Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries.
Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year.
We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as ‘carcinoma not otherwise specified’. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01–1.14] and for the ‘special’ subtypes it was age (OR 1.06, 95% CI 1.01–1.10) and SLE duration (OR 1.05, 95% CI 1.00–1.11).
Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.
Breast cancer; Systemic lupus erythematosus; Histopathology; Epidemiology
To examine change in health-related quality of life (HRQoL) in association with clinical outcomes of neuropsychiatric (NP) events in SLE.
An international study evaluated newly diagnosed SLE patients for NP events attributed to SLE and non-SLE causes. Outcome of events was determined by physician-completed 7-point scale and compared to patient-completed SF-36 questionnaires. Statistical analysis used linear mixed-effects regression models with patient specific random effects.
274 patients (92% female; 68% Caucasian), from a cohort of 1400, had ≥ 1 NP event where the interval between assessments was 12.3 ± 2 months. The overall difference in change between visits in mental component summary (MCS) scores of the SF-36 was significant (p<0.0001) following adjustments for gender, ethnicity, center and previous score. A consistent improvement in NP status (N=295) was associated with an increase in the mean(SD) adjusted MCS score of 3.66(0.89) in SF-36 scores. Between paired visits where NP status consistently deteriorated (N=30), the adjusted MCS score decreased by 4.00(1.96). For the physical component summary (PCS) scores the corresponding changes were +1.73(0.71) and −0.62(1.58) (p<0.05) respectively. Changes in SF-36 subscales were in the same direction (p<0.05; with the exception of role physical). Sensitivity analyses confirmed these findings. Adjustment for age, education, medications, SLE disease activity, organ damage, disease duration, attribution and characteristics of NP events did not substantially alter the results.
Changes in SF-36 summary and subscale scores, in particular those related to mental health, are strongly associated with the clinical outcome of NP events in SLE patients.
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Health related quality of life; SF-36
To describe vascular events during an 8 year follow-up in a multicentre SLE inception cohort and their attribution to atherosclerosis.
Clinical data including co-morbidities are recorded yearly. Vascular events are recorded and attributed to atherosclerosis or not. All events met standard clinical criteria. Factors associated with atherosclerotic vascular events were analysed using descriptive statistics, t-tests and χ2. Stepwise multivariate logistic regression was used to assess the association of factors with vascular events attributed to atherosclerosis.
Since 2000, 1249 patients have been entered into the cohort. There have been 97 vascular events in 72 patients. These include: myocardial infarction (13), angina (15), congestive heart failure (24), peripheral vascular disease (8), transient ischemic attack (13), stroke (23), pacemaker insertion (1). Fifty of the events were attributed to active lupus, 31events in 22 patients were attributed to atherosclerosis, and 16 to other causes. Time from diagnosis to first atherosclerotic event was 2.0 ± 1.5 years. Compared to patients followed for 2 years without atherosclerosis events (615), at enrolment patients with AVE were more frequently Caucasian, male, older at diagnosis of SLE, obese, smokers, hypertensive and had a family history of coronary artery disease. On multivariate analysis only male gender and older age at diagnosis were associated factors.
In an inception cohort with SLE followed for up to 8 years there were 97 vascular events but only 31 were attributable to atherosclerosis. Patients with atherosclerotic events were more likely to be male and to be older at diagnosis of SLE.
To determine the frequency, accrual, attribution and outcome of neuropsychiatric (NP) events and impact on quality of life over 3 years in a large inception cohort of SLE patients.
The study was conducted by the Systemic Lupus International Collaborating Clinics. Patients were enrolled within 15 months of SLE diagnosis. NP events were identified using the ACR case definitions and decision rules were derived to determine the proportion of NP disease attributable to SLE. The outcome of NP events was recorded and patient perceived impact determined by the SF-36.
There were 1206 patients (89.6% female) with a mean (±SD) age of 34.5±13.2 years. The mean disease duration at enrollment was 5.4±4.2 months. Over a mean follow-up of 1.9±1.2 years 486/1206 (40.3%) patients had ≥1 NP events which were attributed to SLE in 13.0%–23.6% of patients using two a priori decision rules. The frequency of individual NP events varied from 47.1% (headache) to 0% (myasthenia gravis). The outcome was significantly better for those NP events attributed to SLE especially if they occurred within 1.5 years of the diagnosis of SLE. Patients with NP events, regardless of attribution, had significantly lower summary scores for both mental and physical health over the study.
NP events in SLE patients are variable in frequency, most commonly present early in the disease course and adversely impact patients’ quality of life over time. Events attributed to non-SLE causes are more common than those due to SLE, although the latter have a more favourable outcome.
