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 (IMIDs). 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 [26, 53]. Perhaps the best known noncutaneous condition associated with psoriasis is joint disease, mostly expressed as psoriatic arthritis (PsA). In hospitalised psoriasis patients, a diagnosis of PsA [according to the European Spondyloarthropathy Study Group (ESSG) criteria] was present in 7.7% (71/936) of patients; however, many more patients also reported paresthesias (12.3%), arthralgia (7%), stiffness (4.2%), swelling (3.7%) and ankylosis (1.2%) without meeting all of the ESSG criteria for PsA [19]. Further estimates place the occurrence of PsA in patients with psoriasis at upwards of 30% [31]. An additional study by Zachariae et al. [83] 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. [41] 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% [83]. Inflammatory bowel disease is also more frequently observed in patients with psoriasis. An increased relative risk for Crohn’s disease (CD) of 2.9 was found to be associated with a prior diagnosis of psoriasis in a Swedish case-control study [54]. Conversely, patients with CD are about seven times more likely to develop psoriasis than controls [5, 37, 82].
Analysis of data from more than 40,000 dermatological inpatients with psoriasis compared with control patients with nonpsoriatic skin diseases (adjusting for age and gender) revealed high ratios of observed versus expected frequencies for obesity (2.05, P < 0.05), hypertension (1.90, P < 0.01), heart failure (1.83, P < 0.001) and diabetes mellitus (1.47, P < 0.05) [26]. An additional analysis (retrospective chart review, 1997–2000) of 753 patients from an academic dermatology practice also confirms the presence of comorbidities in patients with psoriasis [53]. In fact, a comorbid diagnosis was confirmed in 551 patients (73%), with hypertension, dyslipidemia, diabetes and heart disease being the most common comorbidities identified [53]. 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 (a) and triglycerides are significantly increased in patients with psoriasis compared with healthy control subjects [73], while high-density lipoprotein (HDL) cholesterol is significantly decreased [60]. 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 [30].
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 [44]. 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 [86]. The most recent definition of metabolic syndrome requires central obesity (defined as body mass index >30 kg/m2) plus any two of the following: elevated plasma triglycerides, reduced HDL cholesterol, elevated blood pressure and raised fasting plasma glucose (Table 1). Such clustering of risk factors has been observed in patients with psoriasis [26].
Table 1Diseases associated with psoriasis [65]ConditionPrevalence in psoriasis n (%)Hospital controls OR (95% CI)RKI sample OR (95% CI)Diabetes mellitus type I11 (1.9)3.99 (1.30–12.2)*6.34 (2.80–14.3)***Diabetes mellitus type II68 (11.7)2.48 (1.70–3.61)**2.07 (1.50–2.85)***Arterial hypertension127 (21.9)3.27 (2.41–4.43)***1.39 (1.09–1.77)*Hyperlipoproteinemia30 (5.2)2.09 (1.23–3.54)**0.83 (0.54–1.28)fCoronary heart disease32 (5.5)1.77 (1.07–2.93)*0.93(0.60–1.43)fMetabolic syndrome25 (4.3)5.92 (2.78–12.8)***2.20 (1.41–3.43)**Alcohol consumption none vs. moderate246 (42.3)2.78 (2.14–3.62)***2.03 (1.62–2.55)***None vs. regularly75 (12.9)3.33 (2.20–5.05)***2.00 (1.45–2.77)***None vs. heavya24 (4.1)3.61 (1.85–7.07)***8.50 (5.28–16.8)***Cigarette smoking264 (45.4)2.96 (2.27–3.84)***2.49 (2.00–3.10)***The prevalence of diseases in plaque-type psoriasis patients (n = 581) was compared with hospital-based controls (n = 1,044) and a population-based survey (RKI sample; n = 4,705). Common odds ratios adjusted for age and sex are presented with their 95% confidence intervals (95% CI), 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 [39] with a reported prevalence of alcoholism of 18% among psoriatic patients compared with 2% in other dermatologic controls [22, 46]. 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 (odds ratios of 1.9 and 1.7, respectively), and smoking was strongly associated with the occurrence of pustular lesions (odds ratio = 5.3 for smokers) [48]. 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 (P < 0.001 for both). The prevalence of obese smokers was significantly higher (P < 0.001) [27].
