Use of FDG-PET in differentiating benign from malignant compression fractures

Objective The objective was to evaluate the use of fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating benign from malignant compression fractures.
Introduction
Differentiating between malignant and benign vertebral compression fractures can represent a diagnostic challenge and is particularly difficult in elderly patients, who frequently have a history of malignancy and are also predisposed to benign compression fractures from osteoporosis or treatment-related changes [1–3]. Differentiating between benign and malignant compression fractures has important therapeutic and prognostic implications.
Computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used in the evaluation of compression fractures; however, these imaging modalities do not always permit definite diagnosis [2–5]. In contrast to MRI or CT, fluorodeoxyglucose positron emission tomography (FDG-PET) can yield metabolic information that is based on increased glucose metabolism of malignant and inflammatory lesions. Tumor cells typically accumulate FDG, while traumatic fractures are not expected to significantly accumulate FDG. Therefore, FDG-PET may allow differentiation between malignant and benign compression fractures [6–9].
The purpose of our study was to evaluate the use of FDG-PET in differentiating benign from malignant compression fractures.
Materials and methods
This study was approved by the institutional review board of our institution, which waived the need for informed consent. The study was compliant with the Health Insurance Portability and Accountability Act. A retrospective search was performed using Boolean operators (Folio; Open Market, Proto, UT, USA) to identify all patients who had undergone whole-body FDG-PET at our institution from 2003 to 2006 and had the finding of a compression fracture mentioned in the PET report. Imaging studies and reports, medical records, and pathology reports of selected cases were reviewed.
Patients
We identified 33 patients with compression fractures who underwent whole-body FDG-PET. There were 23 women and 10 men, aged 48–93 years, with a mean age of 72 years. Twenty-nine patients had a history of malignancy (1 had leukemia, 5 lung cancer, 1 ovarian cancer, 2 breast cancer , 5 colon cancer,  9 lymphoma, 1 sarcoma, 1 pancreatic cancer, 1 Klatskin tumor, 1 gastrointestinal stromal tumor,  1 laryngeal cancer, and 1 had esophageal cancer). The 4 patients without history of malignancy underwent whole body PET for work-up of indeterminate lung nodules detected on prior CT or radiographs. Sixteen patients underwent FDG-PET and 17 patients underwent FDG-PET/CT at time of evaluation. Nine patients underwent CT and 14 patients underwent MRI of the spine within 4 weeks of FDG-PET. Seventeen patients were followed up with serial FDG-PET studies. Nine patients underwent biopsy and the pathologic results were used as a standard of reference. Twenty-four patients who did not undergo biopsy were followed up clinically and with repeat imaging, with MRI, CT, or FDG-PET for a period of 1–3 years and findings at clinical follow-up and imaging studies were used for lesion verification. In these patients, the development of new lesions and/or progression of existing lesions on imaging were used as criteria for malignant compression fractures.
Image acquisition
Whole-body PET was performed using an ECAT HR+ scanner (CTI Molecular Imaging, Knoxville, TN, USA). All patients fasted for at least 6 h prior to image acquisition, and blood glucose levels were measured prior to the injection of FDG. A dose of 15–20 mCi (555–740 MBq) of FDG was administered intravenously 45 min to 1 h prior to scanning.
Patients were positioned supine on the scanner and emission images were acquired in 6–7 bed positions from the mandible to the mid-thigh or to the level of the ankles in the case of lower extremity lesions. Transmission images obtained with a rotating germanium 68-rod source were used for attenuation correction. Images were reconstructed using the ordered-subset expectation maximization (OSEM) algorithm.
Combined PET/CT studies were performed with a 16-section hybrid PET/CT gantry (Biograph Sensation 16; Siemens, Erlangen, Germany), which comprises a 16-section high-performance multi-detector row CT scanner with a lutetium oxyorthosilicate-based PET scanner. The PET image spatial resolution was 5.0 mm full width at half maximum, with a section thickness of 3.5 mm. Patients fasted for at least 6 h prior to image acquisition, and blood glucose levels were measured prior to the injection of FDG. Two 10-oz cups of water were administered as negative contrast material 1 h prior to scanning. A dose of 15–20 mCi (555–740 MBq) of FDG was administered intravenously 45 min to 1 h prior to scanning. Patients were positioned supine on the scanner and emission images were acquired in 6–7 bed positions from the mandible to mid-thigh or to the level of the ankles in the case of lower extremity lesions. Images were reconstructed with Fourier rebinning and attenuation-weighted ordered-subsets expectation maximization. A low-dose CT scan was performed prior to PET imaging primarily for attenuation correction, with patients holding their breath mid-expiration, and included an area from the mandible to the mid-thigh or to the level of the ankles in the case of lower extremity lesions. Slice thickness was 5 mm. A diagnostic contrast-enhanced CT was performed subsequent to the PET/CT following the administration of 100 mL intravenous contrast material (Isovue 300; Bracco Diagnostics, Princeton, NJ, USA) at an injection rate of 2 mL/s using 2.5-mm sections.
Image analysis
Semiquantitative and qualitative evaluation of PET images was performed on a high-resolution workstation (Reveal-MVS; Mirada Solutions, Oxford, UK) by one investigator, who was blinded to the clinical and pathological results (MAB). The images were displayed in rotating maximum intensity projections and in axial, coronal, and sagittal planes. Semiquantitative analysis of FDG uptake was performed by creating a region of interest over the area of maximal radiotracer activity.
Maximum standardized uptake values (SUVs) were automatically generated according to the following equation: SUVmax (bw) = Ctis/Dinj/bw, where SUVmax (bw) is maximum SUV normalized for body weight; Ctis, tissue concentration expressed as megabecquerels per milliliter; Dinj, injected dose expressed as megabecquerels; and bw, body weight expressed as kilograms. Lesions with SUV greater than 3.0 were considered malignant and less then 3.0 were considered benign. However, lesions with SUV between 2 and 3 are often indeterminate and do not always allow definite diagnosis, and also the pattern of uptake has to be considered. Qualitative assessment was made with the specific aim of establishing whether the lesion was benign or malignant. The radiotracer uptake by the lesion was compared with the liver, and those lesions with uptake greater than the liver were classified as malignant.
Statistical analysis
The recorded data were analyzed using JMP statistical database software (SAS Institute, Cary, NC, USA). The findings on the PET images as well as SUV of benign and malignant compression fractures were correlated with the final diagnosis of the lesion and determined either malignant or benign. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. The Student’s t test was used to determine whether there was a statistically significant difference between the SUV for benign and malignant compression fractures. A difference with p < 0.05 was considered to be statistically significant.
Results
Forty-three compression fractures were identified in 33 patients. Twenty-two fractures involved the thoracic and 21 fractures the lumbar spine. Nine patients underwent biopsy and 24 patients were followed up clinically and with repeat imaging. In the 9 patients who underwent biopsy, there were 3 benign and 6 malignant compression fractures. Of the 24 patients who were followed clinically and with repeat imaging, 6 patients were thought to have malignant and 18 patients were thought to have benign compression fractures. Overall, there were 21 patients with benign and 12 patients with malignant compression fractures. Out of the 43 compression fractures, there were 29 benign and 14 malignant fractures.
Based on clinical history (acute onset of back pain often after minor trauma) and imaging characteristics on MRI (bone marrow edema) there were 5 acute benign compression fractures. Three patients were on bone marrow-stimulating therapy at the time of FDG-PET. Five patients were unable to undergo MRI because of pacemakers (3) or severe pain.