Lupus; Neuropsychiatric; Prospective; Inception cohort
To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial.
In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA.
Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin's lymphoma (infliximab).
Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.
infliximab; psoriatic arthritis; tumour necrosis factor α; ACR 20; PASI 75
To evaluate the effects of adalimumab on patient‐reported outcomes of joint‐related and skin‐related functional impairment, health‐related quality of life , fatigue and pain in patients with psoriatic arthritis (PsA).
Patients with moderately‐ to severely‐ active PsA were treated with adalimumab, 40 mg, every other week, or placebo, in this 24‐week, randomised, controlled trial. Patient‐reported outcomes included the Health Assessment Questionnaire Disability Index (HAQ DI), Short‐Form 36 Health Survey (SF‐36), the Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT‐Fatigue) Scale and the Dermatology Life Quality Index (DLQI).
Adalimumab (n = 151) and placebo (n = 162) groups were comparable with respect to baseline demographics and disease severity. Significant changes from baseline in HAQ DI were reported for adalimumab v placebo (−0.4 v −0.1, p<0.001) at both 12 and 24 weeks. At week 24, significant improvements in the SF‐36 domains of physical functioning, role‐physical, bodily pain, general health, vitality and social functioning, as well as the physical component summary score, were observed for adalimumab versus placebo (p<0.01). These reported changes in HAQ DI and SF‐36 were also clinically important. Significantly more patients treated with adalimumab had complete resolution of functional loss (HAQ DI = 0) and dermatological‐related functional limitations (DLQI = 0) compared with placebo at weeks 12 and 24 (p⩽0.001). Adalimumab led to significantly greater improvements in FACIT‐Fatigue scores, pain scores, and disease activity measures versus placebo at 12 and 24 weeks (p<0.001 for all).
Adalimumab improved physical‐related and dermatological‐related functional limitations, HRQOL, fatigue and pain in patients with PsA treated for 24 weeks.
psoriatic arthritis; radiological assessment; clinical assessment; inflammatory joint diseases; functional assessment
Infliximab is effective in improving signs and symptoms of joint/skin involvement, functional status, and quality of life in patients with psoriatic arthritis (PsA). Using IMPACT trial data, we assessed the effect of infliximab (IFX) on structural damage in PsA.
Patients with active PsA were randomly assigned to receive placebo (PBO/IFX) or infliximab 5 mg/kg (IFX/IFX) at weeks 0, 2, 6, and 14, with the primary endpoint at week 16. The PBO group received infliximab loading doses at weeks 16, 18, and 22. Thereafter, all patients received infliximab 5 mg/kg every 8 weeks through week 50. Hand/feet radiographs were obtained at weeks 0 and 50. Total radiographic scores were determined using the PsA modified van der Heijde‐Sharp (vdH‐S) score. Projected annual rate of progression was calculated by dividing x ray score by disease duration (years).
As reported previously, 65% of infliximab treated patients versus 10% of PBO treated patients achieved an ACR20 response at week 16 (p<0.001). At week 50, 69% of patients achieved an ACR20 response. Radiographs (baseline and week 50) were available for 72/104 patients. At baseline, estimated mean annual rate of progression was 5.8 modified vdH‐S points/year. Mean (median) changes from baseline to week 50 in the total modified vdH‐S score were −1.95 (−0.50) for PBO/IFX and −1.52 (−0.50) for IFX/IFX patients (p = NS). At week 50, 85% and 84% of patients in the PBO/IFX and IFX/IFX groups had no worsening in the total modified vdH‐S score.
Infliximab inhibits radiographic progression in patients with PsA through week 50.
infliximab; psoriasis; psoriatic arthritis; structural damage; tumour necrosis factor α
Tumour necrosis factor α (TNFα) is a cytokine of critical importance in psoriatic arthritis.
(1) To examine the association between TNFα promoter gene polymorphisms and psoriatic arthritis in two well characterised Canadian populations with the disease; (2) to carry out a meta‐analysis of all TNFα association studies in white psoriatic arthritis populations.
DNA samples were genotyped for five TNF variants by time of flight mass spectrometry using the Sequenom platform. All five single nucleotide polymorphisms were in the 5′ flanking region of TNFα gene at the following positions: −1031 (T→C), −863 (C→A), −857 (C→T), −308 (G→A), and −238 (G→A). Primary analyses were based on logistic regression. Summary estimates of disease/genotype relations from several studies were derived from random effects meta‐analyses.