A number of psychiatric/psychological comorbidities have also been observed in patients with psoriasis [22]. 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 [48]. 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 [22]. High depression/anxiety scores, obsessionality and difficulties with verbal expression of emotions (especially anger) have been reported in various cross-sectional surveys [22]. Severely affected psoriatic inpatients (>30% body surface area affected) were likely to suffer clinical depression and suicidal ideation (7.2%); however, suicidal ideation was still relatively high (2.5%) in less severely affected outpatients (<30% total body surface area affected) and comparable to the reported prevalence among general medical patients (2.4–3.3%) [21].
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 [7]. T cells are found in the dermis and epidermis and are accompanied by increased numbers of dermal dendritic cells, macrophages and mast cells [51]. It is thought that a stimulus (such as trauma or infection) 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 (Fig. 1).
Fig. 1Inflammatory pathway in psoriasis [50]. 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 (2004, 113:1664–1675). Copyright 2004, The American Society for Clinical Investigation
Other inflammatory diseases, such as rheumatoid arthritis (RA) and CD, are thought to involve similar pathogenetic mechanisms. Recent research has shown that inflammation plays a key role in atherosclerosis [24]. A T-cell infiltrate is always present in atherosclerotic lesions, with activated T cells producing a type 1 helper (Th1) response. Psoriasis is up to seven times more common in patients with CD than in controls [37, 82] 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 [14].
The term immune-mediated inflammatory disease (I.M.I.D.) 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 [79].
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 [3, 10]. Excess mortality due to coronary heart disease in RA patients was first observed in 1953 [11]. 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 [16]. 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 (eg, number of joints involved) and disease duration [64, 75]: severe coronary artery calcification is more likely in patients with established disease (>10 years) compared with controls after adjusting for cardiovascular risk factors (odds ratio = 3.42, P = 0.002) [10]. However, there is some emerging evidence for increased atherosclerotic disease in early RA [32].
The lipid profile in RA patients is directly affected by the systemic inflammatory response (active inflammation lowers HDL cholesterol, which leads to increased cardiovascular risk) [75]. Endothelial dysfunction, which underlies atherosclerotic plaque development, is associated with markers of systemic inflammation, such as C-reactive protein (CRP), soluble adhesion molecules (sICAM-1 and sE-selectin), IL-6 and TNF-alpha (TNFα) [24, 38, 78]. 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 [28].
Atherosclerosis and psoriasis
An increase in cardiovascular disease has been observed in psoriasis patients [39, 44] and has been shown to be related to disease severity and age of onset [42, 55, 62]. An increased incidence of traditional cardiovascular risk factors is frequently reported [26, 42, 56]. 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 [standardised mortality ratio (SMR) = 1.52]. In those patients with 3 or more hospital admissions, the SMR increased to 1.82 and in those patients admitted at younger ages (20–39 years at first admission), the SMR increased to 2.62 [42]. 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 (SMR = 1.65 in males and 1.59 in females) and the largest single cause of death is myocardial infarction (27.6%) [80].
 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 (high triglycerides, low HDL).• 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 (ApoE), vascular endothelial growth factor (VEGF), sICAM-1, IL-8, soluble interleukin2 receptor (sIL-2R) and TNFα [9, 12, 14, 15]. sICAM-1 and sIL-2R are soluble T-cell products [15]. 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 [81]. Furthermore, the dyslipidaemic profile exhibited in psoriasis has been shown to modify dendritic cell functions in skin [1]. 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 [4]. In psoriasis, VEGF is thought to promote localised angiogenesis and in severe psoriasis may act on renal vasculature to induce hyperpermeability with consequent proteinuria [12]. 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 [4].
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 [69], and first-degree relatives are at a five to tenfold increased risk for developing psoriasis themselves [70]. Concordance rates for psoriasis are three to four times higher in monozygotic twins than dizygotic twins [6], 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 (MHC) region has been repeatedly demonstrated [58]. 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 (RAGE) in patients with plaque-psoriasis seems to be linked to a genetic risk for cardiovascular disorders in psoriasis patients [76].
A combination of disease-specific and inflammatory modifying genes interacting with the environment likely determines the risk of comorbidity. A major susceptibility gene (Psoriasis Susceptibility 1 or PSORS1) 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 [25, 47, 77]. Very recently, through a combination of genomic sequencing and haplotype analysis, HLA-Cw6 itself has been identified as the major disease allele at PSORS1 [47].