Qualitative PET analysis
Forty-three compression fractures were identified in 33 patients. Visual inspection of suspected lesions on FDG-PET characterized 26 compression fractures as benign and 17 fractures as malignant. The malignant lesions demonstrated intense radiotracer uptake (Figs. 1, 2), while benign compression fractures showed only mildly increased or no increased uptake on FDG-PET (Figs. 3, 4). Histological and clinical follow-up data were analyzed. By FDG-PET, 12 lesions were correctly classified as malignant (true-positive) and 24 lesions were correctly classified as benign (true-negative). Two malignant tumors were incorrectly classified as benign (false-negative) and 5 benign tumors were incorrectly classified as malignant (false-positive). In the 2 false-negative cases there was moderately increased uptake of the compression fractures, which was thought to represent acute benign fractures prospectively, but was found to be metastatic disease on subsequent biopsy (Fig. 5). SUV in these patients were 2.5 to 2.8 respectively, and the primaries in these cases were esophageal and lung cancer.
Fig. 1a Malignant compression fracture in a patient with lymphoma. Sagittal FDG-PET image demonstrates intense radiotracer uptake in the L1 vertebral body (SUV = 7.1; arrow). b Axial FDG-PET image demonstrates tumor infiltration of the L1 vertebral body with associated extra-osseous component (arrows). c Sagittal T1-weighted MRI demonstrates diffuse low signal intensity of the bone marrow of the lumbar spine with compression fracture of L1 (arrow). d Sagittal fat-suppressed T1-weighted MRI following the administration of gadolinium demonstrates diffuse enhancement of the L1 compression fracture (arrow). e Axial image from a CT-guided biopsy demonstrates large extra-osseous soft tissue component (white arrow) and infiltration of the L1 vertebral body (black arrows)Fig. 2a Malignant compression fracture from metastatic colon cancer. Sagittal fused FDG-PET/CT image demonstrates intense radiotracer uptake in the T7 compression fracture (SUV = 6.3; arrow). b Axial fused FDG-PET/CT image demonstrates focal increased radiotracer uptake in the T7 vertebral body (arrow). c Sagittal T1-weighted MRI demonstrates compression fracture of T7 with low signal marrow infiltration (arrow). d Sagittal STIR image demonstrates mild hyperintensity of the T7 vertebral compression fracture (arrow). e Sagittal fat-suppressed T1-weighted MRI following the administration of gadolinium demonstrates diffuse enhancement of the T7 compression fracture (arrow). Malignancy was indeterminate on MRIFig. 3Benign compression fracture in a patient with lymphoma. Sagittal fused FDG-PET/CT image demonstrates compression fracture of T9 (arrow) without significant radiotracer uptake (SUV = 0.7)Fig. 4a Benign subacute compression fractures in a patient without history of malignancy. Sagittal FDG-PET image demonstrates mildly increased radiotracer uptake in the upper thoracic spine (SUV = 1.8; arrow). b Axial FDG-PET image at the level of T4 demonstrates mildly increased radiotracer uptake (arrow), consistent with subacute compression fracture. c Sagittal CT image demonstrates compression fracture of T4 (arrow) and multiple chronic osteoporotic compression fractures throughout the thoracic spineFig. 5a False-negative compression fracture on FDG-PET in a patient with metastatic esophageal cancer. Sagittal fused FDG-PET/CT image demonstrates mild to moderately increased radiotracer uptake in the L2 compression fracture (arrow; SUV = 2.5) that was thought to represent a benign compression fracture but was found to be malignant on subsequent biopsy. Note the mildly increased radiotracer uptake in the T11 compression fracture (arrowhead), which was thought to represent a benign fracture. b Axial fused FDG-PET/CT image demonstrates increased radiotracer uptake in the L2 vertebral body (arrow). c Sagittal CT image demonstrates L2 and T11 compression fractures (arrows), for which malignancy was indeterminate
Three of the false-positive patients were on bone marrow-stimulating agents (Fig. 6). One of the false-positive patients had an acute compression fracture (Fig. 7). Except for that patient, there was no significant difference in uptake pattern of benign acute and benign chronic compression fractures (Fig. 8).
Fig. 6a False-positive compression fracture in a patient on bone marrow-stimulating agents. Sagittal FDG-PET image demonstrates diffuse increased radiotracer activity throughout the spine. Note the compression fractures with focal kyphotic angulation at L1–L2 (arrow). The patient was thought to have diffuse metastatic disease with malignant compression fracture. b Sagittal FDG-PET image performed 2 months later demonstrates resolution of diffuse radiotracer uptake. Kyphotic angulation from compression fractures remains (arrow). The patient was off bone marrow-stimulating agents for 6 weeks at the time of the studyFig. 7a False-positive compression fracture in a patient with laryngeal cancer. Sagittal fused FDG-PET/CT image demonstrates increased radiotracer uptake in the T12 compression fracture (SUV = 4.9; arrow). b Sagittal T1-weighted MRI demonstrates compression fracture of T12 with linear low signal of the superior endplate and preservation of the normal marrow signal (arrow). Note compression fracture of L1 with relative preservation of normal marrow signal (arrowhead). c Sagittal STIR image demonstrates hyperintensity of the superior endplates of the T12 and L1 compression fractures, suggesting acute fractures (arrows). d Sagittal fat-suppressed T1-weighted MRI following the administration of gadolinium demonstrates enhancement of the T12 compression fracture (arrow). Mild enhancement is noted, involving the L1 compression fracture (arrowhead). Findings were thought to be benign on MRI and on follow-up imaging, there was resolution of bone marrow edema and enhancementFig. 8a Acute and chronic benign compression fractures in a patient without history of malignancy. Sagittal fused FDG-PET/CT image demonstrates multiple compression fractures throughout the thoracic and lumbar spine with mild increased radiotracer uptake at T11 (SUV = 2.1; arrow). b Sagittal T1-weighted MRI demonstrates multiple chronic compression fractures (arrowheads). Mild decreased signal intensity of the T11 compression fracture suggests edema (arrow). c Sagittal STIR image demonstrates mild edema in the T11 compression fracture suggestive of an acute fracture (arrow). There is no evidence of marrow edema in the remaining compression fractures
Quantitative PET analysis
Standardized uptake values were measured in all 43 compression fractures. SUV for benign compression fractures ranged from 0.7 to 4.9 with a mean of 1.94 ± 0.97 standard deviation (SD) on FDG-PET. Malignant compression fractures showed SUV from 2.2 to 7.1 with a mean of 3.99 ± 1.52 SD on FDG-PET. The difference between the SUV values of benign and malignant compression fractures was statistically significant (p < 0.001, Student’s t test; Fig. 9).
Fig. 9Mean standardized uptake value (SUV) of benign and malignant compression fractures. The top of the boxes represent the mean and error bars represent the range of SUV. There is a statistically significant difference between the SUV values of benign and those of malignant compression fractures (p < 0.001, Student’s t test)
Statistical analysis
Sensitivity, specificity, positive and negative predictive values, and accuracy of FDG-PET in differentiating benign from malignant compression fractures were 86%, 83%, 84%, 71%, and 92% respectively.
Discussion
The correct diagnosis of benign and malignant compression fractures can be problematic, but has important prognostic and therapeutic implications. MRI, CT, or bone scintigraphy are commonly used in the diagnostic work-up of patients with compression fractures. However, in some cases, these imaging techniques do not permit definite diagnosis of the cause of the compression fracture. Diffusion-weighted MRI has been used successfully to differentiate benign from malignant fractures [10–13], but benign and malignant compression fractures can show significant overlap on quantitative assessment with apparent diffusion coefficient maps [12]. Also, some patients are unable to undergo MRI due to pacemakers, claustrophobia, or severe pain. This is especially true in the elderly population. Five of our 33 patients were unable to undergo MRI.
