of disease activity through NSAID use and TNFi has been shown tohave a positive
Table 1
Guidelines for the screening and identification of depression.
Be alert to possible depression (particularly in patients with a past history of depression or a chronic physical health problem
with associated functional impairment) and consider asking patients who may have depression 2 questions, specifically:
- During the last month, have you often been bothered by feeling down, depressed, or hopeless?
- During the last month, have you often been bothered by having little interest or pleasure in doing things?
If a patient with a chronic physical health problem answers 'yes' to either of the depression identification questions, a
practitioner who is competent to perform a mental health assessment should ask 3 further questions to improve the
accuracy of the assessment of depression, specifically:
- During the last month, have you often been bothered by feelings of worthlessness?
- During the last month, have you often been bothered by poor concentration?
- During the last month, have you often been bothered by thoughts of death?
Further points:
- Review the patient's mental state and associated functional, interpersonal, and social difficulties
- Consider the role of both the chronic physical health problem and any prescribed medication in the development or
maintenance of depression
- Ascertain that the optimal treatment for the physical health problem is being provided and adhered to, seeking specialist
advice if necessary.
Adapted from [74].
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
6
effect on BMD. An analysis of the DESIR cohort showed that in TNFi users, BMD increased at the lumbar
spine and did not change at the hip, whereas NSAID treatment also had a protective effect on hip bone
loss (OR: 0.38, p ¼0.006) [92]. Ten-year fracture risk should be assessed using the Fracture Risk
Assessment Tool (FRAX), and adequate osteoporosis treatment should be provided to patients with SpA
as provided to the general public. It is, however, important to acknowledge that FRAX is not validated
for people aged under 50 years [4].
Pulmonary disease
Pulmonary disease in SpA entails several conditions such as chronic obstructive pulmonary disease
(COPD), asthma, and interstitial lung disease (ILD). According to recent data, the prevalence of co-
existing pulmonary disease is 7.9% among patients with axSpA and 12.3% among patients with PsA
[2,3].
The link between inflammatory RMDs and COPD has been shown in previous RA studies reporting
the incidence rate of COPD to be 1.74 times higher in patients with RA than in controls. It was argued
that this connection could simply be due to higher smoking rates in patients with RA; however, more
recent studies have shown that RA is an independent risk factor for COPD after adjusting for smoking
status [93,94].
Similar results were also found in a population-based study from Israel with over 4000 patients
with axSpA. Here, an independent association between axSpA and COPD (OR 1.23; 95%CI: 1.02 to 1.47)
was found after adjusting for age, sex, and smoking status [95]. These results reinforce the autoimmune
component that has been suggested in the pathogenesis of COPD [96]. The overactivity of the immune
system may also be a reason for the elevated incidence of asthma (1.74 fold) that has been reported in
patients with axSpA [97].
Literature is scarce on the relationship of PsAwith pulmonary disease. Patients with psoriasis rather
than PsA have been shown to be at a higher risk of developing COPD (OR 1.9; 95% CI: 1.36 to 2.65), and
the risk further increased in patients with severe psoriasis (OR 2.15; 95% CI: 1.26 to 3.67). A retro-
spective study from 2019 reported that 21 out of 447 patients (4.7%) with ILD had psoriasis, whereas
only 4 patients (0.01%) had PsA [98]. The high prevalence of pulmonary diseases in patients with PsA
may also be explained through concomitant factors such as obesity (for obstructive sleep apnoea) and
smoking (for COPD). The effect of SpA disease activity on pulmonary disease has not been studied in
detail so far.
SpA and pulmonary disease etreatment considerations
Distinct recommendations on the treatment of patients with SpA who have pulmonary disease do
not exist, apart from general recommendations promoting smoking cessation, weight loss, and physical
activity. Although reports on the improvement of pulmonary function with increased chest wall
mobility have differed in the past, it is advisable to encourage patients with axSpA to perform exercises
that may not only improve pulmonary function but also be beneficial in other aspects of the disease
[8,99,100]. Current studies suggest that physiotherapy, especially when supervised, has shown to be
more efficacious than home exercises [101].