The observation that bacterial infections are significantly less common in psoriasis patients with an age of onset ≤40 years while immunological skin disorders (allergic contact dermatitis, urticaria and atopic dermatitis) are reduced regardless of age of onset suggests a genetic link between resistance to infection and early-onset psoriasis [26].
Chronic tonsillitis has been observed over three times more frequently than would be expected in patients with psoriasis [26]. Interestingly, psoriasis is not associated with other forms of streptococcal infection, suggesting a specific role for the tonsils [20]. Recently, identical T-cell receptor rearrangements have been found in the tonsils and lesional skin of psoriatic patients [17]. 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 [20]. There was, however, no difference in asymptomatic carriage between psoriasis patients and controls [20]. 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 (and other) 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 (principally with Chlamydia pneumoniae) has also been implicated in the pathogenesis of atherosclerosis [36, 63]. 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 (WHO), 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 (Fig. 2) [68]. 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 [56]. 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 [39]. 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 [56].
Fig. 2WHO projected major causes of death 2005 [67]. 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 (2005, 366:1578–1582). Copyright 2005, Elsevier Ltd
An increased rate of cardiovascular events has been observed in patients with psoriasis [39, 44], and it appears to be related to the severity of disease and age of onset [42, 55, 62]. 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 [68]. Identification and treatment of modifiable risk factors in patients with psoriasis could result in a lower associated cardiovascular morbidity and mortality [55]. 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 (QoL) [33, 74]. 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 [40] and that arthritis and arthralgia are important related factors affecting QoL in patients with psoriasis [83]. In fact, the effects of psoriasis on QoL are comparable to the effects observed from other major chronic diseases [59]. 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 [59].
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 [13].
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 [85]. 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 [34].
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 (NSAIDs) and tetracycline antibiotics [72]. 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 [84]. The mean age of patients was 50 years (55.9% female, 44.1% male). 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 (34.4%), and 42.4% were taking three or fewer systemic agents. However, nearly a quarter (23.2%) were taking more than three systemic medications and of these, 11.1% were taking more than ten medications (Table 2). 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 (2.7%) and liver cirrhosis (2.4%) were also noteworthy.
Table 2Percentage of psoriasis patients receiving medications for comorbid disease [84]Drug classPatients (%) (n = 1,203)ACE inhibitors12.3Oral anticoagulants11.3Diuretics12.4Thyroid drugs9.9Beta blockers7.9Psycholeptics5.6NSAIDs7.0Lithium 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 (e.g., tetracyclines [doxycyclin] and thiazide diuretics) [67].
Effect of psoriasis treatment on comorbidities
The importance of considering the impact of treatment of diseases associated with psoriasis cannot be stressed enough. Working with physicians in different specialties (e.g., rheumatology, gastroenterology and cardiology) 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 [2, 18, 31, 45]. The TNFα inhibitors etanercept and infliximab have demonstrated halting of joint degradation [45].
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 [50]. 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 [66]. Infliximab has been shown to be effective in both attaining and maintaining remission in CD patients [23] as well as in the treatment of extra-intestinal cutaneous manifestations [61]. Conversely, etanercept has not been shown to be effective in the treatment of CD and may even worsen the condition [52]. 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 [35].
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 [57]. Patients prescribed methotrexate had a significantly reduced risk of vascular disease compared with those who did not receive methotrexate (psoriasis, relative risk [RR] = 0.73; RA, RR = 0.83). Furthermore, risk reduction was greater in those who received a low cumulative dose of methotrexate (psoriasis, RR = 0.50; RA, RR = 0.65) and in those patients also receiving concomitant folic acid (psoriasis, RR = 0.56; RA, RR = 0.77). Further work in RA has suggested that anti-TNFα therapy may provide some cardiovascular protection [29]. A comparison of two cohorts, one receiving TNFα inhibitors and one receiving standard therapy (derived from patient registries), revealed a reduced age–sex adjusted incidence rate of first cardiovascular event in those receiving TNFα inhibitors compared with controls (14.0/1,000 person–years at risk vs. 35.4/1,000 person–years). After controlling for disability, the age–sex adjusted rate ratio was 0.46 (P = 0.013) 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 [24, 43]. 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 [49]. 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 (P = 0.004), a significant reduction in inflammatory markers (CRP 50%, P < 0.0001; ESR 28%, P = 0.005) and a significant reduction in swollen joint count (−2.69 vs −0.53; P = 0.0058) compared with placebo [43]. In addition, simvastatin treatment has been shown to significantly reduce serum CRP and TNFα in patients with RA and improve endothelial function [71]. 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 [49].