In this context, metabolic imaging modalities such as FDG-PET might be used as a management problem solver. FDG-PET has been successfully used to differentiate benign from malignant neoplasms and in the evaluation of metastatic disease [14–16]. Preliminary studies and case reports have shown that FDG-PET might be helpful in differentiating benign from malignant compression fractures [8, 9]. Since elderly patients often have a history of malignancy and are also predisposed to benign compression fractures due to osteoporosis, we thought that FDG-PET might be used as a diagnostic problem solver in this patient population in cases of equivocal MRI or CT findings or if the patient was unable to undergo MRI.
In our study, malignant compression fractures demonstrated significantly increased FDG uptake compared with benign fractures. Mean SUV of malignant and benign fractures were 3.99 ± 1.52 SD for malignant lesions and 1.94 ± 0.97 SD for benign lesions. There were 2 false-negative results. In these cases there was moderately increased uptake of the compression fractures, which were thought to be acute benign fractures prospectively, but were found to represent metastatic disease on subsequent biopsy. SUV in these patients were 2.5 to 2.8 respectively.
There were 5 false-positive results; 3 of those patients were on bone marrow-stimulating agents, which mimicked tumor involvement. This effect on bone marrow FDG uptake has been described in the literature [17]. One to 2 months after cessation of bone marrow-stimulating therapy, FDG uptake returned to normal in our patients. The false-positive results occurred because the investigator was blinded to the clinical history. This is less likely to occur in a clinical setting where this history should be actively sought when interpreting positive findings, especially in cases of diffuse osseous uptake, mimicking a diffuse marrow infiltrative process as was seen in our cases. In fact, when we reviewed the original reports, these cases were reported to be consistent with the known use of bone marrow-stimulating agents.
Only mildly increased or no increased uptake was seen in chronic benign fractures and mild to moderately increased uptake was seen in acute benign fractures, which was less than in malignant fractures. This is in contrast to bone scintigraphy, in which increased uptake persists for many months [18].
Positron emission tomography and PET/CT were equally sensitive in differentiating benign from malignant compression fractures. However, the CT portion of the PET/CT improved the exact fracture localization and was able to provide additional information on fracture morphology, which can be helpful in diagnosing benign vs. malignant fractures.
Our study had several limitations. The first is the retrospective nature of the study. Second is the lack of histologic correlation in all cases. Only 9 patients underwent biopsy of the spine. However, we obtained clinical follow-up and serial imaging studies, including serial FDG-PET for a period of 1–3 years to evaluate for benign or malignant fractures. Also, there were no patients with osteomyelitis/discitis, which can mimic malignancy [8, 19, 20]. Another limitation is the lack of inter-observer variability, since only one observer interpreted the images. However, we compared our results with the reports of the original interpreter, who had access to all data. On the original reports, the 3 cases of patients on bone marrow-stimulating agents were interpreted as being consistent with the known use of bone marrow-stimulating agents. Malignancy was said to be indeterminate in the two false-negative reports. However, in our review, we categorized each fracture as either benign or malignant without the option of an indeterminate lesion.
In summary, FDG-PET is a useful method of differentiating between benign and malignant compression fractures and can serve as a problem solver in cases of equivocal MRI or CT findings, and in patients who are unable to undergo MRI. We do not recommend FDG-PET as a screening test, but rather as an additional imaging modality in problem cases, particularly in elderly patients with osteoporosis and a history of malignancy. In these patients, FDG-PET has the additional advantage of being able to evaluate the entire skeletal system and screen for metastatic disease.

fdg-pet
benign
malignant
compression fractures
spine


Variables affecting the probability of complete fusion of the medial clavicular epiphysis

In this study, we have combined data on clavicle fusion from different studies and applied a binomial logistic regression analysis. As such, we aimed to assess whether or not variables such as sex, socioeconomic status, and ethnicity influence the probability of having mature, i.e., completely fused clavicles at a given age. We further explored whether the method of clavicle examination, i.e., diagnosis from either a dry bone specimen, an examination of X-rays, or an examination of computed tomography scans, affects the probability of being diagnosed with mature clavicles. It appeared that only ethnicity did not significantly affect this probability. Finally, we illustrated how the logit model may be used to predict the probability of being diagnosed with mature clavicles.
Introduction
The medial (or sternal) clavicular epiphysis matures relatively slowly. In the human skeleton, it is generally the last long bone epiphysis to fuse. Its developmental stage is therefore useful when estimating age at death in the post-pubertal period [1] or the age of living persons involved in criminal proceedings [13, 15]. In the Netherlands, a radiological clavicle examination may be applied to verify the age of young asylum seekers without valid identification documents.
Various authors have studied clavicle development to determine the age interval in which fusion of the clavicular epiphyses occurs. Most of the published studies were based on the examination of dry bone specimens [3, 6, 9, 10, 17, 18]. When dealing with living individuals, examiners analyzed either X-rays [4, 13] or computed tomography (CT) scans [5, 15, 16]. In a number of studies, the results for different ethnic groups were evaluated or the results for males were compared with those for females. In most studies, such comparisons were, however, hampered by a relatively small sample size.
In this study, we aim to assess from a large sample whether or not variables such as sex, socioeconomic status, and ethnicity affect the probability of having completely fused clavicles at a certain age. We further aim to compare results from X-ray and CT scan examinations with those from studies based on dry bone specimens. To do so, we have combined data from different studies and performed a binomial logistic regression analysis. We then illustrate how the resulting model can be applied to estimate the probability of completely fused clavicles at a given age.
Data
Published and unpublished data on the individual subjects, taken from various studies on clavicle development [3–6, 8, 10, 13, 15, 18] were combined. For each individual, information on the calendar age in years was combined with data on the fusion status of the clavicle, i.e., exhibiting a complete bony fusion of epiphysis and diaphysis (i.e., mature) or not. When data for both left and right clavicles were published, we used the side for which most records were provided. Data on the sex and ethnicity of the individuals were copied when available. In the context of this study, we defined ethnicity as being either of European (Caucasian), Asian, or Afro-American descent. It was further recorded which method was used for determining the fusion status, i.e., using dry bone specimens, X-rays, or CT scans.
The socioeconomic status of individuals was estimated from the human development index (HDI) associated with the country in which the study took place. The HDI is a summary composite index that measures a country’s average achievements in three basic aspects of human development: longevity, knowledge, and the standard of living [19]. The HDI is used by the United Nations Development Programme, and data are available from 1975 onward. To accommodate data from two American studies that took place before this year [6, 18], we extrapolated the HDI by first calculating the linear regression of the HDI on time.
In total, data of 3,552 individuals aged 15–33 years were combined. Figure 1 shows the age distribution within the sample. Table 1 provides further information on the number of individuals per category.
Fig. 1Age distribution of individuals in the sampleTable 1Number of individuals per categoryCategoryValuesTotal number of individuals3,552SexMales2,133Females1,123Unspecified296EthnicityaEuropean descentb1,316Afro-American descent287Asian descent695Unspecified1,254MethodDry bone specimen1,374X-ray1,326CT scan852aA small number of individuals in McKern and Stewart [6] were of Afro-American descent. As no individual data were provided, all 374 individuals are classified “of European descent”.b“Of European descent” includes Caucasian and Latino individuals from North America.
