The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients It is well established that several inflammatory-type conditions , such as arthritis , diabetes , cardiovascular disease , and irritable bowel disease exist comorbidly and at an increased incidence in patients with psoriasis . Psoriasis and other associated diseases are thought to share common inflammatory pathways . Conditions such as these , with similar pathogenic mechanisms involving cytokine dysregulation , are referred to as immune-mediated inflammatory diseases -LRB- IMIDs -RRB- . Considerable evidence for the genetic basis of cormobidities in psoriasis exists . The WHO has reported that the occurrence of chronic diseases , including IMIDs , are a rising global burden . In addition , conditions linked with psoriasis have been associated with increasing rates of considerable morbidity and mortality . The presence of comorbid conditions in psoriasis patients has important implications for clinical management . QoL , direct health care expenditures and pharmacokinetics of concomitant therapies are impacted by the presence of comorbid conditions . For example , methotrexate is contraindicated in hepatic impairment , while patients on ciclosporin should be monitored for kidney function . In addition , some agents , such as beta blockers , lithium , synthetic antimalarial drugs , NSAIDs and tetracycline antibiotics , have been implicated in the initiation or exacerbation of psoriasis . Consequently , collaboration between physicians in different specialties is essential to ensuring that psoriasis treatment benefits the patient without exacerbating associated conditions . Psoriasis : from gene to clinic A satellite symposium held at the Royal College of Physicians , London , United Kingdom , in December 2005 investigated the associations between psoriasis , comorbid diseases and concomitant therapy and their significance for long-term patient treatment . The programme generated substantial debate and raised some clinically significant issues , which are further outlined here . Introduction Psoriasis is a common , chronic , immune-mediated inflammatory disease with a recognised genetic predisposition . It has been observed that , while the frequency of skin conditions such as acne , urticaria and atopic dermatitis are reduced in patients with psoriasis compared with expected frequencies in the general population , the frequency of some noncutaneous , although related , conditions is significantly increased -LSB- 26 , 53 -RSB- . Perhaps the best known noncutaneous condition associated with psoriasis is joint disease , mostly expressed as psoriatic arthritis -LRB- PsA -RRB- . In hospitalised psoriasis patients , a diagnosis of PsA -LSB- according to the European Spondyloarthropathy Study Group -LRB- ESSG -RRB- criteria -RSB- was present in 7.7 % -LRB- 71/936 -RRB- of patients ; however , many more patients also reported paresthesias -LRB- 12.3 % -RRB- , arthralgia -LRB- 7 % -RRB- , stiffness -LRB- 4.2 % -RRB- , swelling -LRB- 3.7 % -RRB- and ankylosis -LRB- 1.2 % -RRB- without meeting all of the ESSG criteria for PsA -LSB- 19 -RSB- . Further estimates place the occurrence of PsA in patients with psoriasis at upwards of 30 % -LSB- 31 -RSB- . An additional study by Zachariae et al. -LSB- 83 -RSB- established even higher rates for psoriasis with joint involvement in 5,795 members of psoriasis associations from the Nordic countries and 702 patients seen by Nordic dermatologists . The result showed that upwards of 30 % of all patients who presented with psoriasis were also diagnosed with arthritis by their dermatologist or a rheumatologist . In a recent study in a geographically defined population in Norway Madland et al. -LSB- 41 -RSB- found a prevalence of PsA in 2 per 1,000 inhabitants , which corresponds to about 10 % in patients with psoriasis assuming a prevalence of psoriasis of 2 % . These results demonstrate that the prevalence of arthritis in patients with psoriasis may actually be higher than the previously accepted rate of 7 % -LSB- 83 -RSB- . Inflammatory bowel disease is also more frequently observed in patients with psoriasis . An increased relative risk for Crohn 's disease -LRB- CD -RRB- of 2.9 was found to be associated with a prior diagnosis of psoriasis in a Swedish case-control study -LSB- 54 -RSB- . Conversely , patients with CD are about seven times more likely to develop psoriasis than controls -LSB- 5 , 37 , 82 -RSB- . Analysis of data from more than 40,000 dermatological inpatients with psoriasis compared with control patients with nonpsoriatic skin diseases -LRB- adjusting for age and gender -RRB- revealed high ratios of observed versus expected frequencies for obesity -LRB- 2.05 , P < 0.05 -RRB- , hypertension -LRB- 1.90 , P < 0.01 -RRB- , heart failure -LRB- 1.83 , P < 0.001 -RRB- and diabetes mellitus -LRB- 1.47 , P < 0.05 -RRB- -LSB- 26 -RSB- . An additional analysis -LRB- retrospective chart review , 1997 -- 2000 -RRB- of 753 patients from an academic dermatology practice also confirms the presence of comorbidities in patients with psoriasis -LSB- 53 -RSB- . In fact , a comorbid diagnosis was confirmed in 551 patients -LRB- 73 % -RRB- , with hypertension , dyslipidemia , diabetes and heart disease being the most common comorbidities identified -LSB- 53 -RSB- . Furthermore , patients with psoriasis appear to be at increased risk of atherosclerosis , which may at least in part be explained by an abnormal plasma lipid metabolism ; serum lipoprotein -LRB- a -RRB- and triglycerides are significantly increased in patients with psoriasis compared with healthy control subjects -LSB- 73 -RSB- , while high-density lipoprotein -LRB- HDL -RRB- cholesterol is significantly decreased -LSB- 60 -RSB- . Indeed , in patients with PsA , alterations of the lipid profile suggest similarities to the diabetic lipid profile , which is known to substantially increase cardiovascular risk -LSB- 30 -RSB- . Nearly 30 years ago it was reported that the rates of occlusive vascular disease were significantly higher in dermatological patients with psoriasis than those without and that the risk was greater in patients with predisposing factors -LSB- 44 -RSB- . Metabolic syndrome has since been identified as a clustering of metabolic abnormalities in individuals and is associated with a threefold increase in type 2 diabetes and a twofold increase in cardiovascular disease -LSB- 86 -RSB- . The most recent definition of metabolic syndrome requires central obesity -LRB- defined as body mass index > 30 kg/m2 -RRB- plus any two of the following : elevated plasma triglycerides , reduced HDL cholesterol , elevated blood pressure and raised fasting plasma glucose -LRB- Table 1 -RRB- . Such clustering of risk factors has been observed in patients with psoriasis -LSB- 26 -RSB- . Table 1Diseases associated with psoriasis -LSB- 65 -RSB- ConditionPrevalence in psoriasis n -LRB- % -RRB- Hospital controls OR -LRB- 95 % CI -RRB- RKI sample OR -LRB- 95 % CI -RRB- Diabetes mellitus type I11 -LRB- 1.9 -RRB- 3.99 -LRB- 1.30 -- 12.2 -RRB- * 6.34 -LRB- 2.80 -- 14.3 -RRB- *** Diabetes mellitus type II68 -LRB- 11.7 -RRB- 2.48 -LRB- 1.70 -- 3.61 -RRB- ** 2.07 -LRB- 1.50 -- 2.85 -RRB- *** Arterial hypertension127 -LRB- 21.9 -RRB- 3.27 -LRB- 2.41 -- 4.43 -RRB- *** 1.39 -LRB- 1.09 -- 1.77 -RRB- * Hyperlipoproteinemia30 -LRB- 5.2 -RRB- 2.09 -LRB- 1.23 -- 3.54 -RRB- ** 0.83 -LRB- 0.54 -- 1.28 -RRB- fCoronary heart disease32 -LRB- 5.5 -RRB- 1.77 -LRB- 1.07 -- 2.93 -RRB- * 0.93 -LRB- 0.60 -- 1.43 -RRB- fMetabolic syndrome25 -LRB- 4.3 -RRB- 5.92 -LRB- 2.78 -- 12.8 -RRB- *** 2.20 -LRB- 1.41 -- 3.43 -RRB- ** Alcohol consumption none vs. moderate246 -LRB- 42.3 -RRB- 2.78 -LRB- 2.14 -- 3.62 -RRB- *** 2.03 -LRB- 1.62 -- 2.55 -RRB- *** None vs. regularly75 -LRB- 12.9 -RRB- 3.33 -LRB- 2.20 -- 5.05 -RRB- *** 2.00 -LRB- 1.45 -- 2.77 -RRB- *** None vs. heavya24 -LRB- 4.1 -RRB- 3.61 -LRB- 1.85 -- 7.07 -RRB- *** 8.50 -LRB- 5.28 -- 16.8 -RRB- *** Cigarette smoking264 -LRB- 45.4 -RRB- 2.96 -LRB- 2.27 -- 3.84 -RRB- *** 2.49 -LRB- 2.00 -- 3.10 -RRB- *** The prevalence of diseases in plaque-type psoriasis patients -LRB- n = 581 -RRB- was compared with hospital-based controls -LRB- n = 1,044 -RRB- and a population-based survey -LRB- RKI sample ; n = 4,705 -RRB- . Common odds ratios adjusted for age and sex are presented with their 95 % confidence intervals -LRB- 95 % CI -RRB- , f not significantaDue to low numbers , only adjusted for sex * P < 0.05 ; ** P < 0.01 ; *** P < 0.0001 by Mantel -- Haenszel test Psoriasis , especially in patients with more severe disease , has also been associated with other factors that can increase cardiovascular risk , thereby increasing morbidity and mortality . Alcoholism and liver cirrhosis are reportedly more common in psoriasis -LSB- 39 -RSB- with a reported prevalence of alcoholism of 18 % among psoriatic patients compared with 2 % in other dermatologic controls -LSB- 22 , 46 -RSB- . Cigarette smoking has also been associated with psoriasis . A recent case-control study revealed that the risk of psoriasis was higher in ex-smokers and current smokers than in those who never smoked -LRB- odds ratios of 1.9 and 1.7 , respectively -RRB- , and smoking was strongly associated with the occurrence of pustular lesions -LRB- odds ratio = 5.3 for smokers -RRB- -LSB- 48 -RSB- . In a cross-sectional study , patients with psoriasis that enrolled in the prospective Utah Psoriasis Initiative had a significantly higher prevalence of obesity and smoking than the general population of Utah -LRB- P < 0.001 