Top

27-02-2017 | Comorbidities | Article

Comorbidities in Spondyloarthritis

Journal: Current Treatment Options in Rheumatology

Authors: Abhijeet Danve, MD FACP FACR, Siba P. Raychaudhuri, MD

Publisher: Springer International Publishing

Abstract

Spondyloarthritides (SpA) are a group of immune-mediated inflammatory diseases that affect the axial and peripheral skeleton as well as the skin, eye, and gut. Patients with SpA are at increased risk of developing certain comorbidities which may have adverse impacts on health outcomes and management of and may be associated with increased health care costs. Rheumatologists should be aware of comorbid conditions associated in order to provide comprehensive care to SpA patients. Common comorbidities include gastroduodenal ulcers, cardiovascular diseases including hypertension, myocardial infarction, and stroke, osteoporosis and vertebral fractures, sleep apnea, and lung disease.

Introduction

The term spondyloarthropathy or spondyloarthritis (SpA) refers to a group of diseases which includes axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), psoriatic arthritis, arthritis associated with inflammatory bowel diseases, and reactive arthritis [1••]. Chronic inflammation involving the axial and peripheral skeleton as well as variable affection of the skin, gut, and eyes are the central features to these diseases. Axial spondyloarthritis (axSpA) is characterized by low back pain from chronic inflammation, which may progress to structural damage to the sacroiliac joints and spine, with or without formation of syndesmophytes and ankyloses. In addition to the joints and extra-articular manifestations, these diseases can be associated with various comorbidities which should be taken into account while managing patients with SpA. In this review, we will focus on comorbidities associated with axial spondyloarthritis, mainly the ankylosing spondylitis as data on comorbidities on non-radiographic axSpA are scant.

What is comorbidity?

“Any distinct additional entity that has existed or may occur during the clinical course of a patient who has the index disease under study” [2]. Comorbidity can have adverse impact on health outcomes, management of index condition, and associated with increased health care costs. Comorbid conditions can either be linked to the disease process, its treatment, or independent important findings. They can contribute to the disease burden, prognosis, morbidity, as well as mortality. Axial spondyloarthritis is associated with various comorbidities. Inflammatory bowel disease, psoriasis, and uveitis are components of various spondyloarthritis, so whether these conditions are part of the disease process or should be considered as comorbidities is debatable. However, as these conditions are very well described in relation to SpA, in this article, we will focus on other common comorbidities of axial SpA such as hypertension, gastroduodenal ulcers, osteoporosis and vertebral fractures, myocardial infarction, stroke, sleep apnea, and lung and renal diseases.

Cardiovascular diseases

Hypertension

Hypertension has been reported to be one of the most prevalent comorbidities in patients with ankylosing spondylitis (AS). In a population-based study involving 11,701 patients with AS in Taiwan, 16.4% of patients had hypertension, and the prevalence was significantly high as compared to 58,505 controls [3•]. Prevalence of hypertension was increased twofold compared to the general population according to the results of a cohort study from Sweden involving 935 patients [4]. In a large international study (ASAS-COMOSPA) involving 3984 axial SpA patients, 33% had hypertension [5•]. Chronic daily intake of NSAIDs may be associated with increased prevalence of hypertension in AS. Young-onset hypertension may contribute to the increased cardiovascular risk in AS.

Dyslipidemia

AS patients can have low high-density lipoprotein (HDL) levels. In a meta-analysis of eight longitudinal studies involving 3279 AS patients and 82,745 controls, AS patients were found to have significantly low levels of HDL, triglyceride, and total cholesterol [6]. A cross-sectional study done by Papadakis et al. revealed increased prevalence of metabolic syndrome (34%) in 60 AS patients as compared to controls (19%); they also confirmed the low HDL in AS compared to controls [7].

Myocardial infarction

The role of inflammation in premature atherosclerosis is well recognized [8••]. Premature inflammatory atherosclerosis as well as conventional risk factors such as hypertension, diabetes, and smoking may contribute towards the increased risk of myocardial infarction among AS patients. Some of the specific contributory factors include decreased physical activity, genetic factors [9], and higher frequency of metabolic syndrome in AS patients [10]. NSAID and Cox-2 inhibitor use has been reported to increase the risk of vascular diseases [11], but a recent study by Haroon et al. showed a protective effect of traditional NSAIDs on vascular mortality in aged 66 or older AS patients and no increased mortality with Cox-2 inhibitor use [12].