Statistical analysis
Analysis of the data was performed using the SPSS (version 10.0) software package for statistical analysis. We carried out a binomial logistic regression analysis to assess the effect of various variables on the probability of mature clavicles. In logistic regression, the dependent variable is transformed into a logit variable, i.e., the natural log of the odds of the dependent occurring or not. This transformation ensures that the estimated probabilities are between 0 and 1. A logit model is a form of the generalized linear model.
Age, sex, ethnicity, and socioeconomic status were considered as potential predictor variables for the probability of mature clavicles. The method of clavicle examination was further considered as a factor influencing the probability of being diagnosed with mature clavicles. Age and socioeconomic status (i.e., HDI) were analyzed as covariates. Sex, ethnicity, and the method of clavicle examination were analyzed as fixed factors. Possible interaction between these fixed factors and the covariate age was also investigated. The initial (exploratory) logit model may be described by the following equation:
where p denotes the probability of the dependent, α the intercept, β the estimated effect of a covariate or factor-by-covariate interaction term on the logit of the probability, and γ the estimated effect of a fixed factor.
Variables to be kept in the model were selected by means of backward elimination using the Wald test. Insignificant interaction terms were successively dropped. After each alteration to the exploratory model, possible significance of the remaining variables was reassessed. A p value lower than 0.05 was considered to be statistically significant.
Not all studies that were used as a source for our data provided individual data on sex or ethnicity. Consequently, the described model (M1) could be tested on the data of a subgroup of 2,002 individuals only. No data from CT scans were available for this subgroup. To be able to include data from all available studies, we therefore also tested simplified models. For the first of these simplified models (M2), we omitted the variable ethnicity and the associated interaction term from the initial model. This model could be fitted to the data of a subgroup of 3,256 individuals. For this subgroup, data resulting from the evaluation of CT scans were drawn from a single study [15], as the second available study [5] did not provide details on the sex of individuals. As a next step, we therefore further omitted the variable sex and the associated interaction term from the initial model. The resulting model (M3) could be fitted to the data of all 3,552 individuals. As a final step, we assessed the significance of the change in −2 log likelihood between the resulting model and a nested model including the main terms only. We further compare the Nagelkerke pseudo R2. As such, we compare the difference in model fit.
Results
Table 2 provides the results for the three different models. Model M1 resulted in a p value higher than 0.05 for ethnicity after all non-significant interaction terms had been removed. Tested for a subgroup of 2,002 individuals, ethnicity therefore did not appear to affect the probability of having mature clavicles. Including this variable in the model does not improve the model fit. Exploring model M1 therefore effectively resulted in model M2, which could be fitted to the data of 3,256 individuals.
Table 2Estimated parameters of logistic regression models for the logit of the probability of mature claviclesModelIndependent variablesBStandard errorp valueM1 N = 2,002Ethnicitya0.355M2 N = 3,256Age0.6290.0340.000Sex (ref: male)0.026 Female0.3680.166Human development index2.7460.5900.000Method (ref: dry bone specimen)0.000 X-ray−21.0463.055 CT scan−7.6242.346Method × age0.000 X-ray1.0290.135 CT scan0.4230.104Constant−18.6381.0020.000M3 N = 3552Age0.6300.0340.000Human development index3.0120.5840.000Method (ref: dry bone specimen)0.000 X-ray−20.7293.060 CT scan−7.5261.928Method × age0.000 X-ray1.0230.135 CT scan0.4010.083Constant−18.8030.9980.000aThe remaining parameters of model 1 (M1) are omitted from this section in the table, as final results for a model without the variable ethnicity are provided for model 2 (M2).
From model M2, it appeared that age, the HDI (i.e., socioeconomic status), sex, and the method of clavicle examination all significantly affected the probability of having completely fused clavicles. Exploring possible interaction between sex and age did not indicate a significant effect. The interaction term method × age, however, yielded a p value of 0.000. The subsequent assessment of the significance of the difference in −2 log likelihood between the resulting model and a nested model omitting the interaction term yielded a p value of 0.000. The Nagelkerke pseudo R2 reduced from 0.815 to 0.795 after omission of the interaction term. All indicates a better model fit when the interaction term is included.
Model M3, which could be fitted to all available data on clavicle fusion, resulted in comparable model parameters for the dummy variable for CT scans. Confounding by an observer effect is therefore reduced.
Application of the model
The most appropriate model to predict the probability of being diagnosed with mature clavicles, i.e., providing the best model fit to the currently available data, appeared to be model M2. The resulting model—i.e., after the removal of non-significant main and interaction terms and using the parameters for covariates and the intercept—may be described by:
Parameters for the appropriate dummies for the categorical variables may be found in Table 2. From this equation, it follows that the predicted probability may be calculated using the following equation:
Based on the currently available data on clavicle fusion, we can now predict the probability of having mature clavicles for different individuals. Here, we provide a few examples.
The predicted probability of mature clavicles is 0.016 (1.6%) for a contemporary 19-year-old German male (HDI is 0.932). For a 20- or 21-year-old German male, this probability increases to 0.029 (2.9%) and 0.054 (5.4%), respectively. For females, the predicted probability values are increased to 0.023 (2.3%), 0.042 (4.2%), and 0.076 (7.6%), respectively. However, if the individuals have a lower socioeconomic status, these values are decreased. For contemporary 19-, 20-, and 21-year-old males from India (HDI is 0.611), for instance, they are 0.007 (0.7%), 0.012 (1.2%), and 0.023 (2.3%), respectively. When diagnosed from X-ray or CT scan, the values increase. For the 21-year-old Indian male, it would be 0.040 (4%) if diagnosed from an X-ray and 0.076 (7.6%) if diagnosed from a CT scan (composed using a slice thickness that is far from optimal).
In Figs. 2 and 3, we show the differences in predicted probabilities at different ages between the various categories. In Fig. 2, we compare the predicted probability values for a German male with that for a German female and an Indian male. Figure 3 illustrates the difference in predicted probability for a German male depending on whether dry bone specimens, X-rays, or CT scans are examined.
Fig. 2Predicted probability of having completely fused clavicles: a comparison between German males, German females and Indian malesFig. 3Predicted probability of being diagnosed with mature clavicles: a comparison between examination by means of dry bone specimens, X-rays and CT scans
Discussion
Ethnicity did not appear to significantly influence the probability of having completely fused clavicles, which is in line with the results of Schmeling et al. [12]. We should, however, keep in mind that the current database is not well balanced. In addition, a small number of individuals taken from McKern and Stewart [6] were misclassified in our analysis (see footnote Table 1). Additional data from future studies may contribute to the knowledge on the possible effect of ethnicity, if not strengthen our conclusion that there is no significant effect.
The effect of sex on the probability of having completely fused clavicles appeared significant. The estimated model parameter for the dummy variable for females being greater than zero indicates a positive effect on the logit of the probability. The predicted probability of mature clavicles is therefore greater for females than for males of similar ages. This would point to a generally earlier onset of fusion in females. A similar disparity has been reported for epiphysial closure of all other long bones [11]. There was no indication of significant interaction between sex and age. We may therefore assume similarly shaped probability curves for males and females, indicating an equal number of years during which complete fusion may generally be achieved.
A higher HDI, and therefore a higher socioeconomic status, appears to increase the probability of having mature clavicles. This would mean that under less preferable socioeconomic conditions, the process of fusion is generally delayed. This is in concordance with conclusions drawn by Schmeling et al. [12, 14], and was summarized before by Eveleth and Tanner [2].