for both -RRB- . The prevalence of obese smokers was significantly higher -LRB- P < 0.001 -RRB- -LSB- 27 -RSB- . A number of psychiatric/psychological comorbidities have also been observed in patients with psoriasis -LSB- 22 -RSB- . An association between psoriasis and stressful life events in the year preceding diagnosis has been reported , suggesting that psychological stress may have a role in the pathogenesis of psoriasis -LSB- 48 -RSB- . Furthermore , psoriasis-related stress can play a role in the exacerbation of psoriasis , and greater stress reactivity has been associated with onset of psoriasis at an earlier age -LSB- 22 -RSB- . High depression/anxiety scores , obsessionality and difficulties with verbal expression of emotions -LRB- especially anger -RRB- have been reported in various cross-sectional surveys -LSB- 22 -RSB- . Severely affected psoriatic inpatients -LRB- > 30 % body surface area affected -RRB- were likely to suffer clinical depression and suicidal ideation -LRB- 7.2 % -RRB- ; however , suicidal ideation was still relatively high -LRB- 2.5 % -RRB- in less severely affected outpatients -LRB- < 30 % total body surface area affected -RRB- and comparable to the reported prevalence among general medical patients -LRB- 2.4 -- 3.3 % -RRB- -LSB- 21 -RSB- . These identified diseases associated with psoriasis have led clinicians to look at underlying mechanisms that might be involved and start considering how managing comorbid conditions may impact treatment selection and outcome for the psoriasis patient . Common inflammatory pathways in psoriasis and associated diseases The immune system has been strongly implicated in the pathogenesis of psoriasis that resembles a T cell-mediated , autoimmune , inflammatory disease -LSB- 7 -RSB- . T cells are found in the dermis and epidermis and are accompanied by increased numbers of dermal dendritic cells , macrophages and mast cells -LSB- 51 -RSB- . It is thought that a stimulus -LRB- such as trauma or infection -RRB- triggers a plexus of cellular events by inciting a cascade of cytokines , creating an inflammatory response . Dendritic cells and T cells become activated with the formation of an immunological synapse -- a multimolecular complex at the T cell-antigen-presenting cell interface that facilitates immune cell interactions . Once activated , dendritic antigen-presenting cells and T cells release cytokines , chemokines and growth factors , which trigger keratinocyte proliferation , altered differentiation and an angiogenic tissue response , giving rise to psoriatic lesions -LRB- Fig. 1 -RRB- . Fig. 1Inflammatory pathway in psoriasis -LSB- 50 -RSB- . Working model for immunopathogenesis of psoriasis . Multiple stages are proposed for trafficking patterns of immunocytes , involving signals in which symptomless skin is converted into a psoriatic plaque . Key inflammatory events include intraepidermal trafficking by CD8 + T cells and neutrophils . Reproduced with permission from J Clin Invest -LRB- 2004 , 113:1664 -- 1675 -RRB- . Copyright 2004 , The American Society for Clinical Investigation Other inflammatory diseases , such as rheumatoid arthritis -LRB- RA -RRB- and CD , are thought to involve similar pathogenetic mechanisms . Recent research has shown that inflammation plays a key role in atherosclerosis -LSB- 24 -RSB- . A T-cell infiltrate is always present in atherosclerotic lesions , with activated T cells producing a type 1 helper -LRB- Th1 -RRB- response . Psoriasis is up to seven times more common in patients with CD than in controls -LSB- 37 , 82 -RSB- and , as discussed previously , there is often joint involvement in psoriasis . Such extracutaneous manifestations of the disease substantiate that psoriasis is a systemic disease and not just a skin disease -LSB- 14 -RSB- . The term immune-mediated inflammatory disease -LRB- I.M.I.D. -RRB- has been developed to describe conditions , such as psoriasis , CD and RA , with common inflammatory mechanisms described above involving cytokine dysregulation . This term also encompasses type 1 diabetes mellitus , ulcerative colitis , systemic lupus erythematosus , multiple sclerosis , ankylosing spondylitis and uveitis and may further be expanded to include asthma and atherosclerosis -LSB- 79 -RSB- . Atherosclerosis and rheumatoid arthritis The prevalence of coronary artery atherosclerosis has been found to be increased in patients with chronic inflammatory conditions , such as RA and systemic lupus erythematosus -LSB- 3 , 10 -RSB- . Excess mortality due to coronary heart disease in RA patients was first observed in 1953 -LSB- 11 -RSB- . In a study of 236 RA patients , the age - and sex-adjusted incidence rate ratio of incident cardiovascular events was calculated to be 3.96 -LSB- 16 -RSB- . After adjusting for cardiovascular risk factors such as age , weight and smoking status , this figure decreased slightly to 3.17 , suggesting that there are additional mechanisms responsible for cardiovascular disease in RA . The risk of cardiovascular disease increases with disease severity -LRB- eg , number of joints involved -RRB- and disease duration -LSB- 64 , 75 -RSB- : severe coronary artery calcification is more likely in patients with established disease -LRB- > 10 years -RRB- compared with controls after adjusting for cardiovascular risk factors -LRB- odds ratio = 3.42 , P = 0.002 -RRB- -LSB- 10 -RSB- . However , there is some emerging evidence for increased atherosclerotic disease in early RA -LSB- 32 -RSB- . The lipid profile in RA patients is directly affected by the systemic inflammatory response -LRB- active inflammation lowers HDL cholesterol , which leads to increased cardiovascular risk -RRB- -LSB- 75 -RSB- . Endothelial dysfunction , which underlies atherosclerotic plaque development , is associated with markers of systemic inflammation , such as C-reactive protein -LRB- CRP -RRB- , soluble adhesion molecules -LRB- sICAM-1 and sE-selectin -RRB- , IL-6 and TNF-alpha -LRB- TNFα -RRB- -LSB- 24 , 38 , 78 -RSB- . Indeed , treatment with the anti-TNFα agent infliximab , which affects expression of all markers described above , has been shown to improve endothelial function in RA patients -LSB- 28 -RSB- . Atherosclerosis and psoriasis An increase in cardiovascular disease has been observed in psoriasis patients -LSB- 39 , 44 -RSB- and has been shown to be related to disease severity and age of onset -LSB- 42 , 55 , 62 -RSB- . An increased incidence of traditional cardiovascular risk factors is frequently reported -LSB- 26 , 42 , 56 -RSB- . In psoriatic patients with a history of at least one hospital admission due to psoriasis , there is about a 50 % increase in cardiovascular death as compared with the general population -LSB- standardised mortality ratio -LRB- SMR -RRB- = 1.52 -RSB- . In those patients with 3 or more hospital admissions , the SMR increased to 1.82 and in those patients admitted at younger ages -LRB- 20 -- 39 years at first admission -RRB- , the SMR increased to 2.62 -LSB- 42 -RSB- . However , the SMR was not increased in those treated as outpatients only , indicating a relationship to disease severity . In patients with PsA , an increase in mortality has also been observed -LRB- SMR = 1.65 in males and 1.59 in females -RRB- and the largest single cause of death is myocardial infarction -LRB- 27.6 % -RRB- -LSB- 80 -RSB- . The increased cardiovascular risk in psoriasis may result from • The increased prevalence of associated risk factors , such as smoking , obesity , hypertension and alcohol misuse . • The use of dyslipidaemic therapies , such as corticosteroids , acitretin and ciclosporin . • An associated unfavourable lipid profile -LRB- high triglycerides , low HDL -RRB- . • Endothelial dysfunction . • Uncontrolled inflammation . • Combination of some or all of the above . Unfortunately , there is a shortage of published studies corrected for traditional risk factors and no published study has formally assessed systemic vasculature inflammation in psoriasis . Both psoriasis and atherosclerosis are T cell-mediated inflammatory conditions and a number of similarities exist between their pathogenetic mechanisms . Numerous factors have been shown to be increased in the serum of psoriatic patients including apolipoprotein E -LRB- ApoE -RRB- , vascular endothelial growth factor -LRB- VEGF -RRB- , sICAM-1 , IL-8 , soluble interleukin2 receptor -LRB- sIL-2R -RRB- and TNFα -LSB- 9 , 12 , 14 , 15 -RSB- . sICAM-1 and sIL-2R are soluble T-cell products -LSB- 15 -RSB- . ApoE plays a central role in lipoprotein metabolism and has been found to be significantly raised in patients with psoriasis , indicating that abnormal metabolism of lipoprotein exists in psoriasis patients -LSB- 81 -RSB- . Furthermore , the dyslipidaemic profile exhibited in psoriasis has been shown to modify dendritic cell functions in skin -LSB- 1 -RSB- . The impaired dendritic cell emigration from the skin parallels impeded migratory clearance of monocyte-derived dendritic cell-like cells from atherosclerotic plaques . VEGF mediates endothelial cell mitogenesis and enhances vascular permeability -LSB- 4 -RSB- . In psoriasis , VEGF is thought to promote localised angiogenesis and in severe psoriasis may act on renal vasculature to induce hyperpermeability with consequent proteinuria -LSB- 12 -RSB- . A role for VEGF has been postulated in the atherosclerotic process as changes in levels of VEGF and its receptors are present in atherosclerosis , and angiogenesis may play a role in plaque development and destabilisation -LSB- 4 -RSB- . Genetic