Majority of, but not all, studies until now have suggested that patients with AS are at higher risk of developing acute coronary syndrome (ACS) as compared to the general population. In a recent study from Sweden, cardiovascular risk was assessed in 5358 AS patients, 37,245 rheumatoid arthritis (RA) patients, and 25,006 matched general population subjects. They found a 30% increased risk of ACS in AS patients as compared to the general population; the age-/sex-adjusted relative risk for ACS was 1.3 (95% CI = 1.0–1.7) [13]. In a nationwide retrospective study from Taiwan involving 6262 AS patients and 25,048 controls, the overall incidence rate of ACS was higher (4.4 per 1000 person-years) in the AS cohort than in the non-AS cohort (2.9 per 1000 person-years) [14]. Peters et al. reported an overall prevalence for myocardial infarction (MI) of 4.4% in patients with AS and 1.2% in the general population, resulting in an age- and sex-adjusted odds ratio of 3.1 (95% CI = 1.9–5.1) for patients with AS [15]. A meta-analysis of seven longitudinal studies revealed a significant increase in MI in AS patients as compared to controls (OR = 1.6, 95% CI = 1.32–1.93). The incidence of MI was found to be 5.3% (1.6–11%) [16••] (see Fig. 1). The increased risk of MI was highest for younger individuals with AS and similar for both sexes [17] (Fig. 1).

However, there were two studies which reported no increased risk of cardiovascular disease in AS [18, 19]. In the study by Brophy et al., 1686 AS patients were compared to 1,206,621 controls. Age- and gender-adjusted hazard ratios for MI (1.28) and stroke (1.0) were not significantly elevated as compared to the controls despite the higher prevalence of hypertension and diabetes in AS patients [18]. In a recent study by Essers et al. involving 3809 AS patients and 26,197 controls, only a non-significant risk of ischemic heart disease (AMI, coronary artery bypass surgery, and percutaneous coronary intervention) was found in female AS patients after adjustment for age and NSAID use [19].

Stroke

Patients with AS are at 25% higher increased risk of cerebrovascular diseases including ischemic stroke compared to the general population. Risk of cerebrovascular disease tends to be higher in patients aged between 20 and 39 years [17]. In a study involving 4562 AS patients aged 20–39 years, the hazard ratio (HR) for stroke was reported to be 1.93 after controlling for medical and demographic comorbidities [20]. The risk of recurrent stroke was also reported to be 2.3 times higher compared to the control population [21]. AS patients have significantly increased carotid intima media thickness, which correlates with age and disease duration [22]. Cerebrovascular disease in AS is thought to be from accelerated atherosclerosis as well as increased prevalence of traditional risk factors. Studies on the effect of traditional and biologic disease-modifying anti-rheumatic drugs (DMARDs) on stroke risk in patients with AS have yielded conflicting results [23, 24]. In a meta-analysis of three longitudinal studies involving 9791 AS patients, the risk of stroke was higher among AS patients compared to the controls (OR = 1.50, 95% CI = 1.39–1.62). The incidence of stroke in AS patients in ten longitudinal studies was found to be 3.6% (1.5–6.5%) [16••]. However, in the study by Brophy et al., the risk of MI and stroke was not found to be higher in AS patients as compared to controls despite having a higher prevalence of hypertension in the former group [18] (Fig. 2).

Osteoporosis and fractures in AS

It is well known that patients with AS are at increased risk of osteoporosis [25‐27] as well as vertebral fractures [28‐31] even at the early stages of the disease. Osteoporosis in patients with AS is often under-recognized and possibly undertreated [32]. The reported prevalence of osteoporosis in AS ranges from 13 and 25% [26, 33, 34]. Simultaneous presence of new syndesmophytes and bone loss in AS suggest uncoupling of bone formation and resorption [35]. The frequency of osteoporosis among AS patients is greater in patients >50 years of age, and the osteoporosis is associated with elevated CRP levels [33].

Measuring bone density at the spine in AS patients poses a particular challenge of the false high dual-energy X-ray absorptiometry (DXA) readings due to syndesmophyte formation, sclerosis of the vertebral margins, and ligament ossification [36, 37]. Measurement of hip BMD (total hip or femoral neck) may be the more accurate means of detecting osteopenia or osteoporosis. Femoral neck BMD is also reduced in patients with AS, both with early and advanced disease, and correlates with increased risk of vertebral fractures [38, 39]. Lateral lumbar DXA can detect more cases of osteoporosis as compared with traditional anterior–posterior DXA measurement as the presence of syndesmophytes does not influence the lateral measurement [26]. In some cases, quantitative CT may be considered, which can show trabecular bone loss even in the presence of false elevated DXA readings [40]. The ACR-SPARTAN guidelines for axial spondyloarthritis recommend “DXA scanning of the spine as well as the hips, compared to DXA scanning solely of the hip or other non-spine sites. The age and sex of the patient, the patient’s level of physical activity, the duration and severity of AS, and presence or absence of other risk factors for osteoporosis should be considered in deciding when to begin screening and at what interval scans should be done” [41•].