The method of clavicle examination appeared to also be significant. The significant interaction term method × age indicates that we should assume a difference in the estimated effect of age depending on the method applied. For the age interval in which mature clavicles have been observed, the predicted probability of being diagnosed with mature clavicles is greater when X-rays or CT scans are used instead of dry bone specimens. It is noteworthy that the difference in the predicted probability is initially very small, but becomes increasingly greater with increasing age during a limited age interval. When keeping in mind that the curve for the predicted probability will be s-shaped, one may image that the difference is again only minimal for the older individuals.
A number of theories can be postulated to explain a difference in the predicted probabilities between methods of examination.
Inappropriate slice thickness Regarding the results from CT scans, one could postulate that the slice thickness affected the diagnosis. Mühler et al. [7] concluded that reconstructions composed with a slice thickness of 1 mm should be used. The vast majority of the analyzed data were, however, obtained from reconstructions with a greater slice thickness (up to 8 mm) [5, 15]. One can foresee that an almost completely fused clavicle may be diagnosed as being mature when details are lost due to the greater slice thickness. Schulze et al. [16]—from whom no data were included in our analysis, as no individual data were provided—observed two 19-year-olds with completely fused clavicles. Both observations were done from reconstructions with a slice thickness of 7 mm (Schulze, personal communication). We therefore think there is a realistic possibility of these cases having been misdiagnosed.
Persistent small grooves or notches between diaphysis and epiphysis When comparing the results from their study based on CT scans with two studies based on dry bone specimens [6, 9], Kreitner et al. [5] hypothesized that persistent small grooves or notches seen in dry bone specimens may be classified as partial fusions of the epiphysis with the clavicular shaft. This would reduce the probability of dry bone specimens being classified as completely fused.
Reduced visibility of the epiphyseal disc on X-rays X-rays used in the published studies have not been made with the purpose of examining the clavicles. Possibly, this has hindered a correct classification of the clavicle at times.
Interobserver variability As the sample included results from two studies based on X-rays and two studies based on CT scans, we hold it unlikely that what we perceive to be an effect of the applied method is in fact an observer effect.
Expectation bias In some X-rays, the (nearly fused) epiphyseal disc will have been more difficult to judge than in others. In such cases, knowing the actual age of the individuals could have affected the interpretation of the observation. Clavicles of relatively young individuals would then more often be classified as “not completely fused”, while those of relatively old individuals would be classified as “completely fused” more often. We know, however, that in at least two out of four studies, one based on X-rays [13] and one on CT scans [15], the examiner was not aware of the age of the subjects when classifying the images. We therefore do not believe that expectation bias could have played a role of any great importance.
Statistical artifact In theory, it may be possible that due to an unfortunate coincidence, there were no relatively late maturing individuals examined by X-ray or CT scan.In theory, all of these aspects could have contributed to the significant effect of the variable method. However, if significance of the interaction between method and age is not explained as a statistical artifact, only expectation bias would have resulted in a significant change in the shape of the probability curve. In case of misclassifications of nearly fused clavicles or differences in the classification system among studies, we would have expected a higher number of individuals with completely fused clavicles in the relatively young subjects, even below the age of 20.If we, however, were to conclude that significance of the interaction term is in fact a statistical artifact, the term should be removed from the model, and model parameters should be recalculated. It is our ambition to investigate the matter further by comparing high quality CT scans, expected to allow a correct diagnosis, with X-rays taken from the same person.
Conclusions
The probability of having mature clavicles at a certain age is affected by the sex and socioeconomic status of the individual. The probability of being diagnosed with mature clavicles further appears affected by the method of clavicle examination. Predicted probabilities from the model may be used to illustrate acceptance or rejection of individual age claims.
Please note that the odds on having mature clavicles given a certain age should not be confused with the (posterior) odds of having reached a certain age given that the clavicles have matured. These probabilities are only equal if we assume a prior odds of 1.

clavicle
age estimation
medial epiphysis
epiphyseal fusion


The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab

A large-scale, pooled analysis of safety data from five Phase III clinical trials (including open-label extensions of two of these studies) and two Phase III open-label clinical trials of efalizumab was conducted to explore whether arthropathy adverse events (AEs) were associated with efalizumab treatment in patients with moderate-to-severe chronic plaque psoriasis. Data from patients who received subcutaneous injections of efalizumab or placebo were stratified for analysis into phases according to the nature and duration of treatment. These included: the ‘first treatment’ phase (0–12-week data from patients who received either efalizumab, 1 mg/kg once weekly, or placebo in the five placebo-controlled studies); the ‘extended treatment’ phase (13–24-week data from seven trials for all efalizumab-treated patients); and the ‘long-term treatment’ phase (data from efalizumab-treated patients who received treatment for up to 36 months in two long-term trials). Descriptive statistics were performed and the incidence of arthropathy AEs per patient-year was calculated using 95% confidence intervals (CIs). During the first treatment phase, a similar proportion of patients had an arthropathy AE in the efalizumab group (3.3%; 58/1740 patients) compared with the placebo group (3.5%; 34/979 patients); the incidence of arthropathy AEs per patient-year was 0.15 in the efalizumab group (95% CI 0.11–0.19) and 0.16 in the placebo group (95% CI 0.11–0.22). Analysis of first treatment phase data from one study (n = 793) showed that the incidence of psoriatic arthropathy per patient-year was lower in efalizumab-treated patients (0.10; 95% CI 0.05–0.18) than in those given placebo (0.17; 95% CI 0.08–0.30). During the extended treatment phase, the incidence of arthropathy remained low (0.17; 95% CI 0.14–0.22). Data from two long-term studies showed that there was no increase in the incidence of arthropathy AEs over time in patients treated with efalizumab for up to 36 months. Patients who had an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Efalizumab does not appear to increase the risk of arthropathy AEs compared with placebo.
Introduction
Psoriasis is a chronic, immune-mediated, inflammatory skin disorder that is currently incurable. Consequently, the majority of people with psoriasis require long-term treatment to maintain disease control. Traditional immunosuppressive systemic treatments, such as acitretin, methotrexate, cyclosporine, hydroxyurea, and thioguanine, may be effective in controlling psoriasis in some patients but significant toxicity and the need to closely monitor patients limit the viability of these treatments for long-term, continuous use [23]. Recently developed systemic therapies that selectively target specific pathways in the inflammatory cascade of psoriasis generally have a much improved safety profile compared with traditional therapies [26].
Efalizumab (anti-CD11a; Raptiva®) is a recombinant humanized monoclonal IgG1 antibody that has been approved for the treatment of moderate-to-severe chronic plaque psoriasis. It interferes with the pathogenesis of psoriasis via multiple mechanisms, including inhibition of T-lymphocyte trafficking and T-lymphocyte activation and reactivation [1, 10, 11, 21, 25]. The safety and efficacy profile of efalizumab has been established in numerous clinical trials, in which more than 3,500 patients were enrolled and treatment was assessed for up to 3 years [4–6, 12–17, 22].
Although psoriasis can be associated with the co-morbidity of psoriatic arthritis, a minority of patients with psoriasis (7–30%) will develop this joint disease [27]. Nevertheless, psoriatic arthritis constitutes a major consideration in patients who are receiving long-term treatment for their psoriasis. A Nordic study of more than 5,000 patients with psoriasis showed that patients with arthritis exhibited greater impairment of psoriasis-related quality of life (QoL), longer disease duration, and greater self-reported disease severity, compared with patients who had psoriasis but no co-morbid arthritis [27].