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 [8]. 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 [8].
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 (eg, angiotensin-converting enzyme inhibitors, beta blockers, NSAIDs) 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 (systemic) 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.

psoriasis inflammation comorbid biologics quality-of-life


Successful outcome of six-level cervicothoracic corpectomy and circumferential reconstruction: case report and review of literature on multilevel cervicothoracic corpectomy

The authors report the successful outcome of a six-level corpectomy across the cervico-thoracic spine with circumferential reconstruction in a patient with extensive osteomyelitis of the cervical and upper thoracic spine. To the authors’ knowledge, this is the first report of a corpectomy extending across six levels of the cervico-thoracic spine. Clinical relevance: the authors recommend anterior cage and plate-assisted reconstruction and additional posterior instrumentation using modern spinal surgical techniques and implants.
Introduction
Multi (two or more)-level disease of the anterior cervical and upper thoracic spine can occur from degenerative, traumatic, infectious, and neoplastic causes. Successful treatment is dependent upon adequate decompression, immediate spinal reconstruction, and ultimately, the achievement of bony fusion. Decompression of the anterior cervical spinal canal can be achieved either by anterior cervical discectomy and fusion (ACDF) or anterior corpectomy and fusion (ACF). Across multiple levels, ACF offers several advantages over ACDF, including wider decompression and more complete removal of pathology causing spinal cord compression, and fewer graft-host interfaces that must consolidate for successful bony fusion. Corpectomies of the cervical and cervico-thoracic spine have been reported to extend across as many as four levels [5, 15, 16]. More extensive corpectomies have not been reported perhaps because of concerns for instrumentation failure and expected difficulty in obtaining adequate exposure of the anterior cervicothoracic spine.
We present a successful six-level cervicothoracic corpectomy and circumferential reconstruction in a patient with vertebral osteomyelitis and epidural abscess.
Case report
History and presentation
A 50-year-old HIV-positive woman with a history of alcohol and drug abuse presented to our institution with a 7-month history of progressive neck pain, dysphagia, and radiculomyelopathy. Her past medical history was also significant for hepatitis B and multiple episodes of alcohol-induced acute pancreatitis. She denied a history of opportunistic infections. She had not been compliant with anti-retroviral therapy.
Physical examination
On physical examination, the patient was unable to extend her neck above the horizon and demonstrated 4+ out of 5 motor strength throughout all muscle groups. Preoperative halo traction was not applied as the patient reported an intolerable amount of pain with any manipulation of her cervical spine.
Imaging studies
Plain radiographs and computed tomography (CT) imaging demonstrated extensive bony destruction and a marked kyphotic angulation of the cervicothoracic spine (Fig. 1). Magnetic resonance imaging revealed extensive prevertebral and epidural enhancement surrounding the cervical and upper thoracic spinal cord resulting in circumferential narrowing of the thecal sac (Fig. 2). These findings were consistent with the diagnosis of vertebral osteomyelitis/discitis and epidural abscess.
Fig. 1(Left) Swimmer’s view radiograph demonstrating kyphosis related to C4–T2 osteomyelitis. (Right) Sagittal reformatted CT scan demonstrating extensive osseous erosion with kyphotic angulation from C6–T2. Note that the apex of the kyphotic deformity is at the junction of the cervical and thoracic spineFig. 2(Left) Sagittal T1 post-gadolinium MR sequence revealing extensive prevertebral and circumferential enhancing epidural abscess and enhancing vertebrae, compatible with osteomyelitis. (Right) Sagittal T2-weighted MR image demonstrating abnormal T2 signal within the spinal cord at the T1–2 level (arrow)
Operation
An anterior approach to the cervical spine was performed first. The patient was positioned supine with traction on a halo ring in extension to partially reduce the kyphotic deformity. Next, a longitudinal incision along the medial border of the right sternocleidomastoid muscle was made and connected to a median sternotomy which was performed for exposure of the T1–T3 vertebral bodies. Wide exposure of the C3–T3 vertebral bodies was then carried out. Leksell rongeurs were used to remove the C4, C5, C6, C7, T1 and T2 vertebral bodies down to the posterior longitudinal ligament. Next, an appropriately-sized lordotic titanium cage (Pyramesh; Medtronic Sofamor Danek, Memphis, TN, USA) was packed with iliac crest autograft and recombinant human bone morphogenic protein (rhBMP) and impacted into position. A slotted dynamic Aesculap ABC plate (Aesculap AG, Tutlingen, Germany, and Aesculap Instrument Corp., South San Francisco, CA, USA) was then affixed to the spine with variable-angle screws into the C3 and T3 bodies.