Early recognition of osteoporosis followed by timely and effective treatment, and along with prevention of physical trauma, may reduce the fracture risk in patients with AS. Monitoring for the response is also important [42]. ACR-SPARTAN recommends fall evaluation and counseling of patients with AS to prevent vertebral fractures. The treatment of osteoporosis in patients with AS should follow general guidelines and consensus for the management of osteoporosis, as in any other patient without AS. TNF inhibitors may have favorable effects on the bone density in AS patients [43, 44].

Prevalence of vertebral fractures in AS is variable, ranging from 10 to 40% [45‐47]. The study by Cooper et al. reported an increased odd ratio of 7.7% (95% CI = 4.3–12.6) for clinically significant vertebral fractures in AS as compared to the rate in the general population [48]. The consequences can be severe as patients with AS are 11 times more likely to sustain a spinal cord injury after a vertebral fracture as compared to the general population [49]. The morbidity and mortality associated with vertebral fractures in AS are high, with about 65% of fractures being associated with neurological complications [50].

Hyperextension injury is the most common mechanism of fracture, and the most common site is the lower cervical spine [51]. Underdiagnosis of vertebral fractures is common in AS patients as they have chronic back or neck pain, and any worsened pain is attributed to the disease itself rather than to a fracture. Also, it can be difficult to recognize fracture on plain radiograph in an AS patient with an already abnormal radiograph [52]. Patients with suspected fractures should undergo additional imaging, such as CT and/or MRI, if plain radiographs are inconclusive.

Obstructive sleep apnea

The prevalence of obstructive sleep apnea (OSA) in AS is reported to be higher than that in the general population. According to the study by Kang and Lin, 12 out of 1411 AS patients had OSA (prevalence, 0.85%) as compared to 0.50% in the control population [53]. In a prospective study by Solak et al., 7 (22%) of 31 AS patients had OSA. The prevalence of OSA was higher in patients aged >35 years (40%) compared to those aged <35 years (6%) and also was higher with disease duration >5 years (35%). Sixteen (53%) patients had restrictive patterns on pulmonary function tests. Mean BMI was higher in the OSA group (28.2 ± 6.6) than in the non-OSA group (24.5 ± 4.3), but not statistically significantly different [54•]. AS could predispose subjects to sleep apnea syndrome through several mechanisms, including restriction of the oropharyngeal airway from cervical spine disease and compression of the respiratory center in the medulla from cervical spine involvement, resulting in central depression of respiration or restrictive pulmonary physiology [53, 54•].

On the other hand, OSA seems to be a chronic pro-inflammatory state by virtue of hypoxia-induced release of cytokines. Patients with OSA are at elevated risk of developing autoimmune inflammatory conditions, mainly RA, but also AS and SLE 6[53].

Gastroduodenal ulcers

Gastric and duodenal ulcers represent one of the most common comorbidities associated with AS. Gastrointestinal ulcer was reported in 10.7% (95% CI = 9.7–11.7) among 3984 AS patients in the ASAS-COMOSPA Study [4], which is higher compared to the population-based 1-year prevalence of peptic ulcer disease of 0.12–1.5% among the general population [55]. In a retrospective study by Kang et al., the prevalence of peptic ulcer among 11,701 patients with AS in Taiwan was 13.9%, which was increased as compared to 4.4% in 58,505 general population [2]. The increased prevalence of gastric and duodenal ulcers in AS is possibly related to NSAID use. Prospective cross-sectional endoscopic studies have reported that the prevalence of gastric and duodenal ulcers is 10–25% in patients with chronic arthritis treated with NSAIDs [56].

Depression

Even after adjusting for age, sex, comorbidities, urbanization, and monthly income, AS patients are at 1.7-fold increased risk of developing depression as compared to the general population [57]. In 1993, Barlow et al. reported that about one third of patients with AS experience a high level of depressive symptoms and that women report depression more frequently than men [58]. However, a recent study by Chen et al. reported no increased risk of developing depressive and anxiety disorders among female patients with AS [57]. A study by Meester et al. involving 1738 AS patients and 967,012 controls found an 80% increased rate of doctor-diagnosed depression in women with AS and 50% in men with AS compared to the general population seeking care [59].