A low incidence of arthropathy adverse events (AEs; any form of joint disease) associated with efalizumab treatment has been reported in both clinical studies and routine clinical practice [8, 12]. However, anecdotal reports of arthropathy in routine clinical practice have expressed concern that efalizumab may be associated with exacerbation of arthropathy [8]. To address this concern, we conducted a large-scale pooled analysis of safety data from five Phase III clinical trials (including open-label extensions of two of these studies) and two Phase III open-label clinical trials of efalizumab to explore whether arthropathy AEs were associated with efalizumab treatment in patients with psoriasis.
Methods
The primary objective of this pooled safety analysis was to assess the incidence of arthropathy AEs in patients who had received either efalizumab or placebo. Safety data were pooled from five randomized, double-blind, placebo-controlled clinical trials (including data from two open-label extension studies of two of these trials) and two open-label clinical trials of efalizumab [4–6, 12–17, 22]. Patients included in these Phase III studies were aged ≥18 years and had moderate-to-severe chronic plaque psoriasis, a psoriasis area and severity index (PASI) score of ≥12 at screening, and plaque psoriasis covering ≥10% of body surface area. All patients were candidates for either systemic anti-psoriatic therapy or had received systemic anti-psoriatic therapy. Patients included in these trials received subcutaneous injections with efalizumab, 1–4 mg/kg once weekly or 2 mg/kg once-every-other week, or placebo. Details of individual study methodologies are described in other publications [4–6, 12–17, 22].
Arthropathy AEs were defined according to the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) [3] preferred terms ‘arthritis’ and ‘arthrosis’, or the Medical Dictionary for Regulatory Activities (MedDRA, http://www.meddramsso.com/NewWeb2003/index.htm) preferred terms ‘arthritis not otherwise specified (NOS)’, ‘psoriatic arthropathy’, ‘arthropathy NOS’, ‘monoarthritis’, ‘polyarthritis’, and ‘osteoarthritis NOS’.
Treatment groups analyzed
Due to the variety of study designs, five analyses were considered: ‘first-treatment phase’, ‘first exposure phase’, ‘extended treatment phase’, ‘re-treatment phase’, and ‘long-term treatment’ (see Table 1).
Table 1Summary of the Phase III data from five placebo-controlled clinical trials (including data from two open-label extension studies of two of these trials) and two open-label clinical trials of efalizumab included in the pooled safety analysisPublication (protocol number)Study designNumber of patients in each analysisFirst treatment (0–12 weeks)Efalizumab sc 1–4 mg/kg qw or 2 mg/kg qowFirst exposure  Extended treatment (13–24 weeks)Long-term treatmenta (≤36 months)Re-treatmentPlaceboEfalizumab 1 mg/kgEfalizumab 2 mg/kgLeonardi [13] (ACD2058g)Randomized, double-blind, parallel-group, placebo-controlled170162166462123–55Lebwohl [12] (ACD2059g)Randomized, double-blind, parallel-group, placebo-controlled 122232243579289––Gordon [4] (ACD2390g)Randomized, double-blind, parallel-group, placebo-controlled 187368–368–––Papp [17] (ACD2600g)Randomized, double-blind, parallel-group, placebo-controlled 236449–449–449–Sterry [22] (IMP24011)Randomized, double-blind, parallel-group, placebo-controlled264529–772308–145Papp [16] (ACD2062g)Open-label–––34137–365Gottlieb [5, 6] (ACD2243g)Open-label–––339b290339–Menter [14] (ACD2391g)Open-label extensionc of study ACD2390g [4]–––174342––Menter [15] (ACD2601g)Open-label extensionc of study ACD2600 g [17]–––217622635d–Pooled analysis 97917404093,3942,111n.a.e565qow once-every-other week, qw once weekly, sc subcutaneousaNumber of patients at startbPatients received combined therapy with fluocinolone acetate (n = 169) or petrolatum (n = 170) for weeks 9–12; for months 3–15, the dose of efalizumab could be escalated to 4 mg/kg per week for up to 4 weeks if clinically indicatedcSome patients are included in the analyses more than once because patients in the open-label extension studies are also included in analyses of the parent studiesdIncluded patients who received either efalizumab or placebo in the parent study [17]eNot applicable because data are analyzed and reported separately for the study by Gottlieb et al. [6] and the study published by Papp [17] and Menter [15]
It is worth noting that most of the studies included in this pooled analysis were designed and conducted before efalizumab had received regulatory approval and before it was known that doses of more than 1 mg/kg once weekly (the approved dose) did not confer additional treatment benefit (EMEA, Raptiva Summary of Product Characteristics; FDA US, FDA Prescribing Information for Raptiva). For this reason, only the efalizumab 1 mg/kg once-weekly dose data are reported for the ‘first treatment phase’ of the analysis. Due to the wide variety of study designs included in the pooled analysis, data for patients receiving any dose of efalizumab are combined for all other treatment phases analyzed.
The ‘first treatment phase’ analysis included 0–12-week data from patients in the five placebo-controlled studies who received either efalizumab 1 mg/kg once weekly or placebo. This analysis allows a comparison between the efalizumab and placebo treatment groups.
The ‘first exposure phase’ included 12-week data from all studies in patients who had their first exposure to any dose of efalizumab and, thus, did not include placebo data. This analysis was conducted to include the maximum number of patients who received efalizumab for their first 12 weeks of treatment (i.e., it included those patients who first received efalizumab treatment after crossing over from a placebo group, as well as the patients who first received efalizumab during weeks 0–12).
The ‘extended treatment phase’ analysis included 13–24-week data in patients given any dose of efalizumab who had already received efalizumab during the first treatment phase.
The ‘long-term treatment phase’ analysis included all patients who received continuous long-term treatment (up to 36 months) with any dose of efalizumab. Data were analyzed in 12-week segments to assess change in the incidence of arthropathy AEs over time. This analysis included data from two long-term studies [6, 15, 17], which were analyzed separately due to differences in study design.
The ‘re-treatment phase’ analysis included all patients who re-started treatment with efalizumab following a treatment-free observation period.
Statistical analyses
Descriptive statistics were used to explore the association between efalizumab and the occurrence of arthropathy AEs. Results are expressed as point-estimates of the incidence rates (ratio of the number of patients with an arthropathy AE to the total number of patient-years at risk of an arthropathy AE) with their 95% confidence intervals (CIs). Descriptive comparisons are provided; no formal statistical tests were performed.
Analyses were also conducted to explore the relationship between onset of arthropathy AEs during efalizumab treatment and a previous history of arthropathy (reported as a narrative by patients at the baseline visit) and the incidence of arthropathy AEs and clinical response to efalizumab treatment [measured at 12 weeks using the Physician Global Assessment (PGA) and PASI scales]. Differences in patient and psoriasis characteristics at baseline were also compared between patients who had arthropathy AEs and those who did not. An additional analysis of data from patients included in the first treatment phase of the study by Sterry et al. [22] (Table 1) was conducted to assess the incidence of psoriatic arthropathy in these patients. This was the only study to define arthropathy AEs according to MedDRA; other studies used the COSTART, which did not include ‘psoriatic arthropathy’ specifically as a preferred term.
Baseline demographics and psoriasis characteristics and the proportion of patients with a previous history of arthropathy (as reported by patients at the baseline visit) were tabulated by presence/absence of an arthropathy event.