basis of comorbidities There is considerable evidence for a genetic element in psoriasis . About 30 % of individuals with psoriasis have an affected first-degree relative -LSB- 69 -RSB- , and first-degree relatives are at a five to tenfold increased risk for developing psoriasis themselves -LSB- 70 -RSB- . Concordance rates for psoriasis are three to four times higher in monozygotic twins than dizygotic twins -LSB- 6 -RSB- , and twin and family studies show that 60 -- 90 % of the variance in psoriasis liability is due to genetic factors . Finally , linkage and association to the major histocompatability complex -LRB- MHC -RRB- region has been repeatedly demonstrated -LSB- 58 -RSB- . However , the presence of many different phenotypes means that not all psoriasis is the same and polygenic inheritance is likely . Interestingly , by analysing gene polymorphisms of the receptor of advanced glycation end products -LRB- RAGE -RRB- in patients with plaque-psoriasis seems to be linked to a genetic risk for cardiovascular disorders in psoriasis patients -LSB- 76 -RSB- . A combination of disease-specific and inflammatory modifying genes interacting with the environment likely determines the risk of comorbidity . A major susceptibility gene -LRB- Psoriasis Susceptibility 1 or PSORS1 -RRB- is located in the MHC class I region and maps to an approximately 300-kb interval containing HLA-C and 10 other genes in strong linkage disequilibrium with it -LSB- 25 , 47 , 77 -RSB- . Very recently , through a combination of genomic sequencing and haplotype analysis , HLA-Cw6 itself has been identified as the major disease allele at PSORS1 -LSB- 47 -RSB- . The observation that bacterial infections are significantly less common in psoriasis patients with an age of onset ≤ 40 years while immunological skin disorders -LRB- allergic contact dermatitis , urticaria and atopic dermatitis -RRB- are reduced regardless of age of onset suggests a genetic link between resistance to infection and early-onset psoriasis -LSB- 26 -RSB- . Chronic tonsillitis has been observed over three times more frequently than would be expected in patients with psoriasis -LSB- 26 -RSB- . Interestingly , psoriasis is not associated with other forms of streptococcal infection , suggesting a specific role for the tonsils -LSB- 20 -RSB- . Recently , identical T-cell receptor rearrangements have been found in the tonsils and lesional skin of psoriatic patients -LSB- 17 -RSB- . The prevalence of streptococcal infection during sore throat was 10 times higher in people with psoriasis than in controls and can exacerbate chronic plaque psoriasis -LSB- 20 -RSB- . There was , however , no difference in asymptomatic carriage between psoriasis patients and controls -LSB- 20 -RSB- . These results suggest either that psoriatic patients are more susceptible to streptococcal infection or that they respond more vigorously to it and are more likely to develop symptoms . This apparently defective response to streptococci combined with resistance to a variety of skin infections in psoriasis patients provides an interesting paradox . It is known that streptococcal -LRB- and other -RRB- infections may initiate psoriasis in genetically predisposed individuals , and psoriasis is characterised by strong Th1 immune deviation . Once the psoriatic cascade has been initiated , increased skin and/or systemic inflammation directed by Th1 cells may be responsible for a lower risk of other infections . Interestingly , bacterial infection -LRB- principally with Chlamydia pneumoniae -RRB- has also been implicated in the pathogenesis of atherosclerosis -LSB- 36 , 63 -RSB- . A phenomenon similar to that seen in psoriasis could contribute to increased risk of cardiovascular disease . Clinical importance of comorbidities in psoriasis According to the World Health Organization -LRB- WHO -RRB- , the occurrence of chronic disease is a rising global burden . In 2005 , all chronic diseases accounted for 72 % of the total global burden of disease in the population aged 30 years and older -LRB- Fig. 2 -RRB- -LSB- 68 -RSB- . More than 80 % of the burden of chronic diseases occurs in people under age 70 years . While psoriasis causes significant morbidity , it is not generally associated with mortality ; however , conditions linked with psoriasis are associated with excess mortality -LSB- 56 -RSB- . For example , the higher prevalence of smoking in the psoriatic population may explain why psoriasis has been associated with lung cancer in middle-aged women -LSB- 39 -RSB- . A registry of 5,687 patients admitted to the hospital for psoriasis between 1973 and 1984 who were followed for up to 22 years until 1995 found a significantly increased mortality for both alcohol - and smoking-related causes -LSB- 56 -RSB- . Fig. 2WHO projected major causes of death 2005 -LSB- 67 -RSB- . The occurrence of chronic disease is a rising global burden and accounted for 72 % of the total global burden of disease in the population aged 30 years and older in 2005 . Reproduced with permission from Lancet -LRB- 2005 , 366:1578 -- 1582 -RRB- . Copyright 2005 , Elsevier Ltd An increased rate of cardiovascular events has been observed in patients with psoriasis -LSB- 39 , 44 -RSB- , and it appears to be related to the severity of disease and age of onset -LSB- 42 , 55 , 62 -RSB- . Worldwide , cardiovascular disease is estimated to be the cause of 30 % of all deaths in 2005 making it the leading single cause of death worldwide -LSB- 68 -RSB- . Identification and treatment of modifiable risk factors in patients with psoriasis could result in a lower associated cardiovascular morbidity and mortality -LSB- 55 -RSB- . Conceptually , the effective systemic control of inflammation in psoriasis could also lead to improvements in comorbid conditions driven by inflammation . Implications of comorbidities The presence of comorbid conditions in psoriasis patients can have some important implications for clinical management . The general health status of the patient will be affected by all of these associated diseases , with substantial impact on quality of life -LRB- QoL -RRB- -LSB- 33 , 74 -RSB- . The precise impact of comorbid conditions on QoL in psoriasis patients has not been quantified ; however , it is known that the presence of joint involvement can significantly reduce health-related QoL -LSB- 40 -RSB- and that arthritis and arthralgia are important related factors affecting QoL in patients with psoriasis -LSB- 83 -RSB- . In fact , the effects of psoriasis on QoL are comparable to the effects observed from other major chronic diseases -LSB- 59 -RSB- . The authors performed an analysis of 317 patients with psoriasis and found that these patients reported a reduction in physical and mental functioning comparable to that observed in patients with cancer , arthritis , hypertension , heart disease and depression -LSB- 59 -RSB- . A US study looking at the direct health care expenditures associated with psoriasis found that psoriasis patients treated with systemic therapy or phototherapy have significantly more comorbidities and higher mean total health care expenditures compared with non-psoriasis patients . Furthermore , selected comorbidities lead to significantly higher mean total health care expenditures in those patients with psoriasis than in those with the same condition without psoriasis -LSB- 13 -RSB- . Many of the conditions associated with psoriasis could affect the way drugs are absorbed and eliminated from the body . For example , alcoholism impairs liver function , obesity affects drug distribution in the body , diabetes can impair kidney function , inflammatory bowel disease can reduce absorption from the gastrointestinal tract and smoking can impact the efficacy of some drugs -LSB- 85 -RSB- . Of course , the presence of these conditions will also lead to increased polypharmacy , increasing the likelihood of drug interactions and making it harder to implement an ` ideal ' psoriasis treatment in individuals -LSB- 34 -RSB- . The implications of managing a patient with comorbid conditions areFocus on inflammation control.Consider impact on patient as a whole.Monitor all associated diseases . Drug interactions in psoriasis It has been suggested that some drugs may trigger or exacerbate psoriasis . The most commonly proposed causative agents are beta blockers , lithium , synthetic antimalarial drugs , nonsteroidal anti-inflammatory drugs -LRB- NSAIDs -RRB- and tetracycline antibiotics -LSB- 72 -RSB- . Analysis of co-medication according to patients ' files in 1203 consecutive inpatients hospitalised for treatment of severe psoriasis was conducted between 2003 and 2005 in 9 dermatology departments in Germany -LSB- 84 -RSB- . The mean age of patients was 50 years -LRB- 55.9 % female , 44.1 % male -RRB- . The mean Psoriasis Area and Severity Index was 26.0 , average body mass index was 27.5 and mean age of first manifestation was 33.5 years . About one third of patients were found to be taking no systemic medication -LRB- 34.4 % -RRB- , and 42.4 % were taking three or fewer systemic agents . However , nearly a quarter -LRB- 23.2 % -RRB- were taking more than three systemic medications and of these , 11.1 % were taking more than ten medications -LRB- Table 2 -RRB- . Therefore , physicians caring for patients with psoriasis may consider withdrawal of agents that potentially exacerbate this condition . Further analysis suggests that comorbid cardiac and metabolic disorders are common in these patients : hypertension , 28.8 % ; type 2 diabetes , 10.5 % ; dyslipidaemia , 12.5 % ; hyperuricaemia , 5.3 % ; arrhythmias , 5.1 % ; coronary artery disease , 3.2 % ; and cardiac insufficiency , 2.1 % . The presence of renal insufficiency -LRB- 2.7 % -RRB- and liver cirrhosis -LRB- 2.4 % -RRB- were also noteworthy . Table 2Percentage of psoriasis patients receiving medications for comorbid disease -LSB- 84 -RSB- Drug classPatients -LRB- % -RRB- -LRB- n = 1,203 -RRB- ACE inhibitors12 .3 Oral anticoagulants11 .3 Diuretics12 .4 Thyroid drugs9 .9 Beta blockers7 .9 Psycholeptics5 .6 NSAIDs7 .0 Lithium salts0.70Interferon-alpha0.25 Risk of interactions with psoriasis therapies There is a high risk of drug interactions with both ciclosporin and methotrexate , while retinoids and leflunomide exhibit a lower risk of drug -- drug interactions . Conversely , treatments with biologics , such as TNFα inhibitors , and fumaric acid esters have no known risk of interactions . A number of medications can cause photosensitivity , which is an issue for any UV treatment of psoriasis -LRB- e.g. , tetracyclines -LSB- doxycyclin -RSB- and thiazide diuretics -RRB- -LSB- 67 -RSB- . Effect of psoriasis treatment on comorbidities The importance of considering the impact of treatment of diseases associated with psoriasis can not be stressed enough . Working with physicians in different specialties -LRB- e.g. , rheumatology , gastroenterology and cardiology -RRB- would allow physicians an opportunity to ensure that the psoriatic treatments do not worsen the associated condition and where possible provide additional benefits . Benefits of psoriasis therapy on comorbid conditions Since many comorbid conditions have inflammatory mechanisms in common with psoriasis , drugs targeting inflammation and/or suppressing the immune response are often effective in treating both psoriasis and related comorbidities . A number of treatments have shown some efficacy in treating both psoriasis and PsA including methotrexate , ciclosporin , leflunomide , etanercept and infliximab -LSB- 2 , 18 , 31 , 45 -RSB- . The TNFα inhibitors etanercept and infliximab have demonstrated halting of joint degradation -LSB- 45 -RSB- . Crohn 's disease There are few treatments that are effective in both psoriasis and CD . Azathioprine and 6-mercaptopurine are often used in CD , and they have also shown some efficacy in PsA in small , uncontrolled trials ; however , toxicity is likely to restrict their use -LSB- 50 -RSB- . Low-dose methotrexate has shown some efficacy in CD patients resistant to other therapies ; however , its usefulness in the long term has yet to be established -LSB- 66 -RSB- . Infliximab has been shown to be effective in both attaining and maintaining remission in CD patients -LSB- 23 -RSB- as well as in the treatment of extra-intestinal cutaneous manifestations -LSB- 61 -RSB- . Conversely , etanercept has not been shown to be effective in the treatment of CD and may even worsen the condition -LSB- 52 -RSB- . The difference between the effects of TNFα inhibitors on inflammation in CD are thought to be due in part to their different mechanisms of binding TNFα . Infliximab has higher affinity than etanercept , binding more forms of TNFα , and may induce cell apoptosis -LSB- 35 -RSB- . Cardiovascular disease Evidence for the improvement of psoriasis-associated cardiovascular risk following psoriasis treatment is limited to a trial of methotrexate in patients with psoriasis or RA -LSB- 57 -RSB- . Patients prescribed methotrexate had a significantly reduced risk of vascular disease compared with those who did not receive methotrexate -LRB- psoriasis , relative risk -LSB- RR -RSB- = 0.73 ; RA , RR = 0.83 -RRB- . Furthermore , risk reduction was greater in those who received a low cumulative dose of methotrexate -LRB- psoriasis , RR = 0.50 ; RA , RR = 0.65 -RRB- and in those patients also receiving concomitant folic acid -LRB- psoriasis , RR = 0.56 ; RA , RR = 0.77 -RRB- . Further work in RA has suggested that anti-TNFα therapy may provide some cardiovascular protection -LSB- 29 -RSB- . A comparison of two cohorts , one receiving TNFα inhibitors and one receiving standard therapy -LRB- derived from patient registries -RRB- , revealed a reduced age -- sex adjusted incidence rate of first cardiovascular event in those receiving TNFα inhibitors compared with controls -LRB- 14.0 / 1,000 person -- years at risk vs. 35.4 / 1,000 person -- years -RRB- . After controlling for disability , the age -- sex adjusted rate ratio was 0.46 -LRB- P = 0.013 -RRB- in the anti-TNFα-treated cohort versus the not-treated cohort . Statins are used to lower lipids in people at risk for cardiovascular events and have been shown to reduce cardiovascular morbidity and mortality ; however , statins have also been shown to have anti-inflammatory properties -LSB- 24 , 43 -RSB- . Statins down-regulate the expression of adhesion molecules and the expression of Th1 chemokine receptors on T cells , as well as block the expression of TNFα and interferon-gamma in macrophages among other immunomodulatory actions -LSB- 49 -RSB- . A double-blind , placebo-controlled trial in 116 patients with RA demonstrated that 40 mg atorvastatin daily , in addition to existing RA therapy , produced a significant reduction in disease activity -LRB- P = 0.004 -RRB- , a significant reduction in inflammatory markers -LRB- CRP 50 % , P < 0.0001 ; ESR 28 % , P = 0.005 -RRB- and a significant reduction in swollen joint count -LRB- − 2.69 vs − 0.53 ; P = 0.0058 -RRB- compared with placebo -LSB- 43 -RSB- . In addition , simvastatin treatment has been shown to significantly reduce serum CRP and TNFα in patients with RA and improve endothelial function -LSB- 71 -RSB- . Therefore , it has been suggested that statins may have beneficial effects in inflammatory dermatological conditions including psoriasis , and the results of controlled trials are awaited -LSB- 49 -RSB- . Potential drawbacks of psoriasis therapy on comorbid conditions Other common comorbidities could influence the choice of psoriasis therapies available to the dermatologist . Ciclosporin can induce hyperglycaemia and acitretin can alter glucose tolerance ; therefore , they are best avoided in diabetic patients . Methotrexate has been reported to precipitate diabetes and increase insulin requirements due to increased disease progression -LSB- 8 -RSB- . Ciclosporin is contraindicated in patients with uncontrolled hypertension and acitretin is contraindicated in hyperlipidaemia . Methotrexate and acitretin are contraindicated in the presence of hepatic impairment , which may result from psoriasis-associated alcohol misuse , while ciclosporin may need dosage adjustment and regular monitoring of kidney function since renal dysfunction is a known side effect -LSB- 8 -RSB- . Drug interactions and precipitating disease in psoriasis A diagnosis of psoriasis also has implications regarding treatment for physicians from specialities other than dermatology . The potential of some drugs -LRB- eg , angiotensin-converting enzyme inhibitors , beta blockers , NSAIDs -RRB- to ` trigger ' psoriasis means that these drugs should be avoided where possible and awareness of this potential should be raised . The potential for drug interactions with some psoriasis drugs is high and this should also be considered when designing therapeutic regimens . Furthermore , the increased risk of cardiovascular events associated with psoriasis should be considered when conducting global cardiovascular risk assessments . If possible , lower cut-off points for treatment should be used in psoriasis patients in an effort to take into consideration their overall cardiovascular risk . Discussion and conclusions Psoriasis is a multifaceted systemic condition that is not restricted to cutaneous symptoms . There is a need for further research to fully understand the reasons for comorbidities and their implications on treatment and management of psoriasis patients . Data are required to fully characterise risk of cardiovascular disease in psoriasis patients and whether treatment can impact this level of risk . Could effective -LRB- systemic -RRB- treatment of psoriasis reduce the risk of comorbidities or , conversely , could effective treatment of comorbidities improve psoriasis ? Investigation of the genetics of psoriasis and related inflammatory conditions may provide insight into their pathogenesis and points of commonality , which could reveal novel drug targets However , while research is conducted , there is a pressing need for education about comorbidities in psoriasis . Dermatologists need to be aware of the likelihood of comorbid conditions to ensure their detection and that psoriasis is managed with consideration of the possible impact on associated comorbid inflammatory conditions . Similarly , physicians from other specialities should be aware of the potential impact of their management strategies on psoriasis and take care not to exacerbate psoriasis when treating associated conditions . A focus on rapid and profound systemic control of inflammation in psoriasis may have added benefits by controlling inflammation associated with comorbid conditions . It is clear that TNFα is a central mediator in psoriasis and many of the recognised associated diseases . Knowledge and awareness of the common inflammatory processes involved should provide the opportunity to more effectively treat the common causes of inflammatory conditions benefitting both physicians and patients . Managing the psoriasis patient as a whole with integrated therapy is likely to maximise outcomes .

