Abstract
Comorbidities in spondyloarthritis (SpA) add to the burden of disease by contributing to disease activity, functional and work disability, and mortality. Thus, awareness of comorbidities in SpA is crucial to improve their screening and management and to ultimately improve outcomes in those affected. Osteoporosis has been reported to be the most prevalent comorbidity in SpA, and its risk is increased in these patients, compared with the general population; the risk of vertebral fractures requires further evaluation. Cardiovascular risk is also increased in this population, both due to an increase of the traditional cardiovascular risk factors in these patients, but also due to the presence of inflammation. The role of non-steroidal anti-inflammatory drugs in this increased risk needs further elucidation, but there is consensus on the need to encourage smoking cessation and to perform periodic evaluation of cardiovascular risk in these patients, particularly in the case of change in treatment course. Concerning the risk of cancer, no increased risk inherent to SpA seems to exist. However, an increased neoplastic risk can occur due to SpA treatments, e.g., P-UVA. Data are sparse on the risk of infections compared with rheumatoid arthritis, but there appears to be no risk in the absence of TNF-inhibitor exposure. Regardless of which comorbidity, a gap exists between recommendations for their management and actual implementation in clinical practice, suggesting that there is still a need for improvement in this area. Systematic screening for these comorbidities should improve both short- and long-term outcomes in SpA patients.
Introduction
The term “spondyloarthritis” (SpA) encompasses inflammatory rheumatic diseases affecting mainly the axial skeleton. In SpA, extra-axial manifestations can be seen, namely, enthesitic and peripheral articular manifestations, but also extra-articular manifestations, such as skin, eye, or gut involvement [psoriasis, uveitis, and inflammatory bowel disease (IBD), respectively] (). Apart from these manifestations, which are directly related to SpA patients may also suffer from other distinct additional entities, classically referred to as “comorbidities”; the latter may have existed or may occur during the clinical course of a patient who has the index disease under study (, ). This is unlike extra-articular manifestations, which may occur during the course of the disease and belong to the spectrum of SpA but do not by definition fulfill the criteria for comorbidity.
Most of the evidence on the impact of comorbidities in rheumatic diseases comes from rheumatoid arthritis (RA), where the presence of comorbidity has been found to be a more significant predictor of premature death than shared epitope, rheumatoid factor, or erosions (). Although less-well studied in SpA, evidence is increasing on the prevalence of several comorbid conditions () and their added burden on excess disease activity, functional disability, poor work-related outcomes (), and mortality (). Thus, it is crucial to increase awareness on comorbidities, especially those more frequently associated with the disease and/or its treatment. This way, their screening and management can be improved, ultimately resulting in better outcomes for these patients.
The focus of this review will be on four key disease areas that have been observed in SpA patients, focusing mainly in the axial forms of the disease, i.e., axial spondyloarthritis (axSpA), but also, for some of the comorbidities we will also present data from the peripheral forms of SpA [e.g., peripheral SpA or psoriatic arthritis (PsA)]: osteoporosis, cardiovascular disease (CVD), cancer, and infections (). Although some of these conditions, especially the former two listed above, have been referred to in literature as complications of the underlying index disease, here we refer to them as comorbidities. In this review, we will also make the distinction between these conditions or comorbidities and related risk factors for these (i.e., hypertension, dyslipidemia, diabetes mellitus, or smoking for CVD).
Osteoporosis
Osteoporosis in SpA
Bone formation is the cornerstone lesion in axSpA, which leads to ankylosis and permanent disability of patients; paradoxically, osteoporosis or low bone density has been found to be the most prevalent comorbidity in these patients (). Osteoporosis in RA has been largely documented, both related to the phenotype of RA patients (postmenopausal women), to glucocorticoid treatment (very frequently used in RA and well-known osteoporosis inducer), but also related to inflammation (, ). Indeed, several studies have highlighted that a better control of disease activity (i.e., inflammation) leads to lower rates of bone loss in RA patients (, ). Osteoporosis in SpA patients can be hardly explained by the phenotypic characteristics such as age and gender, or systemic treatments, since usually the disease occurs in young males () and glucocorticoids are barely used, particularly in axial forms, unless they present with concomitant IBD ().
Osteoporosis in axSpA, particularly in long-standing forms, can be related to ankylosis and immobilization: indeed, prevalence of osteoporosis in radiographic axSpA (r-axSpA) patients has been reported to range between 19 and 50% (, ) and disease duration and ankylosis of the spine [e.g., measured by the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS)] have been classically found to be predisposing factors: in a study including 80 patients with r-axSpA with a mean disease duration of 10.8 years, disease duration was significantly and independently associated with osteoporosis [odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.03–1.25], while body mass index (BMI) was found to be inversely associated (OR = 0.82, 95% CI = 0.69–0.93) (). Another study including 204 r-axSpA patients and a mean disease duration of 15 ± 11 years reported that low BMD was associated with older age, disease duration, mSASSS, and Bath Ankylosing Spondylitis Metrology Index; furthermore, mSASSS significantly inversely correlated with lumbar bone mass density (BMD) (r = −0.389, P < 0.001) ().
However, osteoporosis has also been reported in early forms of the disease and thus cannot be related only to spine ankylosis and immobilization (). Briot et al. reported a prevalence of osteoporosis of 13.0% in a sample of 332 patients with early SpA (less than 3 years duration) from the DESIR cohort. Interestingly, the factors associated with osteoporosis were inflammation, systemic (increased ESR or CRP, OR = 2.60, 95% CI = 1.06–6.35) or local, defined by bone marrow edema (inflammatory lesions) on MRI (OR = 4.63, 95% CI = 1.90–11.31) and male gender (OR = 9.60, 95% CI = 2.73–33.78) ().
Inflammation has been linked to increased bone resorption and impaired bone formation, by inflammatory mediators’ action on osteoclast activity. Thus, there is a rationale to suggest that inflammation has an unfavorable effect on bone remodeling, and is the basis of the use of potent anti-inflammatory drugs to protect bone.
Fractures in SpA
Vertebral Fractures (VFs)
The prevalence of VFs in SpA patients is controversial: it has been classically reported that 30–40% patients with SpA present with VFs () and have greater risk of VFs (ranging from threefold to sevenfold) when compared with the general population (, ). Actually, there is concern regarding the definition of VFs across studies, since patients with SpA can present with vertebral deformities, particularly at the dorsal spine (e.g., due to lesions at anterior corners, wedging secondary to inflammatory lesions and hyperkyphosis). Semiautomated methods of morphometry are often used to assess VFs in large studies, and these methods might also capture these vertebral deformities, overestimating the prevalence of osteoporotic VFs in this population, since not all vertebral deformities are VFs (, ).
Incidence of VFs in a 4-year prospective study including in 298 r-axSpA patients 13.6% at 4 years, and risk factors included the presence of VFs at baseline and the presence of elevated CRP (). Conversely, a very recent analysis of the incidence of VFs in an early axSpA population (the DESIR cohort) of 433 patients prospectively followed for 5 years and with X-rays available both at baseline and at 5 years revealed only seven incident VFs over the 5 years of follow-up, i.e., a 5-year incidence of VFs of 1.6%. In this recent study, assessment of VFs was not performed by any semiautomated method, but by an expert central reader ().