Results
The number of patients included in each of the pooled safety analyses from each of the seven trials and two open-label extensions is summarized in Table 1. Up to 3,394 patients received at least one dose of efalizumab. A total of 2,719 patients were included in the first treatment phase analysis, of whom the majority (64%; 1,740 patients) received efalizumab 1 mg/kg per week; 979 patients (36%) received placebo. Efalizumab 2 mg/kg per week regimen was given to 409 patients (15%) in two of the five studies [12, 13]; consequently, these patients were not included in the first treatment analysis. Patient demographics and baseline psoriasis characteristics were similar between treatment groups in the first treatment phase (Table 2).
Table 2Baseline demographic and disease characteristics for patients in the placebo-controlled first treatment phaseCharacteristicsPlacebo (n = 979)Efalizumab 1 mg/kg per week (n = 1,740)Efalizumab 2 mg/kg per week (n = 409)Mean age (years), mean (SD)45 (12)45 (12)45 (13)Weight (kg), mean (SD)90.0 (20.0) 89.4 (19.6)93.6 (20.5)Mean BMIa (kg/m2)30.4 (6.4)30.2 (6.3)31.4 (6.6)Race, n (%) Caucasian891 (91)1,569 (90)356 (87) Other88 (9)171 (10)53 (13)Duration of psoriasis, mean number of years (SD)19.2 (11.4)19.1 (11.4)17.6 (11.7)History of arthritis, n (%)286 (29.2)529 (30.4)141 (34.5)BMI body mass indexaDue to missing height data, BMI was calculated for 971 patients in the placebo group, 1,719 patients in the efalizumab 1 mg//kg per week group and 404 patients in the efalizumab 2 mg/kg per week group
First treatment phase (weeks 0–12)
During the first 12 weeks of treatment a similar proportion of patients had an arthropathy AE in the efalizumab 1 mg/kg group (3.3%) and the placebo group (3.5%; Fig. 1a). Correspondingly, the incidence of arthropathy AEs per patient-year was 0.15 in the efalizumab 1 mg/kg group (95% CI 0.11–0.19) and 0.16 in the placebo group (95% CI 0.11–0.22; Fig. 1b). The majority of the arthropathy AEs was mild-to-moderate in intensity in both the efalizumab (41/58 events; 71%; 95% CI 57–82%) and placebo groups (31/34 events; 91%; 95% CI 76–98%).
Fig. 1a Proportion of patients who had arthropathy adverse events (AEs) during each phase of the safety analysis and b incidence of arthropathy AEs per patient-year for each phase
The additional analysis of data from the study by Sterry et al. [22] demonstrated that the incidence of psoriatic arthropathy per patient-year was lower in the group treated with efalizumab 1 mg/kg per week (0.10; 95% CI 0.05–0.18) than in the placebo group (0.17; 95% CI 0.08–0.30); the proportion of patients with psoriatic arthropathy was 2.3% (12/529 patients) in the efalizumab group and 3.8% (10/264 patients) in the placebo group.
First exposure phase
In total, 3,394 efalizumab-treated patients were included in this analysis. A small proportion of patients had an arthropathy AE (3.6%; Fig. 1a) and the incidence of arthropathy AEs per patient-year was also low (0.16; 95% CI 0.14–0.19; Fig. 1b).
The incidence of arthropathy AEs in this group of patients was similar to that in the placebo group in the first treatment phase, as indicated by the overlap in CIs.
Extended treatment phase (weeks 13–24)
In total, 2,111 patients were included in the extended treatment phase analysis. During this phase, a low proportion of patients had an arthropathy AE (3.8%; Fig. 1a) and the incidence of arthropathy AEs per patient-year was also low (0.17; 95% CI 0.14–0.22; Fig. 1b). Overlap in the CIs indicates that the incidence of arthropathy AEs in this group of patients was also similar to that in the placebo group in the first treatment phase.
Long-term treatment phase
The results of two long-term studies were analyzed separately to assess the incidence of arthropathy AEs in patients treated with efalizumab. In both of these studies (Fig. 2), there was no overall increase in the incidence of arthropathy AEs over time. Furthermore, the incidence of arthropathy remained similar to that of the placebo group in the first treatment phase and stable between 12-week periods.
Fig. 2Incidence of arthropathy AEs in long-term studies of patients treated with efalizumab a for up to 36 months and compared indirectly with pooled placebo data from the first treatment (FT) phase [5, 6] and b for up to 15 months and compared with the study’s placebo group during month 0–12 [15, 17]. *Following the first 3-month double-blind, placebo-controlled phase of this study, patients in the placebo group who continued were switched to open-label treatment with efalizumab. Consequently, the month 6, 9, 12 and 15 results included patients who had received placebo during the initial 3 months of the study
In total, 339 patients were included in the analysis of the study by Gottlieb et al. [6]. These patients received continuous treatment with efalizumab 2 mg/kg once weekly for weeks 1–12 (fluocinolone acetate or petrolatum was co-administered during weeks 9–12), followed by continuous maintenance treatment with efalizumab 1 mg/kg once weekly for up to 36 months in patients who had a ≥ 50% improvement in PASI score. For months 3–15, the dose of efalizumab could be escalated to 4 mg/kg per week for up to 4 weeks if clinically indicated, then maintained at 2 mg/kg per week. During the entire study period, there was little variation in the incidence of arthropathy AEs (range 0.06–0.19; Fig. 2a). Reasons for discontinuation were diverse and were representative of the overall population; refer to Gottlieb et al. [6, 7] for details of discontinuations.
For the other long-term study, the analysis included 3-month data from 449 efalizumab-treated patients in the placebo-controlled first treatment phase of the study [17] and data from 635 patients who entered the open-label extension phase and received efalizumab treatment [15]; 218 of the 635 patients included in the open-label extension had switched from placebo to efalizumab after completing the first treatment phase. Patients who entered the open-label extension phase continued to receive, or initiated treatment with, efalizumab 1 mg/kg once weekly for up to 15 months continuously. As in the long-term study by Gottlieb et al. [6], there was little variation in the incidence of arthropathy AEs during the entire study period (range 0.06–0.12; Fig. 2b).
Re-treatment phase
In total, 565 efalizumab-treated patients were included in the re-treatment phase of the analysis. In this phase, a lower proportion of patients had an arthropathy AE (2.7%; Fig. 1a) compared with the first treatment phase, and the incidence of arthropathy AEs per patient-year was also lower (0.12; 95% CI 0.07–0.19; Fig. 1b). The incidence of arthropathy AEs in this group of patients was lower than in the placebo group in the first treatment phase.
Baseline characteristics and previous history of arthropathy
There were no differences in baseline demographics or disease characteristics between the patients who had arthropathy AEs and those who did not. Patients who experienced an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Of the patients who never developed an arthropathy AE during efalizumab treatment, 27% reported a previous history of arthropathy compared with 59% in patients who did have an arthropathy AE.
During the first treatment phase, 88% (n = 34) and 76% (n = 79) of patients who developed an arthropathy AE had a history of arthropathy prior to receiving placebo or efalizumab 1 mg/kg once weekly, respectively.
Arthropathy AEs and clinical response to efalizumab
Arthropathy AEs appeared to be less likely to occur in patients who had a good clinical response to treatment (≥75% improvement in PASI score; 2.3% of patients had events) than in patients who had a partial response (50–74% improvement in PASI score; 3.5% of patients had events; Fig. 3) and non-responders (<50% improvement in PASI score; 4.5% of patients had events). The corresponding incidences of arthropathy AEs per patient-year were 0.10 in patients with a good clinical response (95% CI 0.05–0.18), 0.17 in patients with a partial clinical response (95% CI 0.11–0.25), and 0.21 in patients who did not respond (95% CI 0.15–0.28).