O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O B O O O B O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O B O O O O O O O B O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O B O B O O O O O O B O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O

psoriasis comorbid biologics inflammation


Long-Term

Locoregional

Vascular

Morbidity

After

Isolated

Limb

Perfusion

and

External-Beam

Radiotherapy

for

Soft

Tissue

Sarcoma

of

the

Extremity

Background

Isolated

limb

perfusion

-LRB-

ILP

-RRB-

with

tumor

necrosis

factor

alpha

-LRB-

TNF-α

-RRB-

and

melphalan

followed

by

delayed

surgical

resection

and

adjuvant

external-beam

radiotherapy

is

a

limb

salvage

treatment

strategy

for

locally

advanced

soft

tissue

sarcomas

The

long-term

vascular

side

effects

of

this

combined

procedure

were

evaluated

Optimum

treatment

strategies

for

locally

advanced

soft

tissue

sarcoma

-LRB-

STS

-RRB-

of

the

extremities

have

evolved

considerably

over

the

past

to

years

In

Rosenberg

et

al.

showed

that

amputations

or

exarticulations

of

the

affected

limb

do

not

result

in

higher

survival

rates

This

made

preservation

of

the

extremity

and

good

limb

function

all

the

more

important

An

established

limb

salvage

strategy

is

to

perform

a

hyperthermic

isolated

limb

perfusion

-LRB-

ILP

-RRB-

with

tumor

necrosis

factor

alpha

-LRB-

TNF-α

-RRB-

and

melphalan

followed

by

delayed

tumor

resection

and

in

case

of

marginal

or

nonradical

resection

by

adjuvant

external-beam

radiotherapy

-LRB-

EBRT

-RRB-

Although

ILP

in

which

high

doses

of

chemotherapy

are

regionally

delivered

is

a

technically

demanding

operative

procedure

amputation

necessitated

by

peri

or

postoperative

surgical

complications

occurs

in

of

cases

On

the

other

hand

patients

undergoing

an

intentionally

limb-saving

treatment

with

ILP

still

have

a

short

or

long-term

risk

up

to

of

loss

of

the

affected

limb

due

to

massive

necrosis

of

the

tumor

and

overlying

skin

resulting

in

a

soft

tissue

deficit

late

local

recurrence

or

critical

leg

ischemia

In

ILP

cytotoxic

agents

are

used

which

cause

a

local

toxic

effect

in

the

perfused

extremity

After

investigation

of

several

perfusion

agents

for

STS

the

two-drug

regimen

of

TNF-α

and

melphalan

turned

out

to

be

highly

effective

The

pathological

tumor

microvascularization

is

the

primary

target

for

TNF-α

resulting

in

coagulative

and

hemorrhagic

necrosis

of

the

tumors

Olieman

et

al.