In a nationwide population-based study of comorbidity profiles among patients with AS in Taiwan, it was found that patients with AS had a higher OR for mental illness, including depression and psychosis, than the comparison group [2]. Comorbid depression can lead to work disability, unemployment, decreased quality of life, and fatigue symptoms in patients with AS.

Malignancy risk

In a nationwide study using the Swedish National Patient Register involving 8707 patients with AS between 2001 and 2010, 1908 were treated with biologics. For AS patients, the HR of having lymphoma versus the general population was 0.9 (14 lymphomas, 95% CI = 0.5–1.6). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and psoriatic arthritis (PsA) patients, although the numbers of lymphomas were small. The distribution of lymphoma subtypes did not differ substantially between patients with AS or PsA and the general population [60]. In a recent collaborative study from ARTIS (Anti-Rheumatic Therapy in Sweden) and DANBIO (Danish (DANBIO) biologics) registers, TNF inhibitor use was not associated with increased risk of cancer in patients with spondyloarthritis. Also, spondyloarthritis was not associated with increased risk of the six most common cancer types (prostate, colorectal, breast, lymphoma, lung, and melanoma). There was a decreased risk of colorectal cancer in TNFi-naive patients with AS versus the general population [61••].

Infections

In a systematic review and meta-analysis involving 14 randomized controlled studies, the absolute risk of serious infections in AS patients not treated with TNF inhibitors was found to be low. The risk increased with use of TNF inhibitors, but the difference was significant [62]. In a longitudinal observational study involving 440 patients, biologic therapy was not associated with an increased risk of infection, but DMARD use appeared to confer some risk. The apparent lower rate of infection in patients with AS compared to RA was attributed to several factors: the younger age and lower frequency of comorbidities in AS, differing immunogenetic mechanisms, and differences in treatment [63]. This is in contrast to RA where serious infections and adverse events are common; incidence is about 6 per 10 patient-years [64].

Lung disease

Apical fibrosis is a well-recognized pulmonary complication of AS, particularly in patients with longer disease duration. It can be unilateral or bilateral and is associated with cystic changes. In a systematic review, the overall prevalence of apical fibrosis was low at 7%, but increased to 21% with disease duration of more than 10 years [65].

Apart from apical fibrosis, non-specific and incidental abnormalities on imaging, particularly HRCT, have been frequently reported in AS. In a systematic review of ten studies (303 patients), the prevalence of pulmonary abnormalities on chest HRCT of AS patients was 61%. A total of 185 patients (61%) had an abnormal thoracic HRCT: upper lobe fibrosis in 21 (6.9%), emphysema in 55 (18.1%), bronchiectasis in 33 (10.8%), and ground glass attenuation in 34 (11.2%). Non-specific interstitial abnormalities were observed in 101 (33%) patients [66].

Apical bullae may increase the likelihood of spontaneous pneumothorax. The estimated incidence of spontaneous pneumothorax in patients with AS was 0.29%, which is higher than that in the general population [67]. Reduced spinal mobility has been associated with restrictive lung disease [68].

Renal disease

Renal complications do occur in AS, and physicians need to be vigilant for early identification. Important comorbid renal diseases include chronic kidney disease, nephrolithiasis, IgA nephropathy, and amyloidosis. Patients with AS are at increased risk of developing nephrolithiasis. Predictors for nephrolithiasis include previous history of kidney stones, inflammatory bowel disease, high disease activity, and male sex [69].

A previous study had reported that amyloidosis and IgA nephropathy are the most common among the renal diseases associated with AS, accounting for approximately 60 and 30% of all renal complications [70]. Donmez et al. reported a prevalence of rectal or renal biopsy proven amyloidosis of 1.1% in a cohort of 730 AS patients at an academic center in Turkey [71]. A more recent population-based study involving 8616 patients with AS reported that the prevalence rates of renal complications (acute kidney injury, chronic kidney disease, and amyloidosis) were 3.4% of men and 2.1% of women with AS compared with 2.0% of men and 1.6% of women of the general population. Chronic kidney disease and acute kidney injury were the most common complications, while amyloidosis was rare [72]. With the earlier identification and effective treatment of spondyloarthritis, IgA nephropathy as well amyloidosis may not be as common as reported in older studies. Amyloidosis is a late complication and is associated with longer disease duration, old age, and severe disease activity. The outcome for patients with renal amyloidosis is poor and associated with reduced survival. TNF inhibitors have variable efficacy against IgA nephropathy and renal amyloidosis.