Several factors have been associated with VFs in SpA; for example, mSASSS has been classically associated with VFs in SpA, probably related to lower BMD in patients with ankylosing disease (and therefore more disabled and less active) () but also due to the potential difficulties with peripheral vision secondary to limited range of spinal mobility and consequently higher risk of falls. Disease duration and hyperkyphosis have been reported as risk factors for VFs (). SpA patients with VFs have lower BMD than patients without, and femoral neck is the best discriminant site, but low BMD does not seem sufficient for to prediction of fracture in this population ().
Spinal Fractures
Spinal fractures should be distinguished from VFs, since they are not related to osteoporosis or low BMD and are the consequence of trauma (frequently minor traumatisms) in patients with an ossified spine. This event is a major complication in SpA, but is not strictly considered comorbidity, and thus its prevalence and mechanisms will not be detailed in this review.
Osteoporosis and SpA Treatments
Non-Steroidal Anti-inflammatory Drugs
Since in SpA inflammation leads to stiffness and loss of mobility, anti-inflammatory drugs are expected, through both the increased mobility related to pain relief and the increased activity, to have an effect on BMD. In a prospective analysis of the early SpA DESIR cohort of 265 patients (54% male, mean age 34.4 years) who had BMD measurements at baseline and at 2 years, use of non-steroidal anti-inflammatory drugs (NSAIDs) had protective effects on hip bone loss in patients (OR = 0.09, 95% CI = 0.02–0.50) (). This effect has also been observed for VFs: in a primary care-based nested case–control study, including patients with SpA, the risk of any clinical fracture was decreased in patients taking NSAIDs (OR = 0.65, 95% CI = 0.50–0.84) (). However, conflicting results have been also reported, with an excess risk of any clinical fracture in patients with SpA, and even a higher risk in patients using NSAIDs, probably because these patients had a more severe disease and thus, a higher utilization of NSAIDs, since these latter data are issued from claim databases (). Thus, the effect of NSAIDs on VF prevention needs to be further explored.
Biologic DMARDs
The positive effect of TNF inhibitors (TNFi) on BMD in SpA patients has been reported in several prospective studies in patients: a significant increase in BMD 2.3 and 11.8% was reported in a follow-up study of 106 SpA patients at 2 and 6 years, respectively (, ). This effect has also been confirmed in early forms of the disease (DESIR cohort) where the analysis of the 265 patients with BMD available over the 2-year follow-up, TNFi use was significantly and independently protective for bone loss (OR = 0.43, 95% CI = 0.20–0.93) (). Furthermore the beneficial effect of TNFi has been confirmed by a recent meta-analysis of longitudinal trials and one RCT, with a total of 568 r-axSpA patients (mean disease duration of years): lumbar spine BMD increased by 8.6% (95% CI = 6.8–10.3%, P < 0.00001) after 2 years ().
No clinical data are available yet regarding the potential positive effects on bone of IL-17 blockade with IL-17 inhibitors used in SpA treatment, but animal models seem to confirm this hypothesis ().
Although no specific guidelines for the management of osteoporosis in SpA exist, some national scientific societies have proposed to perform a BMD evaluation at least once in the course of the disease in patients with SpA (). However, in patients with severe osteoporosis, prevalent fractures or several risk factors, available guidelines for osteoporosis management (e.g., male osteoporosis) should be used ().
In summary osteoporosis is a highly prevalent comorbidity in SpA, higher than the general population; however, risk of VF requires further evaluation, as current prevalence and incidence reported in the literature might have been over-estimated by the automate and semiautomate methods of evaluation of such VFs. Nevertheless, these findings support that measurement of BMD should be performed at least once during the disease course.
Cardiovascular Disease
An increase in mortality has been reported in patients with axSpA (, , ). Indeed, a recent study reported an age-adjusted and sex-adjusted mortality hazard ratio (HR) of 1.60 (95% CI = 1.44–1.77), with increased mortality for men [age-adjusted HR = 1.53 (1.36–1.72)] and women [age-adjusted HR = 1.83 (1.50–2.22)] in patients with axSpA and CVD accounted for 34.7% of all deaths (). Indeed, CVD is consistently found as the leading cause of mortality in patients with axSpA (, –), with percentages ranging from 30 to 50% of all-cause deaths in this population (). This increased mortality can be explained both by an increase in the prevalence of CVD in axSpA but also by an increase in cardiovascular risk factors (CVRFs) compared with the general population. This increase in cardiovascular mortality was the rationale to include SpA patients in the scope of the 2015/2016 EULAR recommendations for cardiovascular risk management, as well as in other recommendations (, ).
Ischemic Heart Disease (IHD) and Stroke
A recent cross-sectional study including 3,984 patients with SpA [mean age 44 ()] found a prevalence of IHD and stroke of 2.7% (95% CI = 2.2–3.2) and 1.3% (95% CI = 0.9–1.7), respectively (). A meta-analysis () and some more recent prospective studies (, ) have consistently reported increased risk of CVD in patients with axSpA: the 2011 meta-analysis () reported an increase risk of IHD (OR = 1.60, 95% CI = 1.32–1.93) and stroke (OR = 1.50, 95% CI = 1.39–1.62) in patients with r-axSpA, compared with controls (). A more recent prospective study including patients with axSpA found an increased risk of IHD in patients with r-axSpA and not radiographic axSpA (nr-axSpA) [age- and sex-adjusted HR = 1.54 (95% CI = 1.31–1.82) and HR = 1.36 (95% CI = 1.05–1.76), respectively] and also for stroke but only for r-axSpA [age- and sex-adjusted HR = 1.25 (95% CI = 1.06–1.48) and HR = 1.16 (95% CI = 0.91–1.47), for r-axSpA and nr-axSpA, respectively], compared with the general population ().
Cardiovascular Risk Factors
Classic CVRFs
There are five classic modifiable CVRFs (hypertension, smoking, dyslipidemia, diabetes, and obesity), and they are estimated to account for more than 50% of all CV deaths (). In this review, we will not discuss the non-modifiable CVRF (e.g., age, gender, or family history of CVD).
Hypertension
Hypertension is one of the most prevalent CVRF, estimated to account for 50% of all strokes and IHD events in the general population (). Several studies have reported an increased prevalence of hypertension in SpA patients, compared with controls both in axial and peripheral forms of SpA (including PsA) (, , –): a recent cross-sectional international study including 4,000 SpA patients worldwide () reported hypertension to be the most frequent CVFR in this population, with a prevalence to 33.5% (95% CI = 32.0–35.0%) patients; another study () reported a substantially higher prevalence of hypertension in patients with r-axSpA compared with the general population in the Netherlands (41 vs. 31%, respectively).
The mechanisms underlying this increased prevalence of hypertension in SpA are likely to be multiple: first, hypertension in patients with SpA has been found to be associated with disease activity (), which might be due to increased inflammatory pathways () but also potentially to decreased mobility due to stiffness leading to increased sedentarism in patients with greater disease activity. Furthermore hypertension seems to be underdiagnosed in patients with SpA: the COMOSPA study reported that systematic screening for hypertension revealed an increased systolic blood pressure in 14.7% of the SpA patients without any known history of hypertension ().
Cigarette Smoking
Prevalence of cigarette smoking in the general population has been recently reported to be around 15% (data from the US) (); this prevalence appears to be increased in patients with axSpA, with reported numbers up to 30 and 40% (, ). Furthermore, smoking has been associated with increased acute phase reactants [high sensitivity CRP ()], but also, in the specific case of axSpA, with increased disease activity and structural progression (–54); therefore, smoking in axSpA patients would have a double role, as traditional CVRF but also increasing disability and ankylosis, which might potentially lead to a more sedentary lifestyle, another very well-known traditional CVRF.