demonstrated

by

angiography

findings

of

specific

destruction

of

tumor

vessels

after

perfusion

with

TNF-α

leaving

the

normal

vasculature

unchanged

The

surgical

procedure

of

ILP

however

exposes

the

cannulated

blood

vessels

to

intravascular

manipulation

by

means

of

arteriotomy

venotomy

and

the

insertion

of

catheters

Consequently

a

to

risk

of

developing

acute

vascular

complications

such

as

thrombosis

at

the

arteriotomy

site

and

deep-vein

thrombosis

-LRB-

DVT

-RRB-

has

been

described

in

the

literature

Moreover

chemotherapy

and

atherosclerosis

risk

factors

could

have

a

synergistic

role

on

the

development

of

arterial

stenosis

Adjuvant

EBRT

leads

to

a

high

incidence

of

early

and

late

morbidity

Long-term

vascular

side

effects

in

particular

arterial

stenosis

can

be

induced

by

radiotherapy

Because

little

is

known

with

respect

to

the

late

vascular

morbidity

of

the

combined

procedure

of

ILP

and

EBRT

a

retrospective

study

was

conducted

to

evaluate

the

long-term

locoregional

vascular

side

effects

of

ILP

followed

by

delayed

surgical

resection

and

adjuvant

high-dose

EBRT

PATIENTS

AND

METHODS

From

to

a

total

of

patients

with

a

median

age

of

-LRB-

range

-RRB-

years

and

with

locally

advanced

STS

underwent

perfusions

with

a

combination

of

TNF-α

and

melphalan

with

-LRB-

n

-RRB-

or

without

-LRB-

n

-RRB-

interferon

gamma

at

the

Division

of

Surgical

Oncology

of

the

University

Medical

Center

Groningen

University

of

Groningen

The

perfusion

technique

has

been

previously

extensively

described

Perfusion

was

followed

by

delayed

local

resection

of

the

tumor

remnant

and

in

cases

of

marginal

or

microscopically

positive

resection

margins

high-dose

postoperative

EBRT

was

considered

In

patients

were

still

alive

and

in

follow-up

Information

about

their

past

and

current

oncological

and

vascular

status

was

obtained

from

the

follow-up

notes

in

the

medical

records

Seven

patients

were

unable

to

participate

in

the

study

because

of

severe

or

advanced

morbidity

or

comorbidity

-LRB-

n

-RRB-

or

because

of

nonmedical

reasons

-LRB-

n

-RRB-

Consequently

patients

men

-LRB-

-RRB-

and

women

-LRB-

-RRB-

with

a

median

age

of

-LRB-

range

-RRB-

years

were

included

-LRB-

response

rate

-RRB-

They

completed

a

vascular

checklist

that

asked

questions

about

their

medical

vascular

history

and

they

were

screened

for

risk

factors

of

vascular

disease

such

as

smoking

hypertension

and

diabetes

A

blood

sample

was

drawn

to

determine

the

cholesterol

spectrum

which

was

used

as

an

indicator

of

risk

for

atherosclerosis

All

patients

underwent

a

noninvasive

arterial

and

venous

vascular

work-up

that

comprised

duplex

ultrasonography

and

vascular

pressure

measurements

The

ankle-brachial

index

-LRB-

ABI

-RRB-

and

pulsatility

index

-LRB-

PI

-RRB-

which

are

indications

of

vascular

blood

flow

velocity

were

measured

to

indicate

the

arterial

status

of

the

limb

For

evaluation

of

veins

ultrasonography

was

performed

to

detect

DVT

and

insufficiency

All

investigations

were

performed

by

the

same

examiner

-LRB-

J.L.

-RRB-

Five

patients

had

a

STS

of

the

upper

extremity

-LRB-

-RRB-

treated

with

axillary

perfusion

The

remaining

patients

had

a

STS

located

in

the

lower

limb

-LRB-

-RRB-

and

were

treated

with

iliac

-LRB-

n

-RRB-

femoral

-LRB-

n

-RRB-

or

popliteal

-LRB-

n

-RRB-

perfusion

There

were

primary

STS

and

recurrent

STS

Twenty-four

patients

-LRB-

-RRB-

received

adjuvant

to

Gy

EBRT

in

fractions

of

Gy

Adjuvant

systemic

chemotherapy

was

provided

to

seven

patients

Definite

histopathological

classification

of

tumor

-LRB-

one

embryonal

rhabdomyosarcoma

and

one

extraossal

osteosarcoma

-RRB-

was

the

reason

in

two

patients

three

patients

were

treated

with

chemotherapy

because

they

participated

in

an

European

Organization

for

the

Research

and

Treatment

of

Cancer

trial

-LRB-

EORTC

-RRB-

Two

patients

received

chemotherapy

in

a

palliative

setting

for

distant

metastasis

All

patients

were

treated

after

informed

consent

was

obtained

according

to

institutional

guidelines

Twelve

different

histological

types

of

STS

were

distinguished

The

pathological

grade

of

the

tumor

was

scored

following

the

criteria

of

Coindre

et

al.

and

the

stage

of

the

tumor

was

assigned

according

to

the

American

Joint

Committee

on

Cancer

Patient

and

tumor

characteristics

are

summarized

in

Table

TABLE

Characteristics

of

patientsAge

-LRB-

y

-RRB-

SexDiseaseLocalizationHistologyGradeAJCC

stageLevelEBRTAmputationFollow-up

-LRB-

mo

-RRB-

legEmbryonal

fossaMyxoid

legSynovial

legMyxoid

legWell

differentiated

fossaSynovial

legMyxoid

legSynovial

fossaMyxoid

legMyxoid

fossaMyxoid

fossaSynovial

legSynovial

American

Joint

Committee

on

Cancer

EBRT

external-beam

radiotherapy

PNET

primitive

neuroectodermal

tumor

PUS

pleomorphic

undifferentiated

sarcoma

MPNST

malignant

peripheral

nerve

sheath

tumor

The

results

were

statistically

analyzed

by

the

Wilcoxon

rank

test

and

the

Mann-Whitney

U-test

Values

of

P

were

considered

significant

SPSS

for

Windows

statistical

software

was

used

-LRB-

SPSS

Chicago

IL

-RRB-

RESULTS

Before

ILP

of

the

patients

had

a

history

of

cerebrovascular

insufficiency

coronary

artery

disease

peripheral

arterial

occlusive

disease

or

any

other

vascular

disease

Risk

factors

for

cardiovascular

disease

hypertension

diabetes

smoking

obesity

hypercholesterolemia

and

familiar

arterial

occlusive

disease

were

analyzed

-LRB-

Table

-RRB-

TABLE

Risk

factors

for

atherosclerosisRisk

factorn

Dutch

population

-LRB-

-RRB-

a

bDiabetes

b

Former

BMI

b

BMI

bHypercholesterolemia

-LRB-

total

cholesterol

-RRB-

cardiovascular

body

mass

index

not

available.a

Range

to

b

From

From

Two

patients

underwent

vascular

reconstruction

after

en-bloc

tumor

resection

with

the

artery

One

patient

underwent

a

reconstruction

of

the

femoral

artery

with

an

infragenual

femoral-popliteal

bypass

and

the

second

patient

underwent

a

popliteal

artery

reconstruction

with

an

autologous

vein

graft

A

DVT

in

the

lower

leg

was

diagnosed

in

the

postoperative

period

in

three

patients

-LRB-

-RRB-

Nine

-LRB-

-RRB-

of

the

alive

patients

underwent

a

lower

limb

amputation

at

different

levels

after

ILP

with

or

without

EBRT

No

amputations

of

the

upper

extremity

were

performed

In

two

patients

with

microscopically

involved

resection

margins

an

amputation

of

the

affected

limb

was

indicated

because

adjuvant

radiotherapy

was

contraindicated

One

patient

underwent

amputation

due

to

tumor

recurrence

months

after

ILP

and

EBRT

Amputation

was

performed

for

critical

leg

ischemia

due

to

atherosclerosis

in

two

patients

at

and

months

after

ILP

and

EBRT

Because

of

severe

obstruction

of

the

crural

vessels

reconstructive

therapy

was

not

suitable

The

other

four

amputations

were

performed

for

extensive

postperfusion

necrosis

of

the

involved

tumor

site

-LRB-

three

patients

at

and

months

after

ILP

with

or

without

EBRT

-RRB-

and

arterial

occlusion

without

any

vascular

reconstructive

possibilities

-LRB-

one

patient

months

after

ILP

and

EBRT

-RRB-

-LSB-

-RSB-

Figure

illustrates

treatment

outcome

and

reasons

for

amputation

Five

of

the

patients

included

in

this

study

underwent

amputation

and

could

therefore

only

partially

undergo

vascular

follow-up

FIG.