Conclusion

With improved awareness, modified classification criteria, and better imaging techniques, the early diagnosis of axSpA is possible. Rheumatologists should be aware of the common comorbidities associated with AS, such as hypertension, gastroduodenal ulcers, osteoporosis, MI, stroke, and sleep apnea. Assessment and management of pertinent comorbidities should become an integral part of the management of axSpA. The management of SpA can be tailored according to the presence of comorbid conditions. An ideal treatment regimen for axial SpA should provide a comprehensive multisystem care similar to the proposed Total Care Program for conditions such as psoriasis and psoriatic arthritis [73••, 74•]. Total care for axial SpA should be a comprehensive treatment program which intends to be inclusive of exemplary care of the musculoskeletal system, including care of the spine, peripheral joints, uveitis, along with other internal organ pathologies and psychosocial issues. Table 1 provides an outline of the total care program for axial SpA.

Table 1

Concept of total care in axial SpA

◘ Complete evaluation: musculoskeletal system, systemic examination, and eye and skin examination
◘ Educating both parents and children in the case of young SpA patients
◘ Exemplary physical therapy/exercise for control of spinal inflammation and pain
◘ Aggressive therapy of inflammatory arthritis: early appropriate use of biologics
◘ Identifying/ preventing/treating	• Comorbidities of axial SpA
	• Comorbidities from therapy (infection/malignancies)
◘ Wellness program: exercise, diet, de-addiction, and relaxation
◘ Building self-esteem: support group and counseling

Thus, the therapeutic paradigm for axial SpA has shifted to a multisystem, multidisciplinary approach involving consultation with various subspecialists (including internal medicine, ophthalmology, endocrinology, cardiology, psychiatry, and dietary/lifestyle modification programs) who may best identify and treat the numerous conditions that may occur in concert with SpA. Failing to address the multiple comorbidities associated with SpA is incomplete management of the disease. It is understandable that a rheumatologist cannot be the primary health care provider. However, it is important for the rheumatologists who are managing SpA patients to work closely with the patients’ primary care providers to identify these potential comorbidities and provide appropriate referrals for eye care, physical therapy, management of metabolic syndrome, and other subspecialists as required by an individual patient for proper comprehensive health care of all axial SpA patients.

Compliance with ethical standards

Conflict of interest

Dr. Abhijeet Danve declares no conflict of interest.

Dr. Siba Raychaudhuri declares no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Source and grants

None.

•• Raychaudhuri SP, Deodhar A. The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun. 2014;48–49:128–33. Provides detailed review of the spectrum of spondyloarthritis, including descriptions of non-radiographic axial spondyloarthritis.CrossRefPubMed

Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis. 1970;23(7):455–68.CrossRefPubMed

• Kang JH, Chen YH, Lin HC. Comorbidity profiles among patients with ankylosing spondylitis: a nationwide population-based study. Ann Rheum Dis. 2010;69(6):1165–8. Here, the authors have studied the prevalence and risk of comorbidities in patients with ankylosing spondylitis compared with the general population.CrossRefPubMed

Bremander A, Petersson IF, Bergman S, Englund M. Population-based estimates of common comorbidities and cardiovascular disease in ankylosing spondylitis. Arthritis Care Res (Hoboken). 2011;63(4):550–6.CrossRef

• Molto A, Etcheto A, van der Heijde D, et al. Prevalence of comorbidities and evaluation of their screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA Study. Ann Rheum Dis. 2016;75(6):1016–23. This study informs about comorbidities in axSpA across multiple countries in different human races.CrossRefPubMed

Mathieu S, Gossec L, Dougados M, Soubrier M. Cardiovascular profile in ankylosing spondylitis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2011;63(4):557–63.CrossRef

Papadakis JA, Sidiropoulos PI, Karvounaris SA, et al. High 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(2):292–8.PubMed

•• Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol. 2006;2(2):99–106. Here, the authors have reviewed how autoimmune factors such as autoreactive lymphocytes or autoantibodies contribute to atherosclerosis in autoimmune rheumatic conditions.CrossRefPubMed

Bergfeldt L. HLA-B27-associated cardiac disease. Ann Intern Med. 1997;127(8 Pt 1):621–9.CrossRefPubMed

10.

Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum. 2004;34(3):585–92.CrossRefPubMed

11.

Coxib and Traditional NSAID Trialists’ (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–79.CrossRef

12.

Haroon NN, Paterson JM, Li P, Inman RD, Haroon N. Patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med. 2015;163(6):409–16.CrossRefPubMed

13.

Eriksson JK, Jacobsson L, Bengtsson K, Askling J. Is ankylosing spondylitis a risk factor for cardiovascular disease, and how do these risks compare with those in rheumatoid arthritis? Ann Rheum Dis. 2016. doi:10.1136/annrheumdis-2016-209315.PubMed

14.