Dyslipidemia
Prevalence of dyslipidemia in the general population is estimated to be 12% in adults above 20 years and is significantly increased in patients with premature IHD, i.e., up to 80% in those patients (55). A paradoxical decrease in lipids (e.g., total cholesterol, LDL cholesterol, and HDL cholesterol) has been reported in patients with other rheumatic inflammatory diseases, in particular RA (56). However, while most of the studies have also reported a decrease in HDL cholesterol, a well-known protective factor for CVD (57), in patients with r-axSpA compared with controls, in particular in the presence of active inflammatory disease (, , 58–60), other studies have reported increased total and LDL cholesterol in patients with r-axSpA and PsA (61, 62). Furthermore, some recent studies have reported an impaired endothelial function of HDL in patients with r-axSpA, leading to lower antiatherogenic properties (63). Thus, the role of dyslipidemia in the CV risk in SpA needs further investigation.
Diabetes Mellitus
The overall prevalence of diabetes in adults has increased from 4.7% in 1980 to 8.5% in 2014 (64). Diabetes is associated with CVD, and some studies have reported diabetes to be accountable for 10% of the population-attributable risk of a first myocardial infarction (65).
Several studies have suggested an association between diabetes and peripheral forms of SpA (e.g., PsA), with an increased risk of 1.4 (95% CI = 1.3–1.5) for diabetes among patients with PsA compared with patients without rheumatic diseases (66, 67). These differences might be due to the different treatments used in peripheral vs. axial forms, since glucocorticoids, a know risk factor for diabetes, are more often used in peripheral forms and are not recommended in axial forms ().
Obesity
Prevalence of obesity (defined as a BMI above 30 kg/cm2) in the general population has been estimated to range between 13% [Europe (68)] and 37% [US (69)]. Obesity is associated with a number of risk factors for CVD, including hypertension, diabetes, and dyslipidemia (70), but other studies have reported BMI to independently predict the occurrence of IHD and stroke after adjusting for traditional risk factors, suggesting a continuous linear relationship between higher BMI and greater risk of CVD (71, 72).
Obesity is not that frequent in pure axial forms of the disease (73). However, prevalence of obesity is increased in patients with peripheral forms of SpA (e.g., PsA) and has been reported to involve to 30% of patients with PsA. In contrast to what has been reported in RA, i.e., RA patients with low BMI (<20 kg/cm2) might have greater CV risk due to differences in body composition (56), BMI-CV risk relationship in patients with PsA seem to be similar to the one observed in the general population.
New CVRFs
It has been established that inflammation is associated with an increased risk of atheroma development (56), and while systemic inflammation is less often present in axSpA, several studies have reported increased inflammatory markers such as ultrasensitive CRP, IL-6, and homocystein (58, 74). Furthermore, several studies have observed an increased Carotid intima-media thickness, arterial stiffness and endothelial dysfunction (known CVRFs) in patients with axSpA, compared with controls (, , 75, 76).
CVD and Treatments in SpA
Non-Steroidal Anti-inflammatory Drugs
Non-steroidal anti-inflammatory drugs remain the cornerstone treatment in axSpA (), and these drugs have been reported to increase CVD risk in the general population (77). However, this effect is not apparently found in patients with SpA, and several studies have reported a lack of increase (78) or even a reduction of CVD rates in SpA patients treated with NSAIDs (, 79). The hypothesis for these results is that inflammation would greatly contribute to the CV burden, and NSAIDs would have a beneficial effect by controlling such inflammation. However, it cannot be completely excluded that these results do not simply highlight a different NSAID prescription rate in patients with previously known CVRFs (prescription bias) although some studies did apply statistical methods to overcome this bias (e.g., propensity score adjustment).
Glucocorticoids
Glucocorticoid use is associated with increased CV risk, particularly of IHD (80). Indeed, doses ≥7.5 mg/day of prednisone in several population-based studies have been reported to increase the CV risk (including CV mortality), with a risk ratio ranging from 2.6 to 7.4 (80, 81). However, data support that below this threshold, the risk for CV events seems low, and glucocorticoids are very effective at treating inflammation, which relates to cardiovascular risk (82).
Conventional Synthetic DMARDs
Sulfasalazine is the recommended DMARD to be used in peripheral forms of Ref. (), and there are only few reports suggesting an effect on reducing CV risk (83). This effect might be explained by the inhibitory action of sulfasalazine and its metabolites of arachidonic acid-induced platelet aggregation, which has been reported to be comparable to that achieved by aspirin, a well-known cardioprotective agent (84). Nevertheless in clinical practice, methotrexate if often used for the treatment of peripheral SpA, and greater evidence supports the cardioprotective role of methotrexate in RA (85, 86).
Biologic DMARDs
TNF inhibitors are the most widely used biologics in SpA. TNFi have been proven to reduce inflammation, which has been associated with increased CV risk, and several studies have reported to reduce subclinical atherosclerosis in SpA patients treated with TNFi (86–89). Also, TNFi have been reported to increase weight and abdominal fat mass (90), total cholesterol, HDL cholesterol, and LDL cholesterol in patients with axSpA (91), although these changes probably reflect a normalization in these parameters secondary to inflammation control.
IL-17 inhibitors have not been reported to be associated with CV risk, but studies are sparse (92, 93). More conflicting data have been published regarding IL12/23 inhibition, since significantly more major CV events were reported in the active-treatment arms of phase-3 trials in patients with psoriasis (94), while prospective long-term observational data have not found an increased CV risk (95, 96).
In summary, both CV mortality and morbidity seem to be increased in SpA, both related to an increased prevalence of most of the classic CVRFs, but also linked to inflammation. This forms a strong rationale for the systematic evaluation of CV risk in all SpA patients, at least every 5 years or more frequently in the case of a change in the treatment course, as recommended by EULAR and other societies (, ).
Cancer
Cancer and SpA
While an increased risk of malignancy (i.e., lymphoma) has been reported in patients with RA (97), no increased risk of cancer has been reported in patients with SpA (98, 99). Several registers have consistently reported reassuring data: Swedish registers reported a standardized incidence ratio (SIR) of malignancy of 1.05 (95% CI = 0.94–1.17), for the 1965–1995 period in patients with axial SpA (79); a more recent collaborative analysis of two Scandinavian registers confirmed this findings for the 2001–2011 period, with an RR for malignancy of 1.1 (1.0–1.2) in SpA patients compared with the general population, and very similar results for the r-axSpA and PsA forms [RR = 1.1 (95% CI = 1.0–1.3) and RR = 1.0 (0.9–1.1), respectively] (100). A Canadian prospective cohort of PsA also confirmed these findings, reporting a non-significant malignancy SIR of 0.98 (95% CI = 0.77–1.24) (101).
Colorectal Cancer (CRC) and SpA
The risk of developing a CRC is increased in patients with IBD, which often coexists with SpA: this risk is estimated to be twofold increased in this population, particularly in males (RR = 1.6, 95% CI = 1.2–2.2 vs. RR = 1.9, 95% CI = 1.5–2.4 for males vs. females, respectively) (102).
However, prospective observational data from SpA registers and cohorts have not reported an increased risk of CRC: indeed, in the Swedish register no increased risk for colon cancer was observed (SIR 0.95, 95% CI = 0.58–1.47), and the risk of rectal cancer was found to be significantly less frequent (SIR = 0.41, 95% CI = 0.15–0.89) (103). This latter finding for rectal cancer has not been confirmed in other registers, but no increased risk has been reported either (101).