Next, the patient was turned prone and the halo head holder secured to a Mayfield frame. The posterior spine was dissected out from C1–T5 and Stealth image guidance (Medtronic Sofamor Danek, Memphis, TN, USA) was then used to place pedicle screws bilaterally at C2 and from T1–T4. Next, lateral mass screws were placed bilaterally at C3 and C4 and on the left side at C5. A laminectomy was performed from C4–T2. Tapered rods were then attached to the lateral mass and pedicle screws and secured bilaterally. Thorough decortication of the facet joints from C2–T4 was performed. Additional rhBMP and autograft was packed into the decorticated facets and lateral gutters. A lateral radiograph was obtained before closure to confirm satisfactory graft and hardware placement. After removal from the Mayfield frame, the halo brace and vest were then secured on the patient. Total blood loss was 2,000 cc and the total operating time was 8 h.
Postoperative course
Postoperative AP and lateral plain radiographs showed good hardware positioning with correction of the kyphotic deformity (Fig. 3). The patient was kept in the halo brace postoperatively. She began ambulating with physical therapy on postoperative day (POD) #3. She experienced improvement in her neurological symptoms during the hospitalization. Due to the extensive dissection of her anterior cervical spine, a feeding tube was placed in the immediate postoperative period and was removed on POD #15. She was discharged to home on POD #30 in good condition to complete a 6-week course of intravenous antibiotics for Staphylococcus aureus osteomyelitis.
Fig. 3Postoperative AP and lateral radiographs after six-level corpectomy from C4–T2, anterior interbody contoured cage and anterior plating from C3–T3. Posterior screw-rod fusion is evident from C2–T4. Note that the T1 pedicle screws have been shortened to avoid breeching into the cage anteriorly
Follow-up
At 4-month follow-up, the patient’s neurological exam was improved from presentation and she demonstrated full strength throughout all muscle groups, normal sensation and resolution of neck pain. She was able to ambulate without assistance and denied any problems with breathing or swallowing. Plain flexion-extension radiographs of the cervico-thoracic spine were obtained after the patient was removed from the Halo vest (Fig. 4). At last follow-up (2.5 years), the patient continued to remain neurologically intact without neck pain and no evidence of hardware failure.
Fig. 4Flexion (left) and extension (right) plain radiographs obtained at 4-month follow-up demonstrate good hardware positioning without graft dislodgment. Note that the significant correction of sagittal plane alignment is maintained. There is no motion of the instrumented spinal levels
Discussion
Anterior corpectomy and fusion is perhaps the most effective procedure for wide spinal cord decompression in patients with severe canal stenosis or pathology of the anterior spine [16]. Compared to more conventional surgical techniques for spinal cord decompression, such as ACDF, laminectomy, and laminoplasty, patients treated with ACF have better neurological recovery, less axial neck pain, and lower incidences of postoperative loss of sagittal plane alignment [21, 24, 25]. Extensive ACF involving three or more levels; however, involves more complicated surgical exposure and has been associated with increased rates of graft-related complications, including graft dislodgment, spinal cord compression, and pseudoarthrosis [12, 19, 20, 22]. That the anterior graft is subject to significant compressive forces after extensive ACF has been confirmed in biomechanical studies [8, 23]. Although each surgeon must take into account the clinical indications, risks and benefits of ACF in every patient, it seems logical to assert that the reported experience with ACF has been limited to four or fewer levels out of concern for these potential complications. Reconstruction after extensive ACF, therefore, is critical to prevent graft failure and allow for successful bony fusion.