Chou CH, Lin MC, Peng CL, et al. A nationwide population-based retrospective cohort study: increased risk of acute coronary syndrome in patients with ankylosing spondylitis. Scand J Rheumatol. 2014;43(2):132–6.CrossRefPubMed

15.

Peters MJ, Visman I, Nielen MM, et al. Ankylosing spondylitis: a risk factor for myocardial infarction? Ann Rheum Dis. 2010;69(3):579–81.CrossRefPubMed

16.

•• Mathieu S, Pereira B, Soubrier M. Cardiovascular events in ankylosing spondylitis: an updated meta-analysis. Semin Arthritis Rheum. 2015;44(5):551–5. Excellent meta-analysis about risk of stroke and MI in AS.CrossRefPubMed

17.

Szabo SM, Levy AR, Rao SR, et al. Increased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study. Arthritis Rheum. 2011;63(11):3294–304.CrossRefPubMed

18.

Brophy S, Cooksey R, Atkinson M, et al. No increased rate of acute myocardial infarction or stroke among patients with ankylosing spondylitis—a retrospective cohort study using routine data. Semin Arthritis Rheum. 2012;42(2):140–5.CrossRefPubMed

19.

Essers I, Stolwijk C, Boonen A, et al. Ankylosing spondylitis and risk of ischaemic heart disease: a population-based cohort study. Ann Rheum Dis. 2016;75(1):203–9.CrossRefPubMed

20.

Lin CW, Huang YP, Chiu YH, Ho YT, Pan SL. Increased risk of ischemic stroke in young patients with ankylosing spondylitis: a population-based longitudinal follow-up study. PLoS One. 2014;9(4):e94027.CrossRefPubMedPubMedCentral

21.

Keller JJ, Hsu JL, Lin SM, et al. Increased risk of stroke among patients with ankylosing spondylitis: a population-based matched-cohort study. Rheumatol Int. 2014;34(2):255–63.CrossRefPubMed

22.

Gupta N, Saigal R, Goyal L, Agrawal A, Bhargava R, Agrawal A. Carotid intima media thickness as a marker of atherosclerosis in ankylosing spondylitis. Int J Rheumatol. 2014;2014:839135.CrossRefPubMedPubMedCentral

23.

Ersozlu Bozkirli ED, Bozkirli E, Yucel AE. Effects of infliximab treatment in terms of cardiovascular risk and insulin resistance in ankylosing spondylitis patients. Mod Rheumatol. 2014;24(2):335–9.CrossRefPubMed

24.

Wasko MC, Hsia EC, Kirkham B, et al. Effect of golimumab on carotid atherosclerotic disease measures and cardiovascular events in inflammatory arthritides. J Clin Rheumatol. 2014;20(1):1–10.CrossRefPubMed

25.

Calin A. Osteoporosis and ankylosing spondylitis. Br J Rheumatol. 1991;30(4):318–9.

26.

Klingberg E, Lorentzon M, Mellstrom D, et al. Osteoporosis in ankylosing spondylitis—prevalence, risk factors and methods of assessment. Arthritis Res Ther. 2012;14(3):R108.CrossRefPubMedPubMedCentral

27.

Reid DM, Nicoll JJ, Kennedy NS, Smith MA, Tothill P, Nuki G. Bone mass in ankylosing spondylitis. J Rheumatol. 1986;13(5):932–5.PubMed

28.

Ghozlani I, Ghazi M, Nouijai A, et al. Prevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. Bone. 2009;44(5):772–6.CrossRefPubMed

29.

Klingberg E, Geijer M, Gothlin J, et al. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol. 2012;39(10):1987–95.CrossRefPubMed

30.

Montala N, Juanola X, Collantes E, et al. Prevalence of vertebral fractures by semiautomated morphometry in patients with ankylosing spondylitis. J Rheumatol. 2011;38(5):893–7.CrossRefPubMed

31.

Vosse D, Landewe R, van der Heijde D, van der Linden S, van Staa TP, Geusens P. Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case–control study. Ann Rheum Dis. 2009;68(12):1839–42.CrossRefPubMed

32.

Bessant R, Harris C, Keat A. Audit of the diagnosis, assessment, and treatment of osteoporosis in patients with ankylosing spondylitis. J Rheumatol. 2003;30(4):779–82.PubMed

33.

Magrey MN, Lewis S, Asim KM. Utility of DXA scanning and risk factors for osteoporosis in ankylosing spondylitis—a prospective study. Semin Arthritis Rheum. 2016;46(1):88–94.CrossRefPubMed

34.

van der Weijden MA, Claushuis TA, Nazari T, Lems WF, Dijkmans BA, van der Horst-Bruinsma IE. High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol. 2012;31(11):1529–35.CrossRefPubMedPubMedCentral

35.