Screening recommendations for the most common type of cancer are available for the general population and some are specific depending on the treatment (e.g., dermatology visit in patients receiving TNFi treatment), but their implementation has been reported to be far from optimal: a cross-sectional international study () revealed that SpA patients were in agreement with general population recommendations for cancer prevention in 32.7% (CRC) to 44.0% (breast cancer) of patients at risk; and that only 10.7% of patients with TNFi treatment were optimally screened for skin cancer.
Cancer and SpA Treatments
Radiation Therapy and Cancer
Historically, an increase in malignancy risk and mortality was reported in patients with SpA (particularly in axial forms) due to the historic treatment for SpA, which was based on radiotherapy of the spine: an increased mortality risk up to 28% was reported in SpA patients undergoing this treatment, compared with the general population, and a particular threefold increase in mortality due to leukemia in these patients (104). Fortunately, with the arrival of novel and effective therapeutic options, radiotherapy courses have been abandoned for the treatment of SpA.
Phototherapy for Skin Psoriasis and Cancer
Oral 8-methoxypsoralen-UV-A (P-UVA) and narrowband UVB are phototherapies used in skin psoriasis. An increased skin cancer risk [squamous cell carcinoma (SCC) mainly among the non-melanoma cancers] has been reported in patients undergoing P-UVA therapy, with a dose-ranging effect: the risk of SCC was significantly higher for patients exposed to >200 P-UVA, compared with low-dose exposed patients (<100 sessions), while results for melanoma were conflicting, with most of the US studies suggesting an increased risk of melanoma in exposed patients, while European studies did not find any association (105).
NSAIDs and Cancer
The potential beneficial effect of NSAIDs in recurrent CRC has been reported in systematic reviews: in particular, COX-2 inhibitors (celecoxib and rofecoxib) were reported to be highly effective in reducing the incidence of recurrent colorectal adenomas (106, 107): in a recent meta-analysis, the incidence of recurrent adenomas and advanced adenomas over a 3-year follow-up was significantly reduced [pooled RR = 0.66, 95% CI = 0.59–0.72 for celecoxib and RR = 0.76 (0.69–0.83) for rofecoxib]. However, the increased risk for gastrointestinal events and the relative contra indication in patients with IBBD (the main risk population) represents a crucial drawback to the use of these drugs as prevention therapy in populations at risk. In any case, no data suggest that NSAIDs may increase the risk of CRC.
TNFi and Cancer
Most of the data on TNFi and cancer are derived from RA trials and have not reported any increased risk for malignancy (108–110) although some studies present conflicting data, mainly for lymphoma which is inherently increased in RA (111, 112) and skin cancer (113, 114) as already mentioned. Compared with the literature on cancer in RA patients, treated with TNFi, data on cancer risk in SpA patients exposed to TNFi are limited, and most of the available studies only include RCTs (i.e., short follow-up) (115–117); nevertheless, none of them report an increased risk for malignancy in this population.
A recent collaborative analysis of two Scandinavian registers including 8,703 patients with SpA initiating a first TNFi between 2001 and 2011 reported no increased cancer risk in TNFi exposed SpA patients [compared with TNFi-naïve SpA patients, RR = 0.8 (95% CI = 0.7–1.0)]. Similar results were found for r-axSpA and PsA, when analyzed separately [RR = 0.8 (95% CI = 0.6–1.1) and RR = 0.9 (95% CI = 0.7–1.1), for r-axSpA and PsA, respectively] (100). Data on the increased risk of a second neoplasm in patients with history of cancer and treated with TNFi are controversial with some studies suggesting a greater risk in TNFi SpA treated patients compared with the general population (118), while larger studies focusing in RA have not found any significant increased risk (119, 120). Due to the small number of studies evaluating this subgroup of patients with previous history of cancer, these treatments should be used with caution, and always in agreement with the oncological team.
In summary, it does not seem that SpA patients are at greater risk of cancer compared with the general population, except for those exposed to some treatment modalities (e.g., P-UVA therapy); data on TNFi are controversial but no increased risk appears to exist in SpA, in contrast to RA.
Infection
Infection and SpA
In contrast to RA, data on infectious risk are poor and derive mainly from randomized controlled trials and are therefore issued from selected populations and with a short-follow-up. A 2008 systematic review and meta-analysis including 14 RCTs reported only two serious infections in 2,202 r-axSpA patients not exposed to immunosuppressive drugs [0.09%, i.e., 0.4 per 100 person years (pyrs)] (121). Conversely, data from observational trials yield slightly higher severe infection rates: a recently published analysis of 440 SpA patients followed for a total of 1,712 patient years (pys) revealed 23 serious infections, i.e., a serious infection rate of 1.3 (95% CI = 0.9–2.0)/100 pys (122). Interestingly, in this study, the use of DMARDs, but not specifically the use of TNFi was associated with infection.
Infection and TNFi
In most studies, infection rates are higher in the group of patients exposed to TNFi compared with placebo or any other csDMARD: in the 2008 systematic review (121), 14 serious infections were found in the TNFi exposed group (14/996, 0.7% 95% CI = 0.3–1.4%), i.e., 1.9/100 pyrs, but the meta-analysis of the RCTs showed that the increase in serious infections with TNF blockers compared with placebo was not significant: risk difference = 0.4% (−8 to 1.6%). However, another meta-analysis of etanercept trials including 1,323 subjects (>1,500 subject years of treatment) (117) reported a serious infections rate of 2.19 (95% CI = 0.22–107.79) for the TNFi exposed compared with sulfasalazine exposed or placebo.
Based on this increased risk, specific recommendations for vaccination have been published for patients exposed to biologics and regardless of age, seasonal flu and pneumococcal vaccination are strongly recommended in these patients (123). Despite this, vaccination rates are far from optimal in this population: a cross-sectional study of 1,911 patients at risk among the 3,989 SpA included patients, only 332 (17.3%) had received a pneumococcal vaccination within the past 5 years, and 726 (38.0%) had received an influenza vaccination within the past 12 months (). These results suggest that there remains an unmet need for improving infection prevention in SpA, particularly in high-risk cases such as patients exposed to biologics.
In summary, regarding infection risk, data are sparse compared with RA, but there appears to be no risk in the absence of TNFi exposure.
Conclusion
Osteoporosis is a highly prevalent comorbidity in SpA, higher than the general population; however, risk of VF requires further evaluation, as current prevalence and incidence reported in the literature might have been over-estimated by the automate and semiautomate methods of evaluation of such VFs. Nevertheless, these findings support that measurement of BMD should be performed at least once during the disease course. Cardiovascular risk is also increased in this population, both due to an increase of the classic CVRF in these patients, but also due to the presence of inflammation. The role of NSAIDs in this increased risk needs further elucidation, but there is consensus for the need to encourage smoking cessation and to perform periodic evaluation of CV risk in these patients, particularly in case of treatment change. In the case of cancer, no increased risk inherent to SpA seems to exist. However, an increased neoplastic risk can occur due to SpA treatments, e.g., P-UVA; data on TNFi are controversial but no increased risk appears to exist in SpA, in contrast to RA. Furthermore, regarding infection risk, data are sparse compared with RA, but there appears to be no risk in the absence of TNFi exposure.
Regardless of the comorbidity, what is apparent is that a gap exists between recommendations for their management and implementation in clinical practice, suggesting that there is still room for improvement in this area. Systematic screening for these comorbidities should improve short and long-term outcomes in comorbid SpA patients, but to date the confirmatory data are lacking. Currently, ongoing studies should confirm this hypothesis.