Anterior column reconstruction after extensive ACF may be performed using strut grafts or titanium mesh cages. Allo- or auto-graft struts may subside into the adjacent vertebral bodies or dislodge and cause cord compression [6, 12, 26]. Titanium mesh cages offer several advantages over strut grafts, including better correction of sagittal alignment (with pre-contoured cages), better endplate purchase, variable height and diameter options, and the ability to be packed with auto- or allograft bone [4, 7, 13]. Indeed, we were able to achieve significant correction of sagittal alignment in our patient with the use of a lordotic titanium cage. The addition of anterior plate fixation after interbody grafting enhances the rigidity and stability of the construct and therefore lowers the risk of graft-related complications [3, 5, 9, 16, 20]. Supplemental posterolateral fixation after extensive ACF has been found to further decrease the rates of graft-related complications, deformity correction loss, and pseudoarthrosis rates [8, 10, 16, 18, 20, 23]. Nevertheless, even with posterolateral fixation, in our experience there is inevitably a certain amount of subsidence of the anterior graft after extensive ACF. We used a slotted dynamic plate that allows for changes in the angle and alignment of the vertebral body screws to accommodate this expected subsidence (Fig. 4). Other options to prevent subsidence-related failure of the anterior plate include using a cage only (no plate), buttress plates, or creating flanges in the cage that overlap the adjacent vertebral bodies and are secured with non-constraining screws [1].
It is important to note; however, that we did not perform postoperative CT to demonstrate bridging trabecular bone and therefore cannot definitively conclude that successfully bony fusion occurred in our patient. Nevertheless, we believe the absence of hardware motion on flexion-extension plain radiographs at 4-month follow-up does demonstrate the stability of this patient’s extensive construct. Our patient has subsequently been lost to follow-up and it must be recognized that a pseudoarthrosis may manifest only after several years with a slowly progressive kyphosis.
Finally, both in vitro and in vivo studies have shown that BMP and rhBMP can promote bony fusion and arthrodesis [2, 11, 14, 17, 27]. While fusion-promoting agents such as rhBMP are expensive and their use in the cervicothoracic spine is ‘off-label, we believe it may improve the likelihood of fusion after the very extensive bone removal and instrumentation during this procedure and their use is therefore justified.
Conclusions
A six-level corpectomy across the cervico-thoracic spine can be safely performed by combining a traditional longitudinal exposure of the cervical spine with a median sternotomy. Circumferential reconstruction with modern implants, such as an anterior contoured titanium cage-dynamic plate construct and posterior screw-rod fixation, is necessary to provide sufficient stability of the cervico-thoracic spine to allow for correction of sagittal alignment and to achieve bony fusion. While the lack of a CT scan demonstrating bridging trabecular bone precludes a conclusion that radiographic fusion occurred in our patient, we believe that the absence of new or worsening clinical symptoms at 2.5-year follow-up demonstrates the long-term stability and potential for successful fusion of this reconstruction. Fusion-promoting agents may be used to increase the fusion rate of these kinds of constructs with substantial bone loss and use of extensive instrumentation systems.

corpectomy
reconstruction
fusion
cervical spine
internal fixation


An X-ray template assessment for distal radial fractures

Background The current method for radiological measurements on plain X-rays of distal radius fractures is unreliable. We examined the reproducibility of a new X-ray assessment technique—where the uninjured side is used as a template for the injured side—compared to the conventional assessment technique.
Introduction
The important factors for decision-making in the treatment of distal radial fractures include the patient’s vitality, fracture classification, fracture dislocation and soft tissue condition. Distal radial fracture deformities are quantified by X-ray measurements which are also used to classify the result after reduction (e.g., good or fair result) [1, 2]. However, the clinical usefulness of X-ray measurements is hampered by their limited reproducibility [3, 4]. It is also recognized that the modest reproducibility of X-ray deformations is one of the keystones for the lack of reproducibility in the treatment of distal radial fractures [3–5]. Clearly, when measurements cannot be made reliably, a straightforward clinical comparison of treatment techniques or reduction results is impossible, making it difficult to come to level 1 evidence-based treatment results and advices.
Other studies that have evaluated sources of variance in the assessment of the quantitative X-ray measurements have reported difficulties with respect to the determination of the radial axis in the anterior–posterior (AP) view, which is essential to assess the radial height and the radial inclination. This is obviously much less a problem in the lateral view, where the higher reproducibility value was found [6]. A second source of inaccuracy might be the use of the existing normal values for radial length (11 mm), radial angle (22°) and volar angulation (10°) [7–11], despite the normal variation that exists within the population [12].
To circumvent these difficulties, we designed a technique to assess fracture deformities of the distal radius that is based on the comparison of the injured side to the uninjured side. The approach is based on research findings that indicate that the patients’ left and right side are comparable [13]. The aim of the study was to evaluate the reproducibility of the template assessment technique as compared with the direct quantitative measurement technique. We also examined whether the new technique resulted in a more reliable classification of reduction results for distal radius fractures.