Flow

chart

illustrating

treatment

outcome

and

reasons

for

amputation

EBRT

external-beam

radiotherapy

AMP

amputation

NI

not

included

in

this

study

Arterial

Vascular

Disease

With

a

median

follow-up

of

-LRB-

range

-RRB-

months

no

patient

experienced

peripheral

arterial

occlusive

disease

With

duplex

ultrasonography

however

two

patients

showed

a

complete

arterial

occlusion

at

the

level

of

cannulation

-LRB-

-RRB-

One

of

them

underwent

an

iliac

perfusion

and

EBRT

because

of

a

STS

of

the

lower

leg

in

After

years

she

had

signs

of

critical

leg

ischemia

which

required

a

transfemoral

amputation

She

is

now

free

of

pain

and

can

walk

with

a

well-functioning

prothesis

The

other

patient

showed

an

axillary

occlusion

years

after

an

axillary

perfusion

followed

by

resection

and

EBRT

at

the

forearm

She

did

not

have

any

symptoms

of

arterial

occlusive

disease

and

her

arm

functions

normally

Duplex

ultrasonography

showed

good

collateral

flow

Two

other

patients

-LRB-

-RRB-

showed

an

arterial

stenosis

at

cannulation

level

at

and

months

after

axillary

perfusions

followed

by

EBRT

at

the

upper

arm

and

axilla

in

one

and

systemic

chemotherapy

in

both

patients

They

had

normal

arm

function

without

any

signs

of

ischemia

The

arteries

at

resection

level

were

also

evaluated

One

patient

with

a

fossa

poplitea

STS

had

complete

occlusion

of

the

superficial

femoral

artery

years

after

ILP

and

EBRT

with

open

arteries

below

knee

level

A

femoral-popliteal

bypass

was

considered

but

was

not

performed

because

of

the

absence

of

any

symptoms

At

the

time

of

evaluation

the

ABI

was

the

patient

did

not

have

any

complaints

besides

compression

ulcers

on

his

feet

which

responded

well

to

conservative

therapy

The

patient

who

needed

an

autologous

vein

graft

of

the

popliteal

artery

has

a

stenosis

at

this

level

without

clinical

signs

of

arterial

occlusive

disease

Twenty-two

of

the

total

patients

included

underwent

ABI

measurements

had

their

PI

determined

at

the

femoral

level

and

at

the

popliteal

level

Five

patients

were

excluded

because

of

amputation

of

the

limb

another

five

were

excluded

because

of

a

STS

located

in

the

upper

limb

Of

the

remaining

patients

received

postoperative

EBRT

for

the

above-described

indications

In

of

patients

the

ABI

-LRB-

normal

-RRB-

in

the

treated

leg

was

or

more

As

mentioned

above

one

patient

had

an

ABI

of

without

any

complaints

ABI

measurements

in

the

involved

leg

-LRB-

median

range

-RRB-

showed

a

significant

decrease

compared

with

the

contralateral

leg

-LRB-

median

range

P

-RRB-

Seven

patients

showed

a

decreased

femoral

PI

-LRB-

normal

range

-RRB-

Six

of

them

underwent

an

iliac

perfusion

-LRB-

-RRB-

Popliteal

PI

-LRB-

normal

range

-RRB-

was

decreased

in

six

patients

Perfusion

at

a

more

proximal

level

was

performed

in

four

of

these

patients

-LRB-

-RRB-

When

compared

with

the

contralateral

leg

PI

was

lower

in

the

treated

leg

in

of

patients

at

femoral

level

-LRB-

median

range

vs.

median

range

P

-RRB-

and

in

of

patients

at

popliteal

level

-LRB-

median

range

vs.

median

range

P

-RRB-

-LRB-

Table

-RRB-

There

were

no

differences

in

objective

vascular

side

effects

between

men

and

women

between

patients

who

did

or

did

not

undergo

EBRT

or

between

patients

years

old

versus

older

patients

-LRB-

Table

-RRB-

In

patients

with

a

follow-up

period

of

years

there

was

more

often

a

decrease

in

ABI

compared

with

patients

with

shorter

follow-up

-LRB-

of

patients

vs.

of

patients

P

-RRB-

With

a

longer

follow-up

period

there

was

also

more

often

a

decrease

in

PI

at

the

femoral

level

-LRB-

of

patients

vs.

of

patients

P

-RRB-

but

not

at

the

popliteal

level

-LRB-

of

patients

vs.

of

patients

P

-RRB-

-LRB-

Table

-RRB-

No

patient

required

vascular

intervention

during

follow-up

TABLE

Results

of

ankle-brachial

index

-LRB-

ABI

-RRB-

and

pulsatility

index

-LRB-

PI

-RRB-

measurements

in

lower

extremities

of

patientsIndexTreated

extremity

median

-LRB-

range

-RRB-

Contralateral

extremity

median

-LRB-

range

-RRB-

P

-LRB-

-RRB-

-LRB-

-RRB-

PI

-LRB-

-RRB-

-LRB-

-RRB-

PI

-LRB-

-RRB-

-LRB-

-RRB-

TABLE

P

values

of

differences

between

subgroups

in

decrease

of

ankle-brachial

index

-LRB-

ABI

-RRB-

and

pulsatility

index

-LRB-

PI

-RRB-

for

patientsCharacteristicSexFollow-up

after

EBRTAgeFMYesNo

y

y

y

yNo

of

PI

femoral

decrease

PI

popliteal

decrease

EBRT

external-beam

radiotherapy.TABLE

Differences

in

decreases

in

measurements

according

to

length

of

follow-upDecrease

in

perfused

legFollow-up

n

-LRB-

-RRB-

P

value

y

-LRB-

n

-RRB-

y

-LRB-

n

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

PI

-LRB-

-RRB-

-LRB-

-RRB-

PI

-LRB-

-RRB-

-LRB-

-RRB-

ABI

ankle-brachial

index

PI

pulsatility

index.a

n

data

for

two

patients

were

not

available

Venous

Vascular

Disease

Many

patients

had

some

symptoms

of

venous

insufficiency

such

as

lower

limb

pain

feelings

of

heaviness

and

discomfort

night

palsies

paresthesia

and

edema

One

patient

-LRB-

-RRB-

wore

compression

stockings

because

of

superficial

vena

saphena

magna

insufficiency

and

one

patient

-LRB-

-RRB-

had

unilateral

superficial

varicosis

in

the

treated

leg

Another

three

patients

-LRB-

-RRB-

showed

uni

or

bilateral

deep

insufficient

venous

vasculature

by

duplex

ultrasonography

which

in

all

cases

was

located

at

the

level

of

resection

One

DVT

-LRB-

-RRB-

and

one

partial

venous

obstruction

-LRB-

-RRB-

were

found

both

at

the

resection

level

Venous

vascular

obstruction

was

not

seen

at

the

level

of

cannulation

DISCUSSION

ILP

with

TNF-α

and

melphalan

with

or

without

adjuvant

EBRT

has

become

an

approved

treatment

strategy

for

locally

advanced

STS

of

the

extremities

after

the

publication

of

the

results

of

an

European

multicenter

trial

performed

in

the

Because

our

center

was

one

of

the

first

to

use

this

treatment

modality

we

now

have

had

more

than

years

experience

of

ILP

used

to

treat

STS

This

gives

us

the

opportunity

to

evaluate

the

long-term

treatment-related

morbidity

Critical

leg

ischemia

approximately

years

after

ILP

necessitating

amputation

in

two

patients

led

to

an

interest

of

analyzing

the

vascular

complications

of

ILP

with

or

without

EBRT

Despite

a

complete

destruction

of

tumor

vasculature

ILP

does

not

seem

to

have

any

effect

on

the

macrovasculature

of

the

perfused

limb

However

because

atherosclerosis

risk

factors

and

chemotherapy

could

play

a

synergistic

role

in

the

progression

of

arterial

stenosis

patients

who

already

have

severe

atherosclerotic

disease

are

less

suitable

for

ILP

In

our

study

many

patients

had

one

or

more

risk

factors

for

atherosclerosis

In

the

study

population

there

seemed

to

be

more

patients

with

diabetes

or

hypercholesterolemia

than

in

the

standard

Dutch

population

The

smoking

rate

is

similar

-LRB-

vs.