Statements
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
DougadosMBaetenD. Spondyloarthritis. Lancet (2011) 377:2127–37.10.1016/S0140-6736(11)60071-8
2
FeinsteinAR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis (1970) 23:455–68.10.1016/0021-9681(70)90054-8
3
ValderasJMStarfieldBSibbaldBSalisburyCRolandM. Defining comorbidity: implications for understanding health and health services. Ann Fam Med (2009) 7:357–63.10.1370/afm.983
4
SokkaTAbelsonBPincusT. Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol (2008) 26:S35–61.
5
MoltóAEtchetoAvan der HeijdeDLandewéRvan den BoschFBautista MolanoWet alPrevalence of comorbidities and evaluation of their screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA study. Ann Rheum Dis (2016) 75:1016–23.10.1136/annrheumdis-2015-208174
6
NikiphorouERamiroSvan der HeijdeDNortonSMoltóADougadosMet alComorbidities in spondyloarthritis associate with poor function, work disability and quality of life: results from the ASAS-COMOSPA study. Arthritis Care Res (Hoboken) (2017).10.1002/acr.23468
7
PratiCClaudepierrePPhamTWendlingD. Mortality in spondylarthritis. Joint Bone Spine (2011) 78:466–70.10.1016/j.jbspin.2011.02.012
8
BriotKGeusensPBultinkIELemsWFRouxC. Inflammatory diseases and bone fragility. Osteoporos Int (2017) 28:3301–14.10.1007/s00198-017-4189-7
9
RouxC. Osteoporosis in inflammatory joint diseases. Osteoporos Int (2011) 22:421–33.10.1007/s00198-010-1319-x
10
VisMHavaardsholmEAHaugebergGUhligTVoskuylAEvan de StadtRJet alEvaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis (2006) 65:1495–9.10.1136/ard.2005.044198
11
Güler-YükselMBijsterboschJGoekoop-RuitermanYPMde Vries-BouwstraJKRondayHKPeetersAJet alBone mineral density in patients with recently diagnosed, active rheumatoid arthritis. Ann Rheum Dis (2007) 66:1508–12.10.1136/ard.2007.070839
12
van der HeijdeDRamiroSLandewéRBaraliakosXVan den BoschFSeprianoAet al2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis (2017) 76(6):978–91.10.1136/annrheumdis-2016-210770
13
El MaghraouiABorderieDCherruauBEdouardRDougadosMRouxC. Osteoporosis, body composition, and bone turnover in ankylosing spondylitis. J Rheumatol (1999) 26:2205–9.
14
GhozlaniIGhaziMNouijaiAMounachARezqiAAchemlalLet alPrevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. Bone (2009) 44:772–6.10.1016/j.bone.2008.12.028
15
KlingbergELorentzonMMellströmDGeijerMGöthlinJHilmeEet alOsteoporosis in ankylosing spondylitis – prevalence, risk factors and methods of assessment. Arthritis Res Ther (2012) 14:R108.10.1186/ar3833
16
van der WeijdenMAClaushuisTANazariTLemsWFDijkmansBAvan der Horst-BruinsmaIE. High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol (2012) 31:1529–35.10.1007/s10067-012-2018-0
17
BriotKDurnezAPaternotteSMiceli-RichardCDougadosMRouxC. Bone oedema on MRI is highly associated with low bone mineral density in patients with early inflammatory back pain: results from the DESIR cohort. Ann Rheum Dis (2013) 72:1914–9.10.1136/annrheumdis-2012-201845
18
MontalaNJuanolaXCollantesEMuñoz-GomarizEGonzalezCGratacosJet alPrevalence of vertebral fractures by semiautomated morphometry in patients with ankylosing spondylitis. J Rheumatol (2011) 38:893–7.10.3899/jrheum.100851
19
VosseDLandewéRvan der HeijdeDvan der LindenSvan StaaT-PGeusensP. Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case-control study. Ann Rheum Dis (2009) 68:1839–42.10.1136/ard.2008.100503
20
WeissRJWickMCAckermannPWMontgomerySM. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases – a case-control study with 53,108 patients with fracture. J Rheumatol (2010) 37:2247–50.10.3899/jrheum.100363
21
VosseDHeijckmannCLandewéRvan der HeijdeDvan der LindenSGeusensP. Comparing morphometric X-ray absorptiometry and radiography in defining vertebral wedge fractures in patients with ankylosing spondylitis. Rheumatology (Oxford) (2007) 46:1667–71.10.1093/rheumatology/kem135
22
BriotKRouxC. Inflammation, bone loss and fracture risk in spondyloarthritis. RMD Open (2015) 1:e000052.10.1136/rmdopen-2015-000052
23
KangKYKimIJJungSMKwokS-KJuJHParkK-Set alIncidence and predictors of morphometric vertebral fractures in patients with ankylosing spondylitis. Arthritis Res Ther (2014) 16:R124.10.1186/ar4581
24
SahuguetJFechtenbaumJMoltoAEtchetoARichettePDougadosMet alOP0054 incidence of vertebral fractures in early spondyloarthritis: 5-year prospective data of the desir cohort. Ann Rheum Dis (2017) 76:73–73.10.1136/annrheumdis-2017-eular.6324
25
GeusensPDe WinterLQuadenDVanhoofJVosseDvan den BerghJet alThe prevalence of vertebral fractures in spondyloarthritis: relation to disease characteristics, bone mineral density, syndesmophytes and history of back pain and trauma. Arthritis Res Ther (2015) 17:294.10.1186/s13075-015-0809-9
26
BriotKEtchetoAMiceli-RichardCDougadosMRouxC. Bone loss in patients with early inflammatory back pain suggestive of spondyloarthritis: results from the prospective DESIR cohort. Rheumatology (Oxford) (2016) 55:335–42.10.1093/rheumatology/kev332
27
Prieto-AlhambraDMuñoz-OrtegoJDe VriesFVosseDArdenNKBownessPet alAnkylosing spondylitis confers substantially increased risk of clinical spine fractures: a nationwide case-control study. Osteoporos Int (2015) 26:85–91.10.1007/s00198-014-2939-3
28
BriotKGossecLKoltaSDougadosMRouxC. Prospective assessment of body weight, body composition, and bone density changes in patients with spondyloarthropathy receiving anti-tumor necrosis factor-alpha treatment. J Rheumatol (2008) 35:855–61.