Carter S, Lories RJ. Osteoporosis: a paradox in ankylosing spondylitis. Curr Osteoporos Rep. 2011;9(3):112–5.CrossRefPubMed

36.

Capaci K, Hepguler S, Argin M, Tas I. Bone mineral density in mild and advanced ankylosing spondylitis. Yonsei Med J. 2003;44(3):379–84.CrossRefPubMed

37.

Devogelaer JP, Maldague B, Malghem J, Nagant de Deuxchaisnes C. Appendicular and vertebral bone mass in ankylosing spondylitis. A comparison of plain radiographs with single- and dual-photon absorptiometry and with quantitative computed tomography. Arthritis Rheum. 1992;35(9):1062–7.CrossRefPubMed

38.

Gratacos J, Collado A, Pons F, et al. Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum. 1999;42(11):2319–24.CrossRefPubMed

39.

Jun JB, Joo KB, Her MY, et al. Femoral bone mineral density is associated with vertebral fractures in patients with ankylosing spondylitis: a cross-sectional study. J Rheumatol. 2006;33(8):1637–41.PubMed

40.

Korkosz M, Gasowski J, Grzanka P, et al. Baseline new bone formation does not predict bone loss in ankylosing spondylitis as assessed by quantitative computed tomography (QCT): 10-year follow-up. BMC Musculoskelet Disord. 2011;12:121.

41.

• Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282–98. Recommendations from ACR-SPARTAN-SAA to guide about management of comorbidities.CrossRefPubMed

42.

Davey-Ranasinghe N, Deodhar A. Osteoporosis and vertebral fractures in ankylosing spondylitis. Curr Opin Rheumatol. 2013;25(4):509–16. This study reviews the risks and underlying causes of osteoporosis and fractures in AS.CrossRefPubMed

43.

Siu S, Haraoui B, Bissonnette R, et al. Meta-analysis of tumor necrosis factor inhibitors and glucocorticoids on bone density in rheumatoid arthritis and ankylosing spondylitis trials. Arthritis Care Res (Hoboken). 2015;67(6):754–64.CrossRef

44.

Visvanathan S, van der Heijde D, Deodhar A, et al. Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(2):175–82.CrossRefPubMed

45.

Kang KY, Kim IJ, Jung SM, et al. Incidence and predictors of morphometric vertebral fractures in patients with ankylosing spondylitis. Arthritis Res Ther. 2014;16(3):R124.CrossRefPubMedPubMedCentral

46.

Maas F, Spoorenberg A, van der Slik BP, et al. Clinical risk factors for the presence and development of vertebral fractures in patients with ankylosing spondylitis. Arthritis Care Res (Hoboken). 2016. doi:10.1002/acr.22980.

47.

Sivri A, Kilinc S, Gokce-Kutsal Y, Ariyurek M. Bone mineral density in ankylosing spondylitis. Clin Rheumatol. 1996;15(1):51–4.CrossRefPubMed

48.

Cooper C, Carbone L, Michet CJ, Atkinson EJ, O’Fallon WM, Melton 3rd LJ. Fracture risk in patients with ankylosing spondylitis: a population based study. J Rheumatol. 1994;21(10):1877–82.PubMed

49.

Einsiedel T, Schmelz A, Arand M, et al. Injuries of the cervical spine in patients with ankylosing spondylitis: experience at two trauma centers. J Neurosurg Spine. 2006;5(1):33–45.CrossRefPubMed

50.

Thumbikat P, Hariharan RP, Ravichandran G, McClelland MR, Mathew KM. Spinal cord injury in patients with ankylosing spondylitis: a 10-year review. Spine (Phila Pa 1976). 2007;32(26):2989–95.CrossRef

51.

Westerveld LA, Verlaan JJ, Oner FC. Spinal fractures in patients with ankylosing spinal disorders: a systematic review of the literature on treatment, neurological status and complications. Eur Spine J. 2009;18(2):145–56.CrossRefPubMed

52.

Sambrook PN, Geusens P. The epidemiology of osteoporosis and fractures in ankylosing spondylitis. Ther Adv Musculoskelet Dis. 2012;4(4):287–92.CrossRefPubMedPubMedCentral

53.

Kang JH, Lin HC. Obstructive sleep apnea and the risk of autoimmune diseases: a longitudinal population-based study. Sleep Med. 2012;13(6):583–8.CrossRefPubMed

54.