237 psoriatic arthritis subjects and 103 controls from Newfoundland and 203 psoriatic arthritis subjects and 101 controls from Toronto were studied. A combined analysis of data from both populations, showed a significant association between disease status and the −238(A) variant (p = 0.01). The meta‐analysis estimate for the −238(A) TNFα variant in eight psoriatic arthritis populations was also significant (odds ratio = 2.29 (95% confidence interval, 1.48 to 3.55)).
Analysis of TNFα variants in psoriatic arthritis populations shows that the −238 (A) variant is a significant risk factor for this disease.
psoriatic arthritis; TNFα; meta‐analysis; genetic association studies
To evaluate the effect of infliximab on health related quality of life (HRQoL) and physical function in patients with active psoriatic arthritis (PsA) in the IMPACT 2 trial.
200 patients with PsA unresponsive to conventional treatment were randomised to intravenous infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22; patients with inadequate response entered early escape at week 16. HRQoL was assessed using the Short Form‐36 (SF‐36) at weeks 0, 14, and 24. Functional disability was assessed using the Health Assessment Questionnaire (HAQ) at every visit through week 24. Associations between changes in quality of life (SF‐36) and articular (American College of Rheumatology (ACR)) and dermatological (Psoriasis Area and Severity Index (PASI)) responses were examined.
Mean percentage improvement from baseline in HAQ was 48.6% in the infliximab group compared with worsening of 18.4% in the placebo group at week 14 (p<0.001). Furthermore, 58.6% and 19.4% of infliximab and placebo treated patients, respectively, achieved a clinically meaningful improvement in HAQ (that is, ⩾0.3 unit decrease) at week 14 (p<0.001). Increases in physical and mental component summary (PCS and MCS) scores and all eight scales of the SF‐36 in the infliximab group were greater than those in the placebo group at week 14 (p⩽0.001). These benefits were sustained through week 24. Patients achieving ACR20 and PASI75 responses had the greatest improvements in PCS and MCS scores.
In patients with PsA, infliximab 5 mg/kg significantly improved HRQoL and physical function compared with placebo through 24 weeks.
psoriatic arthritis; infliximab; tumour necrosis factor α; quality of life; physical function
Psoriatic arthritis may progress to joint damage. Joint damage may be assessed clinically, by identifying deformed, fused, or flail joints, or radiologically, by recording erosions, joint space narrowing, ankylosis, lysis, or surgery. The relation between clinical and radiological damage is unclear.
To study the ordering of clinical and radiological damage detection, and the clinical features associated with the type of damage detected first.
The University of Toronto psoriatic arthritis database was used to relate clinical and radiological damage in the hand joints in 655 patients followed prospectively between 1978 and 2003. Generalised estimating equations were used to fit logistic regression models to identify factors that predict classification of damage by radiographic assessment first.
The majority of the joints were not informative, as they either had evidence of damage by both methods at entry, or remained undamaged. Of the remainder, 81% of the joints showed radiological damage first and 19% had clinical damage first. Development of radiological damage first was related to previous detection of swollen joints, and was inversely related to duration of arthritis.
Radiological damage is often detected before clinical damage is observed. Clinical inflammation often precedes the detection of radiological damage.
psoriatic arthritis; radiological damage; joint damage; prognosis
Hypercholesterolaemia and hypertension are risk factors for coronary artery disease in patients with systemic lupus erythematosus (SLE).
To examine the recognition and management of hypercholesterolaemia and hypertension in patients with SLE before and after a quality improvement study.
Patients with SLE have been followed up prospectively at the University of Toronto Lupus Clinic since 1970. The charts of all patients who entered the clinic since 1990 were reviewed to ensure completeness of data on anti‐hypertensive treatment (AHT) and lipid lowering agents (LLA). Recognition and management of hypercholesterolaemia and hypertension were evaluated for the periods 1990–1995 and 1996–2001.
Comparison of treatment between time periods showed that during 1990–1995 204/559 (36%) patients seen were hypertensive, of whom 180 (88%) were receiving AHT, and during 1996–2001 241/576 (42%) patients seen were hypertensive, of whom 232 (96%) were receiving AHT (p = 0.0013). A comparison of treatment for hypercholesterolaemia showed that 21/236 (9%) hypercholesterolaemic patients were being treated with LLA in the earlier period compared with 74/261 (28%) in the later period (p<0.0001).
Treatment for hypertension and hyperlipidaemia has increased in the past 6 years compared with the previous 6 years, but a number of patients eligible for these treatments remain untreated.
hypertension; hypercholesterolaemia; systemic lupus erythematosus; quality improvement
To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion.
Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire.
Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective.
Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.
Objectives: To describe demographic factors, subtypes, and survival of patients with SLE who develop NHL.