-RRB-

however

another

used

to

smoke

-LRB-

Table

-RRB-

Acute

vascular

complications

after

ILP

have

been

described

in

the

literature

Deep-vein

thrombosis

-LRB-

DVT

-RRB-

occurs

in

to

of

cases

in

the

immediate

postoperative

period

In

our

studies

three

patients

-LRB-

-RRB-

had

a

successfully

treated

DVT

after

ILP

DVT

seems

to

be

extremely

difficult

to

diagnose

because

the

postoperative

effects

of

ILP

itself

a

warm

swollen

edematous

limb

mask

the

classical

symptoms

To

prevent

this

undesired

complication

anticoagulant

therapy

is

recommended

Thrombosis

at

the

arteriotomy

site

has

also

been

mentioned

in

earlier

studies

It

was

not

encountered

in

this

study

but

should

be

treated

by

prompt

trombectomy

In

case

of

repeated

ILP

in

the

same

limb

perfusion

through

more

proximal

arterial

and

venous

sites

is

recommended

because

fibrosis

at

the

previous

operative

site

does

not

allow

insertion

of

the

cannulas

at

the

same

level

All

patients

in

this

study

underwent

only

one

ILP

Long-term

effects

after

ILP

are

mainly

functional

and

consist

of

edema

stiffness

functional

impairment

and

muscle

atrophy

Late

vascular

morbidity

after

ILP

without

EBRT

has

not

been

previously

mentioned

in

other

studies

In

our

study

one

partial

arterial

occlusion

-LRB-

-RRB-

was

found

In

contrast

long-term

effects

of

EBRT

have

extensively

been

described

in

the

literature

In

a

study

of

Butler

et

al.

three

types

of

vascular

damage

have

been

described

At

first

thrombosis

occurs

within

years

after

EBRT

a

second

fibrotic

occlusion

is

seen

within

years

and

finally

a

predisposition

to

the

development

of

atheroma

together

with

periarterial

fibrosis

is

associated

with

a

latent

interval

of

or

more

years

Rijbroek

et

al.

mention

claudication

after

a

latent

period

This

is

masked

by

the

other

effects

such

as

pain

functional

impairment

and

edema

According

to

Kalman

et

al.

long-term

vascular

side

effects

of

EBRT

resemble

the

natural

process

of

atherosclerosis

which

is

a

combination

of

direct

damage

periarterial

fibrosis

and

occlusion

of

vasa

vasorum

The

EBRT

accelerates

this

process

sometimes

to

years

after

treatment

Little

is

known

about

the

combined

effects

of

ILP

and

EBRT

Vrouenraets

et

al.

described

one

brachial

arterial

occlusion

but

this

was

only

months

after

treatment

Olieman

et

al.

described

the

occurrence

of

necrosis

after

ILP

but

did

not

find

any

increased

tumor-related

morbidity

after

ILP

followed

by

EBRT

In

another

series

ILP

was

performed

after

EBRT

but

it

did

not

lead

to

more

local

toxicity

or

complications

In

our

study

amputation

was

performed

in

nine

patients

-LRB-

-RRB-

This

is

higher

than

the

to

described

in

the

literature

However

amputations

due

to

long-term

complications

like

critical

leg

ischemia

which

was

performed

in

two

patients

-LRB-

-RRB-

have

not

been

described

in

other

studies

Furthermore

three

complete

-LRB-

-RRB-

and

one

partial

-LRB-

-RRB-

arterial

occlusion

were

found

after

the

combined

procedure

Fortunately

these

patients

did

not

have

invalidating

symptoms

of

arterial

occlusive

disease

In

most

cases

vascular

pressure

measurements

and

duplex

ultrasonographic

evaluation

showed

statistically

lower

values

compared

with

the

contralateral

extremity

but

these

were

still

within

the

normal

range

This

could

explain

the

absence

of

symptoms

The

PI

value

normally

increases

progressively

from

aorta

to

ankle

A

decrease

in

PI

indicates

stenosis

in

a

more

proximal

vascular

segment

In

our

study

six

of

seven

patients

with

an

abnormal

femoral

PI

underwent

iliac

perfusion

This

implies

a

vascular

reaction

at

the

level

of

cannulation

Furthermore

seven

patients

showed

a

decrease

in

popliteal

PI

compared

with

the

femoral

PI

which

implies

that

vascular

damage

is

present

at

a

more

proximal

-LRB-

i.e.

cannulation

or

resection

-RRB-

level

However

with

the

present

data

it

is

not

possible

to

support

this

thesis

because

of

the

relatively

small

study

population

and

the

absence

of

symptoms

and

other

abnormal

outcomes

of

the

vascular

work-up

It

is

important

to

realize

that

blood

vessels

lose

their

elasticity

with

the

years

and

are

subject

to

the

normal

process

of

atherosclerosis

Furthermore

unilateral

peripheral

arterial

occlusive

disease

is

common

However

the

fact

that

lower

rates

of

ABI

and

PI

were

found

in

the

treated

leg

in

almost

all

patients

and

that

no

marked

difference

was

found

between

younger

and

older

patients

makes

the

assumption

of

treatment-induced

differences

plausible

Because

only

four

patients

with

a

lower

leg

STS

were

not

treated

with

adjuvant

EBRT

there

are

still

no

clinically

relevant

data

about

the

late

vascular

damage

of

the

single

procedure

of

ILP

Thijssens

et

al.

showed

that

adjuvant

EBRT

seems

beneficial

in

all

patients

so

it

might

be

impossible

to

evaluate

the

sole

effects

of

ILP

on

the

vascular

system

in

the

future

Major

late

vascular

complications

after

the

combined

procedure

like

critical

leg

ischemia

necessitating

amputation

were

found

in

two

patients

in

this

study

One

patient

had

no

risk

factors

for

peripheral

arterial

occlusive

disease

besides

smoking

He

had

had

intermittent

claudication

years

after

ILP

and

EBRT

and

a

normal

ABI

of

His

condition

did

not

improve

after

years

of

conservative

therapy

and

reconstruction

was

impossible

so

he

underwent

an

amputation

months

after

the

initial

limb

salvage

treatment

strategy

The

second

patient

who

had

diabetes

mellitus

and

familial

cardiovascular

disease

experienced

no

complications

the

first

few

years

after

ILP

and

EBRT

After

years

she

experienced

a

pathological

proximal

tibia

fracture

due

to

radiation-induced

osteonecrosis

in

the

previous

surgically

treated

area

and

needed

to

wear

a

brace

She

lived

for

years

with

a

disabling

function

impairment

of

the

knee

and

then

developed

signs

of

critical

leg

ischemia

An

upper

leg

amputation

was

performed

months

after

the

initial

treatment

She

now

walks

with

a

well-functioning

prothesis

The

importance

of

leg

preservation

has

been

mentioned

before

Even

though

most

patients

still

are

satisfied

with

the

initial

limb-saving

treatment

that

they

underwent

amputations

due

to

major

late

complications

with

severe

morbidity

make

the

rationale

of

limb

salvage

worth

reconsidering

Recently

one

patient

was

successfully

treated

with

thrombectomy

for

an

acute

popliteal

artery

occlusion

This

patient

who

underwent

an

ILP

at

femoral

level

followed

by

EBRT

for

a

STS

in

the

fossa

poplitea

years

before

had

no

complaints

of

peripheral

arterial

occlusive

disease

during

his

vascular

work-up

for

this

study

months

earlier

ABI

-LRB-

-RRB-

and

femoral

PI

-LRB-

-RRB-

were

normal

popliteal

PI

was

low

-LRB-

-RRB-

With

duplex

ultrasonography

some

atherosclerosis

in

the

femoropopliteal

section

was

seen

This

patient

has

diabetes

and

hypertension

is

obese

-LRB-

body

mass

index

-RRB-

and

was

a

former

smoker

so

he

was

especially

at

risk

for

developing

atherosclerosis

This

study

shows

that

despite

the

importance

of

preventing

major

late

vascular

complications

after

the

combined

procedure

of

ILP

and

EBRT

a

routine

noninvasive

vascular

work-up

does

not

seem

to

add

value

to

normal

follow-up

It

is

more

important

to

realize

that

patients

after

the

limb

salvage

treatment

strategy

of

ILP

followed

by

delayed

tumor

resection

and

EBRT

are

at

risk

for

late

vascular

complications

This

risk

is

substantially

raised

when

personal

risk

factors

such

as

smoking

diabetes

hypertension

obesity

and

hypercholesterolemia

are

present

Because

symptoms

of

vascular

complications

can

be

masked

by

the

normal

effects

of

the

treatment

itself

the

possibility

of

vascular

morbidity

should

be

considered

if

the

patient

has

any

complaint

Furthermore

all

patients

must

be

convinced

of

the

importance

of

reducing

their

additional

personal

risk

factors

for

atherosclerosis

In

conclusion

objective

measurements

show

a

time-related

decrease

-LRB-

years

follow-up

-RRB-

of

ABI

and

femoral

PI

in

the

treated

leg

usually

without

subjective

complaints

ILP

followed

by

delayed

resection

and

EBRT

for

a

locally

advanced

STS

can

lead

to

major

late

vascular

morbidity

that

requires

amputation

O O B O O O O B O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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