• Solak O, Fidan F, Dundar U, et al. The prevalence of obstructive sleep apnea syndrome in ankylosing spondylitis patients. Rheumatology (Oxford). 2009;48(4):433–5. An informative study about the association of sleep apnea with AS.CrossRef

55.

Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic ulcer disease. Aliment Pharmacol Ther. 2009;29(9):938–46.CrossRefPubMed

56.

Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999;340(24):1888–99.CrossRefPubMed

57.

Shen CC, Hu LY, Yang AC, Kuo BI, Chiang YY, Tsai SJ. Risk of psychiatric disorders following ankylosing spondylitis: a nationwide population-based retrospective cohort study. J Rheumatol. 2016;43(3):625–31.CrossRefPubMed

58.

Barlow JH, Macey SJ, Struthers GR. Gender, depression, and ankylosing spondylitis. Arthritis Care Res. 1993;6(1):45–51.CrossRefPubMed

59.

Meesters JJ, Bremander A, Bergman S, Petersson IF, Turkiewicz A, Englund M. The risk for depression in patients with ankylosing spondylitis: a population-based cohort study. Arthritis Res Ther. 2014;16(5):418.CrossRefPubMedPubMedCentral

60.

Hellgren K, Smedby KE, Backlin C, et al. Ankylosing spondylitis, psoriatic arthritis, and risk of malignant lymphoma: a cohort study based on nationwide prospectively recorded data from Sweden. Arthritis Rheumatol. 2014;66(5):1282–90.CrossRefPubMed

61.

•• Hellgren K, Dreyer L, Arkema EV, et al. Cancer 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. Excellent study about malignancy risk in AS.

62.

Fouque-Aubert A, Jette-Paulin L, Combescure C, Basch A, Tebib J, Gossec L. 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(10):1756–61.CrossRefPubMed

63.

Wallis D, Thavaneswaran A, Haroon N, Ayearst R, Inman R. Infection risk in ankylosing spondylitis: results from a longitudinal observational cohort. Arthritis Rheum. 2013;65:1507.

64.

Listing J, Strangfeld A, Kary S, et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum. 2005;52(11):3403–12.CrossRefPubMed

65.

Kanathur N, Lee-Chiong T. Pulmonary manifestations of ankylosing spondylitis. Clin Chest Med. 2010;31(3):547–54.CrossRefPubMed

66.

El Maghraoui A, Dehhaoui M. Prevalence and characteristics of lung involvement on high resolution computed tomography in patients with ankylosing spondylitis: a systematic review. Pulm Med. 2012;2012:965956.CrossRefPubMedPubMedCentral

67.

Lee CC, Lee SH, Chang IJ, et al. Spontaneous pneumothorax associated with ankylosing spondylitis. Rheumatology (Oxford). 2005;44(12):1538–41.CrossRef

68.

Berdal G, Halvorsen S, van der Heijde D, Mowe M, Dagfinrud H. Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: a comparative study. Arthritis Res Ther. 2012;14(1):R19.CrossRefPubMedPubMedCentral

69.

Jakobsen AK, Jacobsson LT, Patschan O, Askling J, Kristensen LE. Is nephrolithiasis an unrecognized extra-articular manifestation in ankylosing spondylitis? A prospective population-based Swedish national cohort study with matched general population comparator subjects. PLoS One. 2014;9(11):e113602.CrossRefPubMedPubMedCentral

70.

Strobel ES, Fritschka E. Renal diseases in ankylosing spondylitis: review of the literature illustrated by case reports. Clin Rheumatol. 1998;17(6):524–30.CrossRefPubMed

71.

Donmez S, Pamuk ON, Pamuk GE, Aydogdu E, Inman R. Secondary amyloidosis in ankylosing spondylitis. Rheumatol Int. 2013;33(7):1725–9.CrossRefPubMed

72.

Levy AR, Szabo SM, Rao SR, Cifaldi M, Maksymowych WP. Estimating the occurrence of renal complications among persons with ankylosing spondylitis. Arthritis Care Res (Hoboken). 2014;66(3):440–5.CrossRef

73.

•• Farber EM, Raychaudhuri SP. Concept of total care: a third dimension in the treatment of psoriasis. Cutis. 1997;59:35–9. Here, the authors have provided their original idea about the concept of total care for chronic inflammatory diseases, keeping psoriasis as the disease model.PubMed

74.

• Raychaudhuri SP. Comorbidities of psoriatic arthritis—metabolic syndrome and prevention: a report from the GRAPPA 2010 annual meeting. J Rheumatol. 2012;39:437–40. This article provides the concept of total care for the treatment of comorbidities in psoriatic arthritis by rheumatologists in their day-to-day practice.