Cancer
An overall slightly elevated risk for solid (OR 1.22 95%CI: 1.01e1.47) and all-type cancers has been
reported in axSpA (RR 1.14, 95%CI: 1.03e1.25) [3,102]. Historically, patients with axSpA were at an
increased risk of lymphoma and had 28% higher mortality in comparison with the general population,
mainly explained by the more recently deprecated radiation therapy of the spine [16,103,104]. In the
SLR and meta-analysis by Deng et al. an increased risk of haematological malignancies, including
multiple myeloma (MM) (RR 1.92, 95%CI: 1.37 to 2.69, pooled from 3 studies) and lymphoma (RR 1.32,
95%CI: 1.11 to 1.57, pooled from 9 studies), was reported [102]. Similar results were also reported in a
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
7
cohort of 4641 veterans from the USA, in which the RR of monoclonal gammopathy of undetermined
significance (MGUS) and MM was 2.02 (95%CI: 1.14 to 3.56) and 2.29 (1.55e3.40), respectively [105].
Furthermore, Chang et al. reported an elevated risk for colon cancer (standardised incidence ratio [SIR]:
1.39, 95% CI: 1.03 to 1.82) and prostate cancer (SIR: 1.64, 95%CI: 1.04 to 2.47) in patients with axSpA
using data from the Taiwan National Health Insurance Research Database [106]. However, these results
should be interpreted with caution, taking into account the numerous studies that did not report an
increased risk of malignancies in axSpA. Although these studies primarily investigated the malignancy
risk associated with TNFi, they also reported no increased risk for patients with SpA compared with the
general population [107e109].
The association of PsA with cancer is even less clear. A recent SLR with meta-analysis reported
higher overall risk for malignancy in patients with PsA compared to the general population (RR: 1.29,
95%CI: 1.04 to 1.60). However, almost all of the studies included in the analysis did not individually
show a statistically significant increase in risk and heterogeneity between the studies was considerable
(I
2
¼71%). [104,110]. Patients with PsA under treatment for psoriasis may, however, be at an increased
risk of nonmelanoma skin cancer (NMSC, RR: 2.46, 95%CI: 1.84 to 3.28) [110 ]. This may be largely due to
treatment with phototherapy, which has been reported to increase the risk of NMSC [111 ]. This is also
enforced by the fact that patients with psoriasis (SIR: 1.76, 95%CI: 1.26 to 3.39) rather than patients
with PsA (SIR: 1.25, 95%CI: 0.46 to 2.72) are at an increased risk of NMSC [107].
SpA and cancer etreatment considerations
Although studies on the association between active disease and a potentially increased risk for
malignancies in SpA do not exist, there are studies that have evaluated the association between TNFi
and cancer in SpA, reporting no increased risk of overall malignancies [104,107,112e116 ]. Although data
support regular screening for NMSC in patients with PsA receiving phototherapy, the need for specific
screening for other malignancies in patients with SpA is debatable.
Conclusions
Comorbidities in SpA are common and overall associated with worse outcomes in physical function,
work ability, quality of life, and disease activity and prognosis [117]. In this regard, the active screening
of comorbidities should be a key component during a rheumatology consult. Even better, comorbidity
assessment should be undertaken routinely in dedicated clinics, such as annual review clinics, sign-
posting the patient to other health care professionals and relevant resources, as indicated [73]. Vali-
dated tools such as the “HeartScore”or “QRISK3”for assessing CVD risk and FRAX for assessing fracture
risk in osteoporosis can help assess and communicate the additional comorbidity risk. However, it is
important to recognise that CVD risk scores have not been specifically developed for patients with SpA,
and FRAX is validated for only individuals aged 50 years or older. Owing to the high prevalence of
depression, patients with SpA should also be screened for depression. In line with this, NICE has
proposed two questions that can help health care professionals distinguish patients at risk for
depression (see Table 1). Patients with PsA receiving psoralen plus ultraviolet-A radiation therapy for
psoriasis should have regular dermatology visits for assessing the risk of NMSC development. More-
over, it is advisable to apply additional cancer screening generously in patients with SpA, particularly
when there are other risk factors present. Vaccination status assessment should be performed by the
rheumatology team on a yearly basis.
The knowledge of whether a comorbidity is a result of SpA or its treatment (e.g. osteoporosis due to
glucocorticoid treatment) or whether it can be considered an independent condition is important in
terms of treatment decisions. Disease activity and comorbidities are often closely related, and
addressing either of them can have a significant impact on the other. Therefore, it is key that patient
care for SpA is approached holistically, recognising the interrelatedness of SpA and comorbidities and
treating the patient as a whole rather than focusing on one (index) disease in isolation.
P. Bosch, S.S. Zhao and E. Nikiphorou Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
8
Funding
No funding for this publication.
Declaration of competing interest
No conflicts of interest.
Acknowledgement
SSZ is supported by a National Institute for Health Research Clinical Lectureship and works in
centres supported by Versus Arthritis (grant no. 21173, 21754, and 21755).
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