Materials and methods
Inclusion criteria
Patients aged 18 years or above with a unilateral dislocated distal radial fracture with the history of neither a distal radial fracture nor a distal radial operation were included after informed consent was taken. A stratification for the AO fracture types was performed to reflect the prevalence in clinical practice at a ratio of 5:2:3 for the AO type A, B and C distal radial fractures. The standard post-reduction (postero-anterior (PA) and lateral) X-rays and standard distal radius X-rays of the unaffected side of 30 consecutive patients visiting the emergency department were included after stratification for AO fracture type.
Eight experienced observers, 4 trauma surgeons, 3 orthopedic surgeons and 1 trauma radiologist, independently measured the X-rays and subsequently classified the reduction results using the Lidström score (Fig. 1).
Fig. 1Anatomical radiological classification for distal radial fractures according to Lidström
In the first direct measurement round, the x-rays were only measured quantitatively. The radial length and the radial inclination were measured on the posterior–anterior plain X-ray film, while the dorsal/volar angulation was measured on the lateral X-ray film. The measurements were performed with a goniometer and a ruler. The normal values for radial length (11 mm), radial inclination (22°) and volar angulation (10°) were used to assign a Lidström score (Fig. 2).
Fig. 2Normal value measurement of the distal radius
During the second round, scheduled 2 months later, the template measurement technique of comparing the fractured side with the unaffected side was performed by the same observers measuring the X-rays of the same patients. The observers were instructed to assign a Lidström score using the X-rays of the unaffected distal radius as a template for the fractured side (Fig. 3). The templates of the unaffected side were made by the investigators on transparent sheets, by tracing the distal radius, ulna and first carpal row from the unaffected side plain PA X-Ray film on a overlaid transparent sheet. For the lateral film, only the distal radius and the lunate bone from the unaffected side were drawn on to the overlaid transparent sheet. The reference points on the AP templates were the ulna and/or the first carpal row (Fig. 3). On the lateral template, the reference points were the radial shaft/and or the lunatum. The measurements again were done with a goniometer and a ruler. And again the results were used to assign a Lidström score.
Fig. 3Measurements of distal radial fractures using the unaffected side as template
Statistical analysis
Overall inter-observer reproducibility of quantitative X-ray measurements for the difference in radial length, radial inclination and volar angulation for the eight observers was estimated using intraclass correlation coefficients (case 2, 1) [14]. The reproducibility of the ordinal Lidström scoring was quantified using a weighted kappa coefficient (Kw). Since intraclass correlations (ICC) and Kw are computationally equivalent [15], both were interpreted using the arbitrary classification proposed by Landis and Koch [16]: <0.00 poor; 0.00–0.20 slight; 0.21–0.40 fair; 0.41–0.60 moderate; 0.61–0.80 substantial and 0.81–1.00 almost perfect agreement. Calculation of the reproducibility coefficients were carried out considering the pair-wise ratings of all possible combinations of observers. For example, observer 1 and 2, observer 1 and 3, observer 1 and 4, and so on to observer 1 and 8. Then observer 2 and 3, observer 2 and 4, observer 2 and 5 and so on to observer 2 and 8. This was done for each observer to the last observers 7 and 8. For 8 observers and 30 X-rays this resulted in 28 (8 × 7/2) possible pairs times 30 X-rays, totalling 840 pairs of observations. Sample size and number of observers were chosen to accommodate the precision of the reproducibility estimates we wanted to achieve. When the number of observations is 840, a 2-sided 95% confidence interval (CI) for a reproducibility coefficient arbitrarily set at 0.40 will extend 0.05 around the point estimate (from 0.35 to 0.45). Statistical evaluations were carried out using SPSS 11.5 and StatXact 3.02 for Windows.
Results
Thirty patients with distal radial fractures were included. Of these patients, 15 fractures were of AO classification group A, 6 AO classification group B and 9 of AO classification group C.