29
DurnezAPaternotteSFechtenbaumJLandewéRBMDougadosMRouxCet alIncrease in bone density in patients with spondyloarthritis during anti-tumor necrosis factor therapy: 6-year followup study. J Rheumatol (2013) 40:1712–8.10.3899/jrheum.121417
30
HaroonNNSriganthanJAl GhanimNInmanRDCheungAM. Effect of TNF-alpha inhibitor treatment on bone mineral density in patients with ankylosing spondylitis: a systematic review and meta-analysis. Semin Arthritis Rheum (2014) 44:155–61.10.1016/j.semarthrit.2014.05.008
31
MansooriMNShuklaPSinghD. Combination of PTH (1-34) with anti-IL17 prevents bone loss by inhibiting IL-17/N-cadherin mediated disruption of PTHR1/LRP-6 interaction. Bone (2017) 105:226–36.10.1016/j.bone.2017.09.010
32
BremanderAPeterssonIFBergmanSEnglundM. Population-based estimates of common comorbidities and cardiovascular disease in ankylosing spondylitis. Arthritis Care Res (Hoboken) (2011) 63:550–6.10.1002/acr.20408
33
ExarchouSLieELindströmUAsklingJForsblad-d’EliaHTuressonCet alMortality in ankylosing spondylitis: results from a nationwide population-based study. Ann Rheum Dis (2016) 75:1466–72.10.1136/annrheumdis-2015-207688
34
SariIOkanTAkarSCeceHAltayCSecilMet alImpaired endothelial function in patients with ankylosing spondylitis. Rheumatology (Oxford) (2006) 45:283–6.10.1093/rheumatology/kei145
35
PetersMJLvan EijkICSmuldersYMSerneEDijkmansBACvan der Horst-BruinsmaIEet alSigns of accelerated preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol (2010) 37:161–6.10.3899/jrheum.090667
36
MathieuSGossecLDougadosMSoubrierM. Cardiovascular profile in ankylosing spondylitis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) (2011) 63:557–63.10.1002/acr.20364
37
HaroonNNPatersonJMLiPInmanRDHaroonN. Patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med (2015) 163:409–16.10.7326/M14-2470
38
AgcaRHeslingaSCRollefstadSHeslingaMMcInnesIBPetersMJLet alEULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis (2017) 76:17–28.10.1136/annrheumdis-2016-209775
39
RoubilleCRicherVStarninoTMcCourtCMcFarlaneAFlemingPet alEvidence-based recommendations for the management of comorbidities in rheumatoid arthritis, psoriasis, and psoriatic arthritis: expert opinion of the Canadian dermatology-rheumatology comorbidity initiative. J Rheumatol (2015) 42:1767–80.10.3899/jrheum.141112
40
ChouC-HLinM-CPengC-LWuY-CSungF-CKaoC-Het alA nationwide population-based retrospective cohort study: increased risk of acute coronary syndrome in patients with ankylosing spondylitis. Scand J Rheumatol (2014) 43:132–6.10.3109/03009742.2013.822097
41
BengtssonKForsblad-d’EliaHLieEKlingbergEDehlinMExarchouSet alAre ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study. Arthritis Res Ther (2017) 19:102.10.1186/s13075-017-1315-z
42
PatelSAWinkelMAliMKNarayanKMVMehtaNK. Cardiovascular mortality associated with 5 leading risk factors: national and state preventable fractions estimated from survey data. Ann Intern Med (2015) 163:245–53.10.7326/M14-1753
43
LawesCMMVander HoornSRodgersAInternational Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet (2008) 371:1513–8.10.1016/S0140-6736(08)60655-8
44
AhmedNPriorJAChenYHaywardRMallenCDHiderSL. Prevalence of cardiovascular-related comorbidity in ankylosing spondylitis, psoriatic arthritis and psoriasis in primary care: a matched retrospective cohort study. Clin Rheumatol (2016) 35:3069–73.10.1007/s10067-016-3362-2
45
HeslingaSCVan den OeverIAVan SijlAMPetersMJVan der Horst-BruinsmaIESmuldersYMet alCardiovascular risk management in patients with active ankylosing spondylitis: a detailed evaluation. BMC Musculoskelet Disord (2015) 16:80.10.1186/s12891-015-0532-3
46
PapadakisJASidiropoulosPIKarvounarisSAVrentzosGESpanakisEKGanotakisESet alHigh prevalence of metabolic syndrome and cardiovascular risk factors in men with ankylosing spondylitis on anti-TNFalpha treatment: correlation with disease activity. Clin Exp Rheumatol (2009) 27:292–8.
47
EderLThavaneswaranAChandranVCookRGladmanDD. Increased burden of inflammation over time is associated with the extent of atherosclerotic plaques in patients with psoriatic arthritis. Ann Rheum Dis (2015) 74:1830–5.10.1136/annrheumdis-2014-205267
48
TamL-STomlinsonBChuTT-WLiMLeungY-YKwokL-Wet alCardiovascular risk profile of patients with psoriatic arthritis compared to controls – the role of inflammation. Rheumatology (Oxford) (2008) 47:718–23.10.1093/rheumatology/ken090
49
JamalAKingBANeffLJWhitmillJBabbSDGraffunderCM. Current cigarette smoking among adults — United States, 2005–2015. MMWR Morb Mortal Wkly Rep (2016) 65:1205–11.10.15585/mmwr.mm6544a2
50
GlintborgBHøjgaardPLund HetlandMSteen KroghNKollerupGJensenJet alImpact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry. Rheumatology (Oxford) (2016) 55:659–68.10.1093/rheumatology/kev392
51
TibuakuuMKamimuraDKianoushSDeFilippisAPAl RifaiMReynoldsLMet alThe association between cigarette smoking and inflammation: the Genetic Epidemiology Network of Arteriopathy (GENOA) study. PLoS One (2017) 12:e0184914.10.1371/journal.pone.0184914
52
PoddubnyyDHaibelHListingJMärker-HermannEZeidlerHBraunJet alCigarette smoking has a dose-dependent impact on progression of structural damage in the spine in patients with axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort (GESPIC). Ann Rheum Dis (2013) 72:1430–2.10.1136/annrheumdis-2012-203148
53
PoddubnyyDHaibelHListingJMärker-HermannEZeidlerHBraunJet alBaseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum (2012) 64:1388–98.10.1002/art.33465
54
ChungHYMachadoPvan der HeijdeDD’AgostinoM-ADougadosM. Smokers in early axial spondyloarthritis have earlier disease onset, more disease activity, inflammation and damage, and poorer function and health-related quality of life: results from the DESIR cohort. Ann Rheum Dis (2012) 71:809–16.10.1136/annrheumdis-2011-200180
55
Hus16.Pdf. (2017). Available at: https://www.cdc.gov/nchs/data/hus/hus16.pdf#055
56
NurmohamedMTHeslingaMKitasGD. Cardiovascular comorbidity in rheumatic diseases. Nat Rev Rheumatol (2015) 11:693–704.10.1038/nrrheum.2015.112
57
MuredduGFBrandimarteFDe LucaL. High-density lipoprotein levels and risk of cardiovascular events: a review. J Cardiovasc Med (Hagerstown) (2012) 13:575–86.10.2459/JCM.0b013e32834bb3c8
58
DivechaHSattarNRumleyACherryLLoweGDOSturrockR. Cardiovascular risk parameters in men with ankylosing spondylitis in comparison with non-inflammatory control subjects: relevance of systemic inflammation. Clin Sci (2005) 109:171–6.10.1042/CS20040326
59
van der ValkFMBernelot MoensSJVerweijSLStrangACNederveenAJVerberneHJet alIncreased arterial wall inflammation in patients with ankylosing spondylitis is reduced by statin therapy. Ann Rheum Dis (2016) 75:1848–51.10.1136/annrheumdis-2016-209176
60
PetersMJvan der Horst-BruinsmaIEDijkmansBANurmohamedMT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum (2004) 34:585–92.10.1016/j.semarthrit.2004.07.010
61
GentileMPelusoRDi MinnoMNDCostaLCasoFde SimoneBet alAssociation between small dense LDL and sub-clinical atherosclerosis in patients with psoriatic arthritis. Clin Rheumatol (2016) 35:2023–9.10.1007/s10067-016-3344-4
62
WibetoeGIkdahlERollefstadSOlsenICBergsmarkKKvienTKet alCardiovascular disease risk profiles in inflammatory joint disease entities. Arthritis Res Ther (2017) 19:153.10.1186/s13075-017-1358-1
63
GkolfinopoulouCStratikosETheofilatosDKardassisDVoulgariPVDrososAAet alImpaired antiatherogenic functions of high-density lipoprotein in patients with ankylosing spondylitis. J Rheumatol (2015) 42:1652–60.10.3899/jrheum.141532
64
MathersCDLoncarD. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med (2006) 3:e442.10.1371/journal.pmed.0030442
65
YusufSHawkenSOunpuuSDansTAvezumALanasFet alEffect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet (2004) 364:937–52.10.1016/S0140-6736(04)17018-9
66
HanCRobinsonDWHackettMVParamoreLCFraemanKHBalaMV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol (2006) 33:2167–72.