Methods: A multi-site cohort of 9547 subjects with definite SLE was assembled. Subjects at each centre were linked to regional tumour registries to determine cancer cases occurring after SLE diagnosis. For the NHL cases ascertained, descriptive statistics were calculated, and NHL subtype frequency and median survival time of patients determined.
Results: 42 cases of NHL occurred in the patients with SLE during the 76 948 patient-years of observation. The median age of patients at NHL diagnosis was 57 years. Thirty six (86%) of the 42 patients developing NHL were women, reflecting the female predominance of the cohort. In the patients, aggressive histological subtypes appeared to predominate, with the most commonly identified NHL subtype being diffuse large B cell (11 out of 21 cases for which histological subtype was available). Twenty two of the patients had died a median of 1.2 years after lymphoma diagnosis.
Conclusions: These data suggest aggressive disease in patients with SLE who develop NHL. Continuing work should provide further insight into the patterns of presentation, prognosis, and aetiology of NHL in SLE.
Methods: 103 patients with PsA and 105 ethnically matched controls from Newfoundland and 202 patients with PsA and 100 controls from Ontario were studied. Patients and controls were genotyped for SNP +39604 of SEEK1 by time of flight mass spectrometry, using the Sequenom platform. Genomic DNA was amplified by the Dynal RELI SSO HLA- Cw* typing kit for HLA-C typing.
Results: The frequency of the minor SEEK1(T) allele in subjects with PsA and controls was 48.5% and 32.4%, respectively (odds ratio (OR) = 2.0; p = 0.017), in the Newfoundland population and 46.5% and 38.0%, respectively (OR = 1.4; p = 0.16), in the Ontario population. Although SEEK1 is associated with PsA, particularly in the Newfoundland population, multivariate analysis showed that SEEK1 does not seem to be a further susceptibility factor if the HLA-Cw*0602 status is already known. No association was noted between SEEK1(T) allele and onset of psoriasis, PsA, or arthritis pattern.
Conclusion: SEEK1 is associated with PsA in the Newfoundland founder population. This association is probably due to linkage disequlibrium between SEEK1 and HLA-Cw*0602 in this population.
To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA).
Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study.
After 24 weeks of double-blind treatment, the mean change in mTSS was −0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment.
The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk–benefit profile in patients with PsA.
Trial registration number:
Objective: To investigate the prevalence of autoantibodies in biological agent naive patients with psoriatic arthritis (PsA).
Methods: 94 consecutive, prospectively collected, biological agent naive patients with PsA at the University of Toronto PsA clinic underwent clinical and laboratory assessment. Disease activity was assessed by the number of actively inflamed joints, and the Psoriasis Activity and Severity Index (PASI) score. Antinuclear antibodies (ANA), rheumatoid factor (RF), double stranded DNA (dsDNA), Ro, La, Smith, and RNP were tested. Descriptive statistics and non-parametric tests were used to analyse the data.
Results: 44/94 (47%) patients with PsA were ANA positive (⩾1/40); 13/94 (14%) had a clinically significant titre of ⩾1/80. Three per cent had dsDNA antibodies, 2% had RF and anti-Ro antibodies, 1% had anti-RNP antibodies, and none had anti-La or anti-Smith antibodies.
Conclusions: The background prevalence of ANA ⩾1/80 in patients with PsA was 14%, with very few patients having specific lupus antibodies. This should serve as a baseline figure for the frequency of autoantibodies in biological agent naive patients with PsA for studies of the use of anti-TNFα agents.
In order to measure disease activity, progression, and change with therapy in psoriatic arthritis (PsA), it is important to use accurate, reliable, and feasible outcome measures that can ideally be employed in longitudinal cohorts, clinical trials, and clinical practice. Until recently, there has been little focus on this methodology in PsA. Clinical trials and long term clinical registries have used disparate outcome measures. With emerging therapies, the focus on the methodology of outcome assessment has increased to ensure that discriminant and responsive instruments are used. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), in conjunction with the society, Outcome Measures in Rheumatology (OMERACT), is focused on refining and developing outcome measures for a variety of disease domains reviewed in this report. Key domains to assess include joints, skin, enthesitis, dactylitis, spine, joint damage as assessed radiologically, quality of life, and function. These domains can be assessed by individual and composite measures. A number of measures have been "borrowed" from the fields of rheumatoid arthritis, ankylosing spondylitis, and psoriasis and adapted to PsA. Others are being developed specifically for PsA. Few are validated but most have been shown to perform well in distinguishing placebo from treatment response. This report reviews the current state of the art of assessment in PsA and points toward future directions of development of this field.
Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.