Table 1, shows the reproducibility coefficients for the direct quantitative X-ray measures and the template assessment technique. Slight and insignificant increases in ICCs (95% CI) were observed for the radial length from 0.53 (0.48/0.57) to 0.54 (0.49/0.59) and volar angulation from 0.60 (0.56/0.64) to 0.64 (0.60/0.68). Marked improvements in reproducibility were observed for the radial inclination measurements. Intraclass correlations increased from 0.36 (0.30/0.41) with the old technique to 0.49 (0.43/0.55) with the template technique. The overall kappa for the Lidström score in the old technique was 0.37 (0.31/0.43) and improved in the template technique to 0.59 (0.52/0.63).
Table 1Reproducibility coefficients for the X-ray measurements: old direct measurement technique versus template technique (N = 840 observations)MeasureaOld technique (95% CI) Template technique (95% CI)Radial length 0.53 (0.48/0.57)0.54 (0.49/0.59)Radial inclination 0.36 (0.30/0.41)0.49 (0.43/0.55)Volar angulation 0.60 (0.56/0.64)0.64 (0.60/0.68)Lidström0.37 (0.31/0.43)0.59 (0.52/0.63)aCategorical data, weighted kappa, numerical data, ICC
Discussion
Compared to the traditional quantitative technique, the template assessment technique resulted only in an improved inter-observer reproducibility for the radial inclination. There were slight improvements in reproducibility of the radial length and volar angulation. However, there was a notable improvement in the reproducibility of reduction results as assessed using the Lidström score.
The results of the quantative measurements of radial length and radial inclination are comparable to those reported by Kreder et al. They reported an inter-observer reliability coefficient of 0.49 for the radial length, and 0.32 for the AP radial angle [6]. As in our study, a better reproducibility was found for the volar angulation on the lateral view.
In this comparative study we had the same observers and the same patients with a 2-month interval and X-rays presented in another sequence order to overcome possible bias. The patients’ sample was chosen to reflect the daily practice in which the AO type A fractures are more frequent than the Type B and C.
One could argue that the use of normal values for the traditional quantitative measurement technique would negatively affect its reproducibility since there is variation in anatomical proportions between individuals in the population. For example, the ulnar length varies within 30% of the population [12]. Therefore, the use of normal values may lead to inaccurate classification of the reduction result. However, in our study, the comparison with the normal values did not negatively influenc the reproducibility, since all observers used the same values. By doing so, the only source of error left was the direct measurement of the fractured side. When the normal side is used to compare with in the classical measurement way, there would be measurement errors of the fractured side and of the uninjured side.
The improved reproducibility of the fractures deformity classification as expressed by the Lidström score (from 0.37 to 0.59) was primarily due to improvement in measurement of the radial inclination in the template technique. By using the template technique for the Lidström score, one could expect the most improvements in both the radial length and radial inclinations. The volar angulation would not be expected to improve much since it is measured independently from the other side (Fig. 1).
Surprisingly, we could not demonstrate an influence of the template technique for the radial length in this study, although it is partly dependent on the position of the radial axis on the PA view and could therefore benefit from templating. An explanation for this phenomenon could be that for measuring the difference in radial height (as shown in Fig. 3), there is still an axis needed. This becomes more eminent as the radial styloid is displaced more laterally (or rotated) and both tips of the radial styloid are not in line with the radial axis any more. Differences in placing the axis could be a source for variance, leading to a limited improvement in the Kappa value. In contrast, the radial inclination on the PA view in the template technique is basically independent of the radial axis and therefore more easy to measure with the template.
A limitation of the template technique is that it may not be applicable in patients with a bilateral fracture or patients with a history of a distal radial fracture or deformity on the other side. In this study, only patients with a unilateral distal radial fracture were included, reflecting the most common occurrence of distal radial fractures.
Another limitation of this study was that, in order to avoid learning curves, only experienced observers were used, which may not always be the case in daily practice. Also, the templates of the unaffected side were made by the same investigator. In daily practice, making the template could also be a source of variation since the correct position of the templates may be more difficult in case of severe dislocation or with slight differences in projection of the bones due to the angle of the X-ray beam. Perhaps the use of digital subtraction may be helpful to overcome this.
In conclusion, by using the template technique for X-Ray measurement we improved the reproducibility of the classification of radiological dislocation of distal radius fractures which is a step to come to evidence based distal radial fracture treatment as outlined in two recent Cochrane reviews [4, 5]. This procedure can also be performed for other radiological parameters such as ulnar variance. Future research should focus on the improvement of the template technique and the use of digital measurement—subtraction techniques/software modules in this time of filmless X-Ray pictures.

x-ray
distal radial fractures
radius
radius fracture
classification