67
SolomonDHLoveTJCanningCSchneeweissS. The risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis, and psoriasis. Ann Rheum Dis (2010) 69:2114–7.10.1136/ard.2009.125476
68
GallusSLugoAMurisicBBosettiCBoffettaPLa VecchiaC. Overweight and obesity in 16 European countries. Eur J Nutr (2015) 54:679–89.10.1007/s00394-014-0746-4
69
Adult obesity facts. Overweight & Obesity. CDC (2017). Available at: https://www.cdc.gov/obesity/data/adult.html
70
EckelRHYorkDARössnerSHubbardVCatersonISt JeorSTet alPrevention conference VII: obesity, a worldwide epidemic related to heart disease and stroke: executive summary. Circulation (2004) 110:2968–75.10.1161/01.CIR.0000140086.88453.9A
71
TwigGYanivGLevineHLeibaAGoldbergerNDerazneEet alBody-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N Engl J Med (2016) 374:2430–40.10.1056/NEJMoa1503840
72
WilsonPWFBozemanSRBurtonTMHoaglinDCBen-JosephRPashosCL. Prediction of first events of coronary heart disease and stroke with consideration of adiposity. Circulation (2008) 118:124–30.10.1161/CIRCULATIONAHA.108.772962
73
López-MedinaCJiménez-GómezYMoltóASchiotisREMarzo-OrtegaHvan GaalenFAet alCardiovascular risk factors in patients with spondyloarthritis from Northern European and Mediterranean countries: an ancillary study of the ASAS-COMOSPA project. Joint Bone Spine (2017).10.1016/j.jbspin.2017.07.006
74
Gonzalez-LopezLSanchez-HernandezJDAguilar-ChavezEAGCota-SanchezARLopez-OlivoMAVilla-ManzanoAIet alHyperhomocysteinemia in ankylosing spondylitis: prevalence and association with clinical variables. Rheumatol Int (2008) 28:1223–8.10.1007/s00296-008-0687-4
75
BergIJvan der HeijdeDDagfinrudHSeljeflotIOlsenICKvienTKet alDisease activity in ankylosing spondylitis and associations to markers of vascular pathology and traditional cardiovascular disease risk factors: a cross-sectional study. J Rheumatol (2015) 42:645–53.10.3899/jrheum.141018
76
Rueda-GotorJLlorcaJCorralesABlancoRFuentevillaPPortillaVet alCarotid ultrasound in the cardiovascular risk stratification of patients with ankylosing spondylitis: results of a population-based study. Clin Exp Rheumatol (2016) 34:885–92.
77
Coxib and traditional NSAID Trialists’ (CNT) CollaborationBhalaNEmbersonJMerhiAAbramsonSArberNet alVascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet (2013) 382:769–79.10.1016/S0140-6736(13)60900-9
78
RivièreEEtchetoAden BoschFVder HeijdeDVLandewéRDougadosMet alTHU0350 Effect of nsaid consumption on cardiovascular events in spondyloarthritis. Ann Rheum Dis (2017) 76:336–336.10.1136/annrheumdis-2017-eular.2665
79
BaklandGGranJTNossentJC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis (2011) 70:1921–5.10.1136/ard.2011.151191
80
WeiLMacDonaldTMWalkerBR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med (2004) 141:764–70.10.7326/0003-4819-141-10-200411160-00007
81
AjeganovaSSvenssonBHafströmIBARFOT Study Group. Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial. BMJ Open (2014) 4:e004259.10.1136/bmjopen-2013-004259
82
PalmowskiYButtgereitTDejacoCBijlsmaJWMattesonELVoshaarMet al“Official View” on glucocorticoids in rheumatoid arthritis: a systematic review of international guidelines and consensus statements. Arthritis Care Res (Hoboken) (2017) 69:1134–41.10.1002/acr.23185
83
TamH-WYeoK-JLeongP-YChenC-HLiY-CMaC-Met alSulfasalazine might reduce risk of cardiovascular diseases in patients with ankylosing spondylitis: a nationwide population-based retrospective cohort study. Int J Rheum Dis (2017) 20:363–70.10.1111/1756-185X.12986
84
MacMullanPAMadiganAMPaulNPeaceAJAlaghaANolanKBet alSulfasalazine and its metabolites inhibit platelet function in patients with inflammatory arthritis. Clin Rheumatol (2016) 35:447–55.10.1007/s10067-014-2769-x
85
RoubilleCRicherVStarninoTMcCourtCMcFarlaneAFlemingPet alThe effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis (2015) 74:480–9.10.1136/annrheumdis-2014-206624
86
DeyabGHokstadIWhistJESmastuenMCAgewallSLybergTet alMethotrexate and anti-tumor necrosis factor treatment improves endothelial function in patients with inflammatory arthritis. Arthritis Res Ther (2017) 19:232.10.1186/s13075-017-1439-1
87
van SijlAMvan EijkICPetersMJLSernéEHvan der Horst-BruinsmaIESmuldersYMet alTumour necrosis factor blocking agents and progression of subclinical atherosclerosis in patients with ankylosing spondylitis. Ann Rheum Dis (2015) 74:119–23.10.1136/annrheumdis-2013-203934
88
GenreFLópez-MejíasRMiranda-FilloyJAUbillaBMijaresVCarnero-LópezBet alAnti-TNF-α therapy reduces endothelial cell activation in non-diabetic ankylosing spondylitis patients. Rheumatol Int (2015) 35:2069–78.10.1007/s00296-015-3314-1
89
BrezinskiEAFollansbeeMRArmstrongEJArmstrongAW. Endothelial dysfunction and the effects of TNF inhibitors on the endothelium in psoriasis and psoriatic arthritis: a systematic review. Curr Pharm Des (2014) 20:513–28.10.2174/138161282004140213123852
90
HmamouchiIRouxCPaternotteSKoltaSDougadosMBriotK. Early increase of abdominal adiposity in patients with spondyloarthritis receiving anti-tumor necrosis factor-α treatment. J Rheumatol (2014) 41:1112–7.10.3899/jrheum.131150
91
HeslingaSCPetersMJTer WeeMMvan der Horst-BruinsmaIEvan SijlAMSmuldersYMet alReduction of inflammation drives lipid changes in ankylosing spondylitis. J Rheumatol (2015) 42:1842–5.10.3899/jrheum.150193
92
RungapiromnanWYiuZZNWarrenRBGriffithsCEMAshcroftDM. Impact of biologic therapies on risk of major adverse cardiovascular events in patients with psoriasis: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol (2017) 176:890–901.10.1111/bjd.14964
93
van de KerkhofPCMGriffithsCEMReichKLeonardiCLBlauveltATsaiT-Fet alSecukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol (2016) 75:83–98.e4.10.1016/j.jaad.2016.03.024
94
TzellosTKyrgidisATrigoniAZouboulisCC. Association of ustekinumab and briakinumab with major adverse cardiovascular events: an appraisal of meta-analyses and industry sponsored pooled analyses to date. Dermatoendocrinol (2012) 4:320–3.10.4161/derm.23100
95
AhlehoffOSkovLGislasonGGniadeckiRIversenLBryldLEet alCardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort. J Eur Acad Dermatol Venereol (2015) 29:1128–34.10.1111/jdv.12768
96