Fig. 3a Proportion of patients with an arthropathy AE by response category on the psoriasis area and severity index (PASI) and physician global assessment (PGA) scales and b incidence of arthropathy AEs per patient-year by response category on the PASI and PGA scales
When assessed using the PGA scale, arthropathy AEs also appeared to be less likely to occur in patients who had better clinical responses to treatment with efalizumab (Fig. 3). During the extended treatment phase, the incidence of arthropathy AEs per patient-year was 0.17 in patients with responses categorized as ‘cleared’, ‘excellent’ or ‘good’ on the PGA scale (95% CI 0.10–0.25) and 0.25 in patients with responses categorized as ‘fair’, ‘slight’, ‘unchanged’ or ‘worse’ on the PGA scale (95% CI 0.17–0.35).
Discussion
The placebo-controlled results of this large-scale pooled analysis of arthropathy data from seven clinical trials show that efalizumab does not appear to increase the risk of developing arthropathy AEs compared with placebo during the first 12 weeks of treatment. In addition, for patients treated with efalizumab, the incidence of arthropathy AEs did not appear to increase over time. The proportion of patients who had an arthropathy AE within any 12-week treatment period was low (<4.1%) through all treatment phases (first treatment, first exposure, extended treatment, re-treatment, long-term treatment).
Joint disease has also been reported as a side-effect of other approved biological treatments for psoriasis, namely infliximab (EMEA public statement on infliximab, http://www.emea.eu.int/pdfs/human/press/pus/444500en.pdf) [2, 18, 19], alefacept (Biogen safety presentation on Alefacept to the FDA, http://www.fda.gov/ohrms/dockets/ac/02/slides/3865S1_04_Biogen-Safety/sld007.htm) [20, 24], and etanercept (EMEA Scientific discussion for the approval of Enbrel, http://www.emea.eu.int/humandocs/PDFs/EPAR/Enbrel/014600en6.pdf). Indeed, placebo-controlled studies of infliximab and alefacept indicate that in patients with moderate-to-severe psoriasis the incidence of arthralgia (joint pain) is 7 and 5%, respectively (Biogen safety presentation on Alefacept to the FDA, http://www.fda.gov/ohrms/dockets/ac/02/slides/3865S1_04_Biogen-Safety/sld007.htm) [18, 24]. Psoriatic arthritis has been reported as serious treatment-related AE in three placebo-controlled studies of etanercept in the treatment of chronic plaque psoriasis (incidence data have not been published) (EMEA Scientific discussion for the approval of Enbrel, http://www.emea.eu.int/humandocs/PDFs/EPAR/Enbrel/014600en6.pdf). The incidence of arthropathy AEs in the current analysis of efalizumab appears to be similar to that for arthralgia in studies of infliximab and alefacept. Moreover, the term ‘arthropathy’, used in the current study encompasses a variety of joint diseases, not just a single joint condition such as arthralgia or psoriatic arthritis, and therefore has greater potential to include more patients. However, this between-study comparison is indirect and thus should be treated with caution. Moreover, no arthropathy event (defined by any of the MedDRA or COSTART preferred terms) was excluded from the analysis. Also, data from first treatment phase of the study by Sterry et al. [22] indicate that the proportion of patients with psoriatic arthropathy specifically was low (2.3%) in patients treated with efalizumab 1 mg/kg per week—in fact, lower than in the placebo group (3.8%). It should be noted, however, that psoriatic arthropathy events were not confirmed by a rheumatologist—this is a potential limitation of the study. However, the umbrella term ‘arthropathy’ was designed to capture all joint diseases, including ‘psoriatic arthropathy’. Also, the incidence of psoriatic arthropathy in the study by Sterry et al. was in line with the incidence of ‘arthropathy’ in the overall pooled analysis.
To put the results of this pooled analysis, which by its very nature included select patient populations (determined by the inclusion/exclusion criteria and study designs), in the context of routine clinical practice, post-marketing surveillance data were assessed. During post-marketing surveillance of efalizumab, which accounts for approximately 17,500 patient-years to date, serious arthropathies requiring hospitalization were reported with a frequency of about 4.8 per 1,000 patient-years in patients receiving efalizumab. It should be noted, however, that underreporting of AEs in routine clinical practice setting may lead to an underestimate of the true incidence of arthropathy.
For both the 12-week first treatment and first exposure phases of the current analyses, the proportions of patients reporting an arthropathy AE appeared to be lower in the efalizumab groups than in the placebo group in the first treatment phase. Correspondingly, the incidences of AEs per patient-year in these treatment phases were also lower in the efalizumab groups than that observed in the placebo group in the first treatment phase. However, the proportion of AEs that were moderate or severe was greater in the efalizumab groups than in the placebo groups; too few patients had events to draw any meaningful conclusions.
During the extension phase (weeks 13–24), the incidence of arthropathy AEs in efalizumab-treated patients remained similar to the placebo group in the first treatment phase. Previous history of arthropathy and poor clinical response may potentially indicate a risk for occurrence of new arthropathy AEs during treatment. Indeed, arthropathy AEs were most frequent in patients who did not respond to therapy with efalizumab or in patients with a history of arthropathy.
Importantly, the data from the two long-term studies of efalizumab indicate that the incidence of arthropathy AEs remains stable and low for up to 3 years of continuous treatment. These results, coupled with efficacy data showing that the clinical improvements of the skin after 3 months of efalizumab therapy are maintained throughout 36 months of continuous dosing [5], support the suitability of efalizumab for the chronic, continuous treatment of patients with psoriasis. Reasons for patients’ discontinuations in the 36-month study by Gottlieb et al. [6, 7] were diverse and representative of the overall population included in this analysis and have been described previously. When considering the long-term analysis of the 36-month study (Fig. 2a), it should be noted that the number of patients who remained in the study decreased over time. This discontinuation rate is not unexpected for a study that is 3 years in duration but, by month 36, there is a small number of patients on which to base comparisons with the first treatment phase. Another factor that may confound between-phase analysis comparisons was the possible use of concomitant medications for psoriasis after the first treatment phase in the study by Gottlieb et al. [6], which permitted the use of topical corticosteroids and ultraviolet B phototherapy. Accordingly, it should be noted that comparisons of the results between any of the treatment phases of this analysis are observational (i.e., not direct) but do confirm the results of the long-term treatment phase and the placebo-controlled 12-week first treatment phase studies, suggesting that the risk of joint disease is not increased with continued efalizumab treatment and that the incidence of arthropathy is low and similar to placebo. Further investigation is needed to confirm the results of this preliminary analysis of arthropathy events during long-term treatment with efalizumab.
In patients who re-started treatment for a further 12 weeks following an intervention-free period, the proportion of patients who had an arthropathy AE was lower than during the first treatment phase; the same was true for the incidence of arthropathy AEs per patient-year in re-treated patients. Although this scenario is likely to occur infrequently in clinical practice, these data show that if a patient needs to stop (e.g., during pregnancy) and then restart treatment, there appears to be no increased risk of arthropathy AEs.
Although arthritis in patients with psoriasis has a significant impact on QoL [9, 27], it can, in most cases, be managed effectively [8]. In the small minority of patients who develop arthropathy during treatment, the symptoms can be managed successfully with non-steroidal anti-inflammatory drugs [8].
In conclusion, the results of this pooled analysis show that efalizumab does not appear to increase the risk of developing arthropathy AEs compared with placebo. Long-term studies of efalizumab indicate that the incidence of arthropathy AEs remains stable and low for up to 3 years of continuous treatment.

arthropathy
efalizumab
psoriasis
psoriatic arthritis
arthritis