HughJVan VoorheesASNijhawanRIBagelJLebwohlMBlauveltAet alFrom the Medical Board of the National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol (2014) 70:168–77.10.1016/j.jaad.2013.09.020
97
HellgrenKBaecklundEBacklinCSundstromCSmedbyKEAsklingJ. Rheumatoid arthritis and risk of malignant lymphoma: is the risk still increased?Arthritis Rheumatol (2017) 69:700–8.10.1002/art.40017
98
HellgrenKSmedbyKEBacklinCSundstromCFelteliusNErikssonJKet alAnkylosing spondylitis, psoriatic arthritis, and risk of malignant lymphoma: a cohort study based on nationwide prospectively recorded data from Sweden. Arthritis Rheumatol (2014) 66:1282–90.10.1002/art.38339
99
AsklingJKlareskogLBlomqvistPForedMFelteliusN. Risk for malignant lymphoma in ankylosing spondylitis: a nationwide Swedish case-control study. Ann Rheum Dis (2006) 65:1184–7.10.1136/ard.2005.047514
100
HellgrenKDreyerLArkemaEVGlintborgBJacobssonLTHKristensenL-Eet alCancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers. Ann Rheum Dis (2017) 76:105–11.10.1136/annrheumdis-2016-209270
101
RohekarSTomBDMHassaASchentagCTFarewellVTGladmanDD. Prevalence of malignancy in psoriatic arthritis. Arthritis Rheum (2008) 58:82–7.10.1002/art.23185
102
SöderlundSGranathFBroströmOKarlénPLöfbergREkbomAet alInflammatory bowel disease confers a lower risk of colorectal cancer to females than to males. Gastroenterology (2010) 138:1697–703.10.1053/j.gastro.2010.02.007
103
FelteliusNEkbomABlomqvistP. Cancer incidence among patients with ankylosing spondylitis in Sweden 1965-95: a population based cohort study. Ann Rheum Dis (2003) 62:1185–8.10.1136/ard.2002.004721
104
DarbySCDollRGillSKSmithPG. Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. Br J Cancer (1987) 55:179–90.10.1038/bjc.1987.35
105
ArchierEDevauxSCastelaEGalliniAAubinFLe MaîtreMet alCarcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol (2012) 26(Suppl 3):22–31.10.1111/j.1468-3083.2012.04520.x
106
RostomADubéCLewinGTsertsvadzeABarrowmanNCodeCet alNonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med (2007) 146:376–89.10.7326/0003-4819-146-5-200703060-00010
107
VeettilSKLimKGChingSMSaokaewSPhisalprapaPChaiyakunaprukN. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMC Cancer (2017) 17:763.10.1186/s12885-017-3757-8
108
DreyerLMellemkjaerLAndersenARBennettPPoulsenUEJuulsgaard EllingsenTet alIncidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides – a follow-up study from the DANBIO Registry. Ann Rheum Dis (2013) 72:79–82.10.1136/annrheumdis-2012-201969
109
WolfeFMichaudK. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum (2007) 56:2886–95.10.1002/art.22864
110
AsklingJvan VollenhovenRFGranathFRaaschouPForedCMBaecklundEet alCancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?Arthritis Rheum (2009) 60:3180–9.10.1002/art.24941
111
GeborekPBladströmATuressonCGulfeAPeterssonIFSaxneTet alTumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis (2005) 64:699–703.10.1136/ard.2004.030528
112
BongartzTSuttonAJSweetingMJBuchanIMattesonELMontoriV. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA (2006) 295:2275–85.10.1001/jama.295.19.2275
113
AsklingJFahrbachKNordstromBRossSSchmidCHSymmonsD. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf (2011) 20:119–30.10.1002/pds.2046
114
RamiroSSeprianoAChatzidionysiouKNamJLSmolenJSvan der HeijdeDet alSafety of synthetic and biological DMARDs: a systematic literature review informing the 2016 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis (2017) 76:1101–36.10.1136/annrheumdis-2016-210708
115
BurmesterGRPanaccioneRGordonKBMcIlraithMJLacerdaAPM. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis (2013) 72:517–24.10.1136/annrheumdis-2011-201244
116
DommaschEDAbuabaraKShinDBNguyenJTroxelABGelfandJM. The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials. J Am Acad Dermatol (2011) 64:1035–50.10.1016/j.jaad.2010.09.734
117
van der HeijdeDZackDWajdulaJSridharanSKoenigAS. Rates of serious infections, opportunistic infections, inflammatory bowel disease, and malignancies in subjects receiving etanercept vs. controls from clinical trials in ankylosing spondylitis: a pooled analysis. Scand J Rheumatol (2014) 43:49–53.10.3109/03009742.2013.834961
118
AtzeniFCarlettoAFotiRSebastianiMPanettaVSalaffiFet alIncidence of cancer in patients with spondyloarthritis treated with anti-TNF drugs. Joint Bone Spine (2017).10.1016/j.jbspin.2017.08.003
119
RaaschouPFrisellTAsklingJARTIS Study Group. TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis (2015) 74:2137–43.10.1136/annrheumdis-2014-205745
120
DreyerLCordtzRLHansenIMJKristensenLEHetlandMLMellemkjaerL. Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis treated with biological DMARDs: a Danish population-based cohort study. Ann Rheum Dis (2017).10.1136/annrheumdis-2017-212086
121
Fouque-AubertAJette-PaulinLCombescureCBaschATebibJGossecL. Serious infections in patients with ankylosing spondylitis with and without TNF blockers: a systematic review and meta-analysis of randomised placebo-controlled trials. Ann Rheum Dis (2010) 69:1756–61.10.1136/ard.2008.098822
122
WallisDThavaneswaranAHaroonNAyearstRInmanRD. Tumour necrosis factor inhibitor therapy and infection risk in axial spondyloarthritis: results from a longitudinal observational cohort. Rheumatology (Oxford) (2015) 54:152–6.10.1093/rheumatology/keu255
123
van AssenSAgmon-LevinNElkayamOCerveraRDoranMFDougadosMet alEULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis (2011) 70:414–22.10.1136/ard.2010.137216
Summary
Keywords
spondyloarthritis, comorbidity, cardiovascular, osteoporosis, infection, cancer
Citation
Moltó A and Nikiphorou E (2018) Comorbidities in Spondyloarthritis. Front. Med. 5:62. doi: 10.3389/fmed.2018.00062
Received
06 December 2017
Accepted
20 February 2018
Published
12 March 2018
Volume
5 - 2018
Edited by
Ying Ying Leung, National University of Singapore, Singapore
Reviewed by
Praveena Chiowchanwisawakit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Thailand; Fawad Aslam, Mayo Clinic Arizona, United States
Updates
Copyright
© 2018 Moltó and Nikiphorou.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Anna Moltó, anna.molto@cch.aphp.fr
Specialty section: This article was submitted to Rheumatology, a section of the journal Frontiers in